Lsr2 acts as a cyclic di-GMP receptor that promotes keto-mycolic acid synthesis and biofilm formation in mycobacteria.

Cyclic di-GMP (c-di-GMP) is a second messenger that promotes biofilm formation in several bacterial species, but the mechanisms are often unclear. Here, we report that c-di-GMP promotes biofilm formation in mycobacteria in a manner dependent on the nucleoid-associated protein Lsr2. We show that c-di-GMP specifically binds to Lsr2 at a ratio of 1:1. Lsr2 upregulates the expression of HadD, a (3R)-hydroxyacyl-ACP dehydratase, thus promoting the synthesis of keto-mycolic acid and biofilm formation. Thus, Lsr2 acts as a c-di-GMP receptor that links the second messenger's function to lipid synthesis and biofilm formation in mycobacteria.

Arabinogalactan Alleviates Lipopolysaccharide-Induced Intestinal Epithelial Barrier Damage through Adenosine Monophosphate-Activated Protein Kinase/Silent Information Regulator 1/Nuclear Factor Kappa-B Signaling Pathways in Caco-2 Cells.

Intestinal epithelial barrier (IEB) damage is an important aspect in inflammatory bowel disease (IBD). The objective of this study was to explore the protective effects and mechanisms of arabinogalactan (AG) on lipopolysaccharide (LPS)-stimulated IEB dysfunction. The results show that AG (1, 2, and 5 mg/mL) mitigated 100 µg/mL LPS-stimulated IEB dysfunction through increasing transepithelial electrical resistance (TEER), reducing fluorescein isothiocyanate (FITC)-dextran (4 kDa) flux, and up-regulating the protein and mRNA expression of tight junction (TJ) proteins (Claudin-1, Zonula occludens-1 (ZO-1) and Occludin). In addition, AG ameliorated LPS-stimulated IEB dysfunction by reducing interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and IL-1ß levels, decreasing the reactive oxygen species (ROS) level, increasing superoxide dismutase (SOD) activity, increasing the glutathione (GSH) level, and decreasing the levels of malondialdehyde (MDA) and intracellular calcium ([Ca2+]i). Furthermore, 2 mg/mL AG up-regulated the expression of silent information regulator 1 (SIRT1), the phosphorylated adenosine monophosphate-activated protein kinase (AMPK), and peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α and inhibited the phosphorylation of nuclear factor kappa-B (NF-κB) and the inhibitor of NF-κBα (IκBα). Therefore, AG could maintain IEB integrity by activating AMPK/SIRT1 and inhibiting the NF-κB signaling pathway. In conclusion, AG can regulate the AMPK/SIRT1/NF-κB signaling pathway to reduce inflammation and oxidative stress, thus alleviating LPS-stimulated IEB damage.

Probiotics Alleviate Chemotherapy-Associated Intestinal Mucosal Injury via the TLR4-NFκB Signaling Pathway.

Introduction: Temozolomide (TMZ) induces intestinal mucosa injury that cannot be fully counteracted by supportive treatment. Probiotics regulate gut microbial composition and the host immune system and may alleviate this side effect. We aimed to investigate the potential and mechanism of Lactobacillus rhamnosus GG (LGG) in relieving intestinal mucosal injury induced by TMZ. Methods: Glioblastoma mice were divided into four groups: CON (control), LGG (109 CFU/mL, treated for 7 days), TMZ (50 mg/kg·d, treated for 5 days), LGG+TMZ (LGG for 7 days and TMZ subsequently for 5 days). Body weight, food intake, and fecal pH were recorded. Intestinal tissue samples were collected 1 day after the end of TMZ treatment. Degree of damage to intestine, expression of IL1ß, IL6, TNFα, and IL10 in jejunum were determined. Levels of tight-junction proteins (ZO1, occludin), TLR4, IKKß, IκBα, and P65 with their phosphorylation in jejunum were measured. Results: Decreases in body weight, food intake, spleen index in the TMZ group were mitigated in the LGG+TMZ group, and the degree of intestinal shortening and damage to jejunum villus were also alleviated. The expression of tight-junction proteins in the LGG+TMZ group was significantly greater than that in the TMZ group. IκBα in intestinal tissue significantly decreased in the TMZ group, phos-IKKß and phos-P65 increased compared to the CON group, and LGG reversed such changes in IκBα and phos-P65 in the LGG+TMZ group. Intestinal inflammatory cytokines were significantly increased in the TMZ group, but lower in the LGG+TMZ group. Moreover, expression of TLR4 in LGG group was significantly lower than that in the CON group. LGG inhibited the rise of TLR4 after TMZ in the LGG+TMZ group compared to the TMZ group. Conclusion: LGG inhibits the activation of the TLR4-NFκB pathway and alleviates intestinal mucosal inflammation induced by TMZ, thereby protect the jejunum villi and mucosal physical barrier.

Arabinogalactan ameliorates benzo[a]pyrene-induced intestinal epithelial barrier dysfunction via AhR/MAPK signaling pathway.

Benzo[a]pyrene (B[a]P), a kind of pollutant, can disrupt the gut microbiota, but its effects on the function of intestinal epithelial barrier (IEB) is still unclear. Arabinogalactan (AG), a natural polysaccharide, can protect intestinal tract. Thus, the purpose of this study was to evaluate the effect of B[a]P on IEB function and the mitigation effect of AG on the IEB dysfunction induced by B[a]P using a Caco-2 cell monolayer model. We found B[a]P could damage the IEB integrity by inducing cell cytotoxicity, increasing lactate dehydrogenase leakage, decreasing the transepithelial electrical resistance, and increasing fluorescein isothiocyanate-dextran flux. The mechanism of B[a]P-induced IEB damage may through induction of oxidative stress, including increasing reactive oxygen species levels, decreasing glutathione levels, reducing the activity of superoxide dismutase, and increasing malonaldehyde levels. Moreover, it can be due to increasing secretion of pro-inflammatory cytokines (interleukin [IL]-1ß, IL-6, and tumor necrosis factor [TNF]-α), down-regulated expression of tight junction (TJ) proteins (claudin-1, zonula occludens [ZO]-1, and occludin), and induced activation of aryl hydrocarbon receptor (AhR)/mitogen activated protein kinase (MAPK) signaling pathway. Remarkably, AG ameliorated B[a]P-induced IEB dysfunction through inhibited oxidative stress and pro-inflammatory factor secretion. Our study demonstrated B[a]P could damage the IEB and AG could alleviate this damage.

D-Xylose Blocks the Broad Negative Regulation of XylR on Lipid Metabolism and Affects Multiple Physiological Characteristics in Mycobacteria.

D-xylose is the most abundant fermentable pentose, which usually represents an architectural component of the bacterial cell wall. However, its regulatory function and the involved signaling pathway in bacteria remain largely unclear. Here, we show that D-xylose can act as a signaling molecule to regulate the lipid metabolism and affect multiple physiological characteristics in mycobacteria. D-xylose directly interacts with XylR and inhibits its DNA-binding ability, thus blocking XylR-mediated repression. The xylose inhibitor, XylR, plays a global regulatory role and affects the expression of 166 mycobacterial genes that are involved in lipid synthesis and metabolism. Furthermore, we show that the xylose-dependent gene regulation of XylR affects the multiple physiological characteristics of Mycobacterium smegmatis, including bacterial size, colony phenotype, biofilm formation, cell aggregation, and antibiotic resistance. Finally, we found that XylR inhibited the survival of Mycobacterium bovis BCG in the host. Our findings provide novel insights into the molecular mechanism of lipid metabolism regulation and its correlation with bacterial physiological phenotypes.

Acute effects of ambient air pollution on daily neurology clinic visits for vertigo: a time-series study in Wuhan, China.

This study aimed to disclose the relationship between ambient air pollution and neurology clinic visits (NCVs) for vertigo. A time-series study was conducted to examine relationships between six different criteria air pollutants (SO2, NO2, PM2.5, PM10, CO, and O3) and daily NCVs for vertigo in Wuhan, China, from January 1st, 2017 to November 30th, 2019. Stratified analyses were computed according to gender, age, and season. A total of 14,749 records of NCVs for vertigo were enrolled in this study. Data showed that the increase in daily NCVs for vertigo corresponding to 10 µg/m3 increase of respective pollutants are: SO2 (- 7.60%; 95% CI: - 14.25 to - 0.44%), NO2 (3.14%; 95% CI: 0.23 to 6.13%), PM2.5 (0.53%; 95% CI: - 0.66 to 1.74%), PM10 (1.32%; 95% CI: - 0.36 to 3.06%), CO (0.00%; 95% CI: - 0.12 to 0.13%), and O3 (0.90%; 95% CI: - 0.01% to 1.83%). Males were more susceptible to acute exposure to SO2 and NO2, compared to females (SO2: - 11.91% vs. - 4.16%; NO2: 3.95% vs. 2.92%), whereas the acute effect of O3 exposure was more significantly obvious in females than males (0.94% vs. 0.87%). Moreover, correlations between daily NCVs for vertigo and acute exposure to SO2, NO2, and O3 were all stronger in individuals under 50 years old (SO2: - 12.75% vs. - 4.41%; NO2: 4.55% vs. 2.75%; O3: 1.27% vs. 0.70%). Short-term exposure to PM2.5 was more significantly associated with daily NCVs for vertigo in cool seasons (1.62% vs. - 0.68%), while the correlation between CO exposure and daily NCVs for vertigo was stronger in warm seasons (0.21% vs. - 0.03%). Our study demonstrated acute exposure to ambient NO2 and O3 positively associated with daily NCVs for vertigo. Acute effects of air pollution on daily NCVs for vertigo varied according to gender, age, and season.

Lilly's Technique for Delayed Hemorrhage After Choledochal Cyst Radical Surgery.

Background: Choledochal cysts (CCs) are characterized by dilations of the extra- and/or intrahepatic bile ducts. Surgery (cyst excision and Roux-en-Y hepaticojejunostomy) remains the gold standard for treatment. However, delayed hemorrhage can occur postoperatively, and although rare, it can be life-threatening. This study aimed to determine the risk factors and corresponding prevention of delayed hemorrhage after radical CC surgery, and to apply a technique to lower its incidence. Materials and Methods: This retrospective study enrolled 267 patients who received CC surgery between June 2016 and December 2020 at Shenzhen Children's Hospital. Univariate and multivariate logistic regression analyses were performed to identify risk factors for delayed hemorrhage. Results: Eleven (4.1%) patients had delayed hemorrhage after laparoscopic radical surgery. The most common hemorrhage site was the dissected surface between the cyst and adjacent structures with chronic severe adhesions, postoperatively. The occurrence of recurrent CC-associated complication and excessive total blood loss during surgery were risk factors for delayed hemorrhage after CC radical surgery. Length of disease course, operation when cholangitis/pancreatitis still existed, cyst diameter, and application of trypsin inhibitor after the surgery were not significantly different between the two groups. Conclusion: For patients without adhesions, complete cyst resection is the gold standard. However, for those with intensive adhesions, in cases of delayed hemorrhage on the dissection surface and malignancy transformation risk, the Lilly's technique with Roux-en-Y hepaticojejunostomy could be an alternative.

Adaptation of African swine fever virus to porcine kidney cells stably expressing CD163 and Siglec1.

African swine fever virus (ASFV) is a complex large DNA enveloped virus that causes African swine fever (ASF) with a fatality rate of up to 100%, seriously threatening the global swine industry. Due to the strict cell tropism of ASFV, there is no effective in vitro cell line, which hinders its prevention and control. Herein, we analyzed genome-wide transcriptional profiles of ASFV-susceptible porcine alveolar macrophages (PAMs) and non-susceptible cell lines PK15 and 3D4-21, an found that PAM surface pattern recognition receptors (PRRs) were significantly higher and common differential genes were significantly enriched in phagocytosis compared with that observed in PK15 and 3D4-21 cell lines. Therefore, endocytosis functions of host cell surface PRRs may play key roles in ASFV infection in vitro. ASFV was found to be infective to PK15 and 3D4-21 cell lines overexpressing CD163 and Siglec1, and to the PK15S1-CD163 cell line stably expressing CD163 and Siglec1. However, the PK15 and 3D4-21 cell lines overexpressing CD163 or Siglec1 alone were not infectious. Simultaneous interference of CD163 and Siglec1 in PAMs with small interfering RNA (siRNA) significantly reduced the infectivity of ASFV. However, siRNA interference of CD163 and Siglec1 respectively did not affect ASFV infectivity. ASFV significantly inhibited IFN expression levels in PAMs and PK15S1-CD163 cells, but had no effect on PK15 and 3D4-21 cell lines. These results indicate that CD163 and Siglec1 are key receptors for ASFV-infected host cells, and both play a synergistic role in the process of ASFV infection. ASFV inhibits IFN expression in susceptible cells, thereby downregulating the host immune response and evading the immune mechanism. The discovery of the ASFV receptor provides novel ideas to study ASFV and host cell interactions, pathogenic mechanisms, development of receptor blockers, vaccine design, and disease resistance breeding.

Taxifolin ameliorates lipopolysaccharide-induced intestinal epithelial barrier dysfunction via attenuating NF-kappa B/MLCK pathway in a Caco-2 cell monolayer model.

Intestinal epithelial barrier dysfunction can cause several intestinal diseases. Flavonoids have been shown to be beneficial to the intestinal epithelial barrier function. However, the effects of taxifolin (TAX), a naturally occurring flavonoid, on the intestinal epithelial barrier function are unclear. Thus, the aims of this study were to investigate the protective effect and potential mechanism of TAX against lipopolysaccharide (LPS)-induced intestinal epithelial barrier dysfunction in a Caco-2 cell monolayer model. Our results showed that TAX increased the transepithelial electrical resistance (TEER) and decreased the fluorescein isothiocyanate (FITC)-dextran (4 kDa) flux in the damaged intestinal epithelial barrier. Meanwhile, TAX inhibited an LPS-induced decrease in mRNA and protein expression of tight junction (TJ) proteins (claudin-1, zonula occludens [ZO]-1, and occludin), and ameliorating the continuous distribution pattern disrupted of TJs. These results suggested that TAX ameliorated intestinal epithelial barrier dysfunction. Regarding the underlying mechanism, TAX reduced the LPS-induced secretion of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6 in Caco-2 cell monolayers. In addition, TAX suppressed the phosphorylation of nuclear factor kappa-B (NF-κB), inhibitor protein of NF-κBα (IκBα), and myosin light chain (MLC), and downregulated the expression of myosin light chain kinase (MLCK) in LPS-treated Caco-2 cells. In summary, TAX can maintain TJ proteins by inhibiting the NF-κB/MLCK pathway and pro-inflammatory factor secretion to ameliorate LPS-induced intestinal epithelial barrier dysfunction. Thus, TAX is a promising candidate agent for use in functional food to ameliorate intestinal barrier dysfunction.

Role of long non-coding RNA-adducin 3 antisense RNA1 in liver fibrosis of biliary atresia.

Biliary atresia (BA) is a devastating liver disease in neonates. Liver fibrosis is regarded as a universal and prominent feature of BA. Studies have revealed that long non-coding RNAs (lncRNAs) regulate cellular processes during the development of liver fibrosis in BA. Long non-coding RNA-adducin 3 antisense RNA1 (lnc-ADD3-AS1) has been shown to increase susceptibility to BA. However, the role of lnc-ADD3-AS1 in liver fibrosis in BA remains unclear. Here, we investigated the role of lnc-ADD3-AS1 in the proliferation, migration, and apoptosis of the immortalized human hepatic stellate cell (HSC) line, LX-2. We successfully overexpressed and silenced lnc-ADD3-AS1 in LX-2 cells using adenovirus vectors and evaluated the proliferation of transfected cells using the Cell Counting Kit-8 (CCK8) assay. Cell apoptosis was detected using annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) double staining and flow cytometry. We then analyzed cell migration by performing wound-scratch and transwell migration assays. Our results show that lnc-ADD3-AS1 significantly promoted LX-2 cell proliferation and attenuated apoptosis. More importantly, lncRNA-ADD3-AS1 significantly accelerated the migration of LX-2 cells. Our data indicated that lncRNA-ADD3-AS1 plays a role in the pathogenesis of liver fibrosis in patients with BA and may serve as a potential diagnostic marker for monitoring liver fibrosis in BA or as a therapeutic target for the disease.

Effects of the NF-κB Signaling Pathway Inhibitor BAY11-7082 in the Replication of ASFV.

African swine fever virus (ASFV) mainly infects the monocyte/macrophage lineage of pigs and regulates the production of cytokines that influence host immune responses. Several studies have reported changes in cytokine production after infection with ASFV, but the regulatory mechanisms have not yet been elucidated. Therefore, the aim of this study was to examine the immune response mechanism of ASFV using transcriptomic and proteomic analyses. Through multi-omics joint analysis, it was found that ASFV infection regulates the expression of the host NF-B signal pathway and related cytokines. Additionally, changes in the NF-κB signaling pathway and IL-1ß and IL-8 expression in porcine alveolar macrophages (PAMs) infected with ASFV were examined. Results show that ASFV infection activates the NF-κB signaling pathway and up-regulates the expression of IL-1ß and IL-8. The NF-κB inhibitor BAY11-7082 inhibited the expression profiles of phospho-NF-κB p65, p-IκB, and MyD88 proteins, and inhibited ASFV-induced NF-κB signaling pathway activation. Additionally, the results show that the NF-κB inhibitor BAY11-7082 can inhibit the replication of ASFV and can inhibit IL-1ß and, IL-8 expression. Overall, the findings of this study indicate that ASFV infection activates the NF-κB signaling pathway and up-regulates the expression of IL-1ß and IL-8, and inhibits the replication of ASFV by inhibiting the NF-κB signaling pathway and interleukin-1 beta and interleukin-8 production. These findings not only provide new insights into the molecular mechanism of the association between the NF-κB signaling pathway and ASFV infection, but also indicate that the NF-κB signaling pathway is a potential immunomodulatory pathway that controls ASF.

The African Swine Fever Virus with MGF360 and MGF505 Deleted Reduces the Apoptosis of Porcine Alveolar Macrophages by Inhibiting the NF-κB Signaling Pathway and Interleukin-1ß.

African swine fever virus (ASFV) poses serious threats to the swine industry. The mortality rate of African swine fever (ASF) is 100%, and there is no effective vaccine currently available. Complex immune escape strategies of ASFV are crucial factors affecting immune prevention and vaccine development. CD2v and MGF360-505R genes have been implicated in the modulation of the immune response. The molecular mechanisms contributing to innate immunity are poorly understood. In this study, we discover the cytopathic effect and apoptosis of ΔCD2v/ΔMGF360-505R-ASFV after infection in porcine alveolar macrophages (PAMs) was significantly less than wild-type ASFV. We demonstrated that CD2v- and MGF360-505R-deficient ASFV decrease the level of apoptosis by inhibiting the NF-κB signaling pathway and IL-1ß mRNA transcription. Compared with wild-type ASFV infection, the levels of phospho-NF-κB p65 and p-IκB protein decreased in CD2v- and MGF360-505R-deficient ASFV. Moreover, CD2v- and MGF360-505R-deficient ASFV induced less IL-1ß production than wild-type ASFV and was attenuated in replication compared with wild-type ASFV. We further found that MGF360-12L, MGF360-13L, and MGF-505-2R suppress the promoter activity of NF-κB by reporter assays, and CD2v activates the NF-κB signaling pathway. These findings suggested that CD2v- and MGF360-505R-deficient ASFV could reduce the level of ASFV p30 and the apoptosis of PAMs by inhibiting the NF-κB signaling pathway and IL-1ß mRNA transcription, which might reveal a novel strategy for ASFV to maintain the replication of the virus in the host.

GS-441524 inhibits African swine fever virus infection in vitro.

African swine fever virus (ASFV) is a highly infectious and lethal swine pathogen that causes serious socio-economic consequences in endemic countries for which no safe and effective vaccine is currently available. GS-441524, a 1-cyano-substituted adenine C-nucleoside ribose analogue, inhibits viral RNA transcription by competing with natural nucleosides (ATP, TTP, CTP, and GTP) and effectively inhibits viral RNA-dependent RNA polymerase activity. However, whether GS-441524 can inhibit the replication of DNA viruses is unknown. In this study, we confirmed that GS-441524 inhibits ASFV infection in porcine alveolar macrophages (PAMs) in a dose-dependent manner; GS-441524 significantly inhibited ASFV replication at different time points after ASFV infection, particularly at the early stages of viral replication. Notably, GS-441524 did not increase the levels of antiviral cytokines or ATP in PAMs. However, an increase in the concentration of natural ATP in PAMs promoted the replication of ASFV and attenuated the inhibitory effect of GS-441524 in a dose-dependent manner. Our results suggest that GS-441524 is an effective antiviral against ASFV.

Short-Term Complications After Laparoscopic Choledochal Cyst Radical Surgery: Prevention and Treatment.

Background: Shenzhen Children's Hospital is one of the first hospitals in mainland China to conduct the laparoscopic choledochal cyst radical surgery. We aimed to analyze the short-term complications of treating choledochal cyst with laparoscopic surgery and to provide recommendations to reduce complications. Methods: A retrospective study was carried out from May 2010 to December 2017. The treatment process (preoperative preparation, surgical procedures, and treatment of the short-term complications), age at surgery, the length of surgery, and the length of stay were reviewed and analyzed. Results: A total of 325 cases were included in this study. Four cases (1.2%) were converted to laparotomy. Twenty-three cases (7.1%) exhibited the short-term complications, including bile leakage occurred in nine cases (2.8%), chylous ascites in one case (0.3%), pancreatic fistula in two cases (0.6%), intestinal necrosis in one case (0.3%), hemorrhage in four cases (1.2%), internal hernia in two cases (0.6%), and stoma necrosis in four cases (1.2%). Among patients younger than 3 months old, two cases (10.5%, P < 0.05) were converted to laparotomy, and four cases (21.1%, P < 0.05) exhibited complications. These patients also had a longer operative time (204.9 ± 10.8 min, P < 0.05) and hospital stay (12.2 ± 0.7 d, P < 0.001). Conclusion: In our study, the incidence of short-term complication after laparoscopic choledochal cyst radical surgery was relatively low. This procedure is a quite safe and effective for most patients, even for young children. However, patients younger than 3 months old may require extra attention during the treatment.

Biliary atresia screening in Shenzhen: implementation and achievements.

OBJECTIVE: To elaborate on the implementation and achievements of a biliary atresia (BA) screening programme in Shenzhen. METHODS: In 2015, we partnered with the government in Shenzhen and attached the stool colour card (SCC) to the health handbook for mothers and children. These handbooks have been distributed through official channels to every pregnant woman in Shenzhen since 1 January 2015. A total of 118 patients diagnosed with BA at Shenzhen Children's Hospital were enrolled and divided into two cohorts based on their date of diagnosis: cohort A before and cohort B after introduction of screening. The cohorts were compared to evaluate differences in age at diagnosis, jaundice-free rate, 2-year native liver survival rate and so on. RESULTS: After the implementation of the screening programme, the age at diagnosis decreased from 81±12 to 56±15 days old (p<0.05), the incidence of postoperative complications decreased from 58.8% to 52.6% (p<0.05), the jaundice-free rate increased from 47.1% to 54.4% (p<0.05), and the 2-year native liver survival rate increased from 44.4% to 52.6% (p<0.05). The percentage of patients who underwent surgery increased from 68.0% to 83.8% (p<0.05). CONCLUSION: In Shenzhen, our screening programme led to earlier diagnoses and better prognoses. The latter resulted in an increased willingness to undergo the Kasai procedure. Through a hospital and government collaboration, this programme exerted a considerable influence, and guardians observed benefits with only a small cost of implementation. Our results may eventually help promote the widespread use of the SCC across the whole country.

Epigenetic regulation of hematopoietic stem cell homeostasis.

As one of the best characterized adult stem cells, hematopoietic stem cell (HSC) homeostasis is of great importance to hematopoiesis and immunity due to HSC's abilities of self-renewal and multi-lineage differentiation into functional blood cells. However, excessive self-renewal of HSCs can lead to severe hematopoietic malignancies like leukemia, whereas deficient self-renewal of HSCs may result in HSC exhaustion and eventually apoptosis of specialized cells, giving rise to abnormalities such as immunodeficiency or anemia. How HSC homeostasis is maintained has been studied for decades and regulatory factors can be generally categorized into two classes: genetic factors and epigenetic factors. Although genetic factors such as signaling pathways or transcription factors have been well explored, recent studies have emerged the indispensable roles of epigenetic factors. In this review, we have summarized regulatory mechanisms of HSC homeostasis by epigenetic factors, including DNA methylation, histone modification, chromatin remodeling, non-coding RNAs, and RNA modification, which will facilitate applications such as HSC ex vivo expansion and exploration of novel therapeutic approaches for many hematological diseases.

Eckmaxol, a Phlorotannin Extracted from Ecklonia maxima, Produces Anti-ß-amyloid Oligomer Neuroprotective Effects Possibly via Directly Acting on Glycogen Synthase Kinase 3ß.

Alzheimer's disease is a progressive neurodegenerative disorder that mainly affects the elderly. Soluble ß-amyloid oligomer, which can induce neurotoxicity, is generally regarded as the main neurotoxin in Alzheimer's disease. Here we report that eckmaxol, a phlorotannin extracted from the brown alga Ecklonia maxima, could produce neuroprotective effects in SH-SY5Y cells. Eckmaxol effectively prevented but did not rescue ß-amyloid oligomer-induced neuronal apoptosis and increase of intracellular reactive oxygen species. Eckmaxol also significantly reversed the decreased expression of phospho-Ser9-glycogen synthase kinase 3ß and increased expression of phospho-extracellular signal-regulated kinase, which was induced by Aß oligomer. Moreover, both glycogen synthase kinase 3ß and mitogen activated protein kinase inhibitors produced neuroprotective effects in SH-SY5Y cells. Furthermore, eckmaxol showed favorable interaction in the ATP binding site of glycogen synthase kinase 3ß and mitogen activated protein kinase. These results suggested that eckmaxol might produce neuroprotective effects via concurrent inhibition of glycogen synthase kinase 3ß and extracellular signal-regulated kinase pathways, possibly via directly acting on glycogen synthase kinase 3ß and mitogen activated protein kinase. Based on the central role that ß-amyloid oligomers play in the pathogenesis of Alzheimer's disease and the high annual production of Ecklonia maxima for alginate and other nutritional ingredients, this report represents a new candidate for the treatment of Alzheimer's disease, and also expands the potential application of Ecklonia maxima and its constituents in the field of pharmacology.

Fucoxanthin, a Marine Carotenoid, Attenuates ß-Amyloid Oligomer-Induced Neurotoxicity Possibly via Regulating the PI3K/Akt and the ERK Pathways in SH-SY5Y Cells.

Alzheimer's disease (AD), the most common neurodegenerative disorder, is characterized by neurofibrillary tangles, synaptic impairments, and loss of neurons. Oligomers of ß-amyloid (Aß) are widely accepted as the main neurotoxins to induce oxidative stress and neuronal loss in AD. In this study, we discovered that fucoxanthin, a marine carotenoid with antioxidative stress properties, concentration dependently prevented Aß oligomer-induced increase of neuronal apoptosis and intracellular reactive oxygen species in SH-SY5Y cells. Aß oligomers inhibited the prosurvival phosphoinositide 3-kinase (PI3K)/Akt cascade and activated the proapoptotic extracellular signal-regulated kinase (ERK) pathway. Moreover, inhibitors of glycogen synthase kinase 3ß (GSK3ß) and mitogen-activated protein kinase (MEK) synergistically prevented Aß oligomer-induced neuronal death, suggesting that the PI3K/Akt and ERK pathways might be involved in Aß oligomer-induced neurotoxicity. Pretreatment with fucoxanthin significantly prevented Aß oligomer-induced alteration of the PI3K/Akt and ERK pathways. Furthermore, LY294002 and wortmannin, two PI3K inhibitors, abolished the neuroprotective effects of fucoxanthin against Aß oligomer-induced neurotoxicity. These results suggested that fucoxanthin might prevent Aß oligomer-induced neuronal loss and oxidative stress via the activation of the PI3K/Akt cascade as well as inhibition of the ERK pathway, indicating that further studies of fucoxanthin and related compounds might lead to a useful treatment of AD.

Elevated SLC26A4 gene promoter methylation is associated with the risk of presbycusis in men.

Presbycusis affects approximately one-third of people over the age of 65 and is a worldwide health problem. In the current study, whether the methylation level of solute carrier family 26 member 4 (SLC26A4) predicted an increased risk of presbycusis was investigated. Peripheral blood samples from 102 patients with presbycusis and 104 controls were collected, and the methylation of the CpG sites of SLC26A4 was measured by applying pyrosequencing technology combined with sodium bisulfate DNA conversion chemistry. Within the SLC26A4 promoter region, one CpG site (CpG3) exhibited a significantly (P<0.0001) greater methylation level in the patients with presbycusis (26.5±5.56%) compared with the controls (23.8±3.85%). Significantly different CpG3 methylation levels were observed between the patients with presbycusis and the controls among the male participants (P=0.0004). In addition, a significant decrease in the transcriptional level of SLC26A4 in peripheral blood was observed in the patients with presbycusis compared with the controls. Furthermore, analyses of the receiver operating characteristic (ROC) curves indicated that CpG3 methylation at the SLC26A4 promoter predicted the risk of presbycusis in the male participants (AUC=0.684, 95% CI=0.584­0.784, P=0.001). The results demonstrated the significance of the CpG site methylation level of SLC26A4, and thus provides a potential marker for the diagnosis of presbycusis.