Regulating the Wettability of Hard Carbon through Open Mesochannels for Enhanced K+ Storage.

Hard carbons are deemed as promising anode materials for high-performance potassium-ion battery, but their commercialization is still hindered by the insufficient K+ transfer kinetics and poor potassiophilicity. Herein, these issues are addressed by improving the wettability of hard carbon, which can be achieved by the introduction of open mesochannels. A series of such hollow mesoporous carbon capsules with different dimensions are synthesized, which exhibit markedly enhanced wettability with electrolyte compared to the microporous counterparts. Various characterizations confirm its effects on promoting the kinetics and potassiophilicity of as-synthesized carbons, which can be additionally improved by S-doping. As a result, the 2D mesoporous carbon anode exhibits excellent rate capability (122.2 mAh g-1 at 4 A g-1 ), high reversible capacity (396.6 mAh g-1 at 0.1 A g-1 after 200 cycles), and outstanding cycling stability (197.0 mAh g-1 at 2 A g-1 after 1400 cycles). In addition, the hollow mesoporous architecture can effectively buffer the volume expansion and thus stabilize the carbon anodes, as visualized by in situ transmission electron microscopy. This work provides new insight for enhanced K+ storage performance from the perspective of anode wettability with electrolyte, as well as a universal anode design that combines mesochannels architecture with heteroatom doping.

Association of scalp block with intraoperative hemodynamic profiles and postoperative pain outcomes at 24-48 hours following craniotomy: An updated systematic review and meta-analysis of randomized controlled studies.

BACKGROUND: Despite the demonstrated analgesic efficacy of scalp block (SB) during the immediate postoperative period, the impact of SB on pain outcomes at postoperative 24 and 48 h in adults receiving craniotomy remains unclear. METHODS: The databases of Medline, Embase, and Cochrane Central Register were searched from inception to January 2022 for available randomized controlled trials (RCTs). The primary outcome was the severity of pain at postoperative 24 and 48 h, while the secondary outcomes included morphine consumption, hemodynamic profiles after surgical incision and in the postanesthesia care unit (PACU), and risk of postoperative nausea/vomiting (PONV). RESULTS: Meta-analysis of 12 studies revealed a lower pain score [MD = -0.83, p = 0.03, 375 patients, certainty of evidence (COE): low] and morphine consumption (MD = -9.21 mg, p = 0.03, 246 patients, COE: low) at postoperative 24 h, while there were no differences in these pain outcomes at postoperative 48 h (COE: low). The use of SB significantly decreased intraoperative heart rate (MD = -10.9 beats/min, p < 0.0001, 189 patients, COE: moderate) and mean blood pressure (MD = -13.02 mmHg, p < 0.00001, 189 patients, COE: moderate) after surgical incision, but these hemodynamic profiles were comparable in both groups in the PACU setting. There was also no difference in the risk of PONV between the two groups (RR = 0.78, p = 0.2, 299 patients, COE: high). CONCLUSION: This meta-analysis demonstrated that scalp block not only provided hemodynamic stability immediately after surgical incision but was also associated with a lower pain score and morphine consumption at postoperative 24 h. Further studies are needed for elucidation of its findings.

Case report: the management for a gestational hypertensive woman with influenza A virus pneumonia and peripartum cardiomyopathy.

BACKGROUND: Peripartum cardiomyopathy (PPCM) is defined as an idiopathic cardiomyopathy occurring in the last month of pregnancy or the first 6 months postpartum without an identifiable cause. PPCM is suspected to be triggered by the generation of a cardiotoxic fragment of prolactin and the secretion of a potent antiangiogenic protein from the placental, but no single factor has been identified or defined as the underlying cause of the disease. Influenza virus can cause PPCM through immune-mediated response induced by proinflammatory cytokines from host immunity and endothelial cell dysfunction. We report a case in a parturient woman undergoing a cesarean delivery, who had influenza A pneumonia and PPCM. CASE PRESENTATION: A parturient woman at 40 weeks and 1 day of gestation who had experienced gestational hypertension accompanied by pulmonary edema developed hypotension after undergoing an emergency cesarean delivery. An elevation of N-terminal prohormone of brain natriuretic peptide (NT-proBNP) was noted, and echocardiography revealed a left ventricular ejection fraction of 20%. She underwent a nasopharyngeal swab test, in which influenza A antigen was positive. She was diagnosed as having PPCM and received anti-viral treatment. After antiviral treatment, hemodynamic dysfunction stabilized. We present and discuss the details of this event. CONCLUSION: PPCM is a heart disease that is often overlooked by medical personnel. Rapid swab tests, serum creatine kinase measurement, and echocardiography are imperative diagnostic approaches for the timely recognition of virus-associated cardiomyopathy in peripartum women with influenza-like disease and worsening dyspnea, especially during the epidemic season. Prompt antiviral treatment should be considered, particularly after PPCM is diagnosed.

Direct Evidence of Active SARS-CoV-2 Replication in the Intestine.

BACKGROUND: Currently, there is no direct evidence to prove the active replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the intestinal tract and relevant pathological changes in the colon and rectum. We investigated the presence of virions and pathological changes in surgical rectal tissues of a patient with clinically confirmed coronavirus disease 2019 (COVID-19) with rectal adenocarcinoma. METHODS: The clinical data were collected during hospitalization and follow-up of this patient. Quantitative reverse transcriptase-polymerasechain reaction (RT-PCR) was performed on the rectal tissue specimens obtained from surgical resection, succus entericus and intestinal mucosa of ileostomy, and rectal mucosa during follow-up after recovery. Ultrathin sections of surgical samples were observed for SARS-CoV-2 virions using electron microscopy. Histopathological examination was performed using hematoxylin-eosin stain. Immunohistochemical analysis and immunofluorescence were carried out on rectal tissues to evaluate the distribution of SARS-CoV-2 antigen and immune cell infiltrations. RESULTS: The patient had fever and cough on day 3 postoperatively, was diagnosed with COVID-19 on day 7, and was discharged from the hospital on day 41. RNA of SARS-CoV-2 was detected in surgically resected rectal specimens but not in samples collected 37 days after discharge. Notably, coincident with rectal tissues of surgical specimens testing nucleic acid positive for SARS-CoV-2, typical coronavirus virions in rectal tissue were observed under electron microscopy. Moreover, abundant lymphocytes and macrophages (some were SARS-CoV-2 positive) infiltrating the lamina propria were found with no significant mucosal damage. CONCLUSIONS: We first report the direct evidence of active SARS-CoV-2 replication in a patient's rectum during the incubation period, which might explain SARS-CoV-2 fecal-oral transmission.

miR-128 participates in the pathogenesis of chronic constipation by regulating the p38α/M-CSF inflammatory signaling pathway.

Chronic constipation (CC) is a gastrointestinal disorder that adversely affects the quality of life. MicroRNAs are involved in the pathogenesis of functional gastrointestinal disorders. This study aims to investigate the molecular mechanism of microRNA-128 in CC. Here, we successfully constructed a murine model of CC based on morphine and rhubarb. The expression of stem cell factor (SCF) and neuron-specific enolase (NSE) was low in the models. Using miRNA array and bioinformatic analysis, we predicted and confirmed the expression of miR-128 and its downstream target genes in CC model. Compared with the control group, CC group showed a significant downregulation of miR-128 and upregulation of p38α and macrophage colony-stimulating factors (M-CSFs). Moreover, we observed elevated inflammatory cytokine and decreased anti-inflammatory cytokine levels in colonic tissues. Furthermore, coculture assays indicated that regulating expression of miR-128 in colonic epithelial cells induced the secretion of IL-6 and TNF-α by macrophages. In conclusion, our study demonstrated that miR-128 regulated the p38α/M-CSF signaling pathway to promote chronic inflammatory responses and changes in the immune microenvironment of the colon, thereby offering potential insights into the pathogenesis of CC and therapeutic targets for its treatment.NEW & NOTEWORTHY In this study, we constructed a murine model and identified a novel signaling mechanism involved in the chronic constipation progression. Our findings on the role of miR-128/p38α/M-CSF axis provide new insights into the treatment of chronic constipation.

Vitamin D Deficiency Exacerbates Colonic Inflammation Due to Activation of the Local Renin-Angiotensin System in the Colon.

BACKGROUND: The renin-angiotensin system (RAS) is activated in inflammatory bowel disease (IBD), and vitamin D deficiency aggravates the development of colitis, but the relationship between the local colonic RAS and vitamin D is unclear with regard to the pathogenesis of IBD. AIMS: To investigate whether vitamin D suppresses the local colonic RAS to prevent colonic mucosal inflammation in a mouse model of experimental colitis. METHODS: C57BL/6 mice fed vitamin D-deficient (VDD) diet for 8 weeks were induced to colitis by 2,4,6-trinitrobenzenesulfonic acid (TNBS), with mice fed vitamin D-sufficient (VDS) diet as controls. Colitis severity was assessed by histology, and pro-inflammatory cytokines, RAS components, and signaling pathways were quantified by real-time RT-PCR and Western blotting. RESULTS: C57BL/6 mice fed the VDD diet for 8 weeks exhibited significantly lower serum 25(OH)D3 concentrations compared to mice fed the VDS diet. When these VDD mice were induced to colitis by TNBS, they exhibited more severe colonic inflammation and developed more severe colitis compared to the VDS counterparts. VDD diet feeding resulted in higher production of mucosal pro-inflammatory cytokines, higher activation of the myosin light chain kinase-tight junction regulatory pathway, and greater increases in mucosal permeability. VDD diet feeding also enhanced colonic RAS activation. Treatment with angiotensin II receptor blocker losartan markedly alleviated colitis in TNBS-induced VDD mice. CONCLUSION: Vitamin D deficiency promotes colonic inflammation at least in part due to over activation of the local RAS in the colon.

First Report of Anthracnose Caused by Colletotrichum siamense and C. fructicola of Camellia chrysantha in China.

Camellia chrysantha (Hu) Tuyama, belonging to the Theaceae family, is famous for its large size and golden yellow flowers, which has high ornamental and health care functions (Mo et al. 2013). Anthracnose is one of the most important fungal diseases worldwide, causing serious economic losses to many plants. In October 2019, severe anthracnose symptoms were observed on the leaves of C. chrysantha in a 0.6 hectare field with 15-20% disease incidence in Fangchenggang city, Guangxi Zhuang Autonomous Region of China. Diseased leaves initially appeared irregular chlorotic spots, which afterwards enlarged and coalesced. Finally, the spots became dark brown or black, sunken lesions (8-22 mm in diameter), and covered with plenty of acervuli. For pathogen isolation, the leaf lesions were cut into small tissue pieces (5 mm×5 mm), disinfected by 0.3% sodium hypochlorite for 2 min and 70% ethanol for 40 s, rinsed in sterile distilled water, and then incubated at 28°C on potato dextrose agar (PDA) plates. A total of 7 fungal isolates with whitish to light grey, dense colonies were recovered at 5 days. These isolates were tentatively identified as belonging to Colletotrichum gloeosporioides species complex through morphological and cultural characters (Weir et al. 2012). The conidia were nonseptate, cylindrical with obtuse to rounded ends, 13.9 to 18.3 (average 16.1) µm × 4.5 to 6.2 (average 5.4) µm (n = 50). For further precise identification, the 7 Colletotrichum isolates were analyzed using partial sequences of genomic loci including the internal transcribed spacer (ITS), ß-tubulin (TUB), calmodulin (CAL), actin (ACT), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), glutamine synthetase (GS), and the mating type locus MAT1-2 (ApMat) genes (Liu et al. 2015). The amplification sequences were compared with the sequences registered in the GenBank database based on nucleotide similarity. The above sequences of 4 isolates (JZB-PF4232, JZB-PF2231, JZB-PF42 and JZB-PF22) had 99-100% identity to the sequences of Colletotrichum siamense strains retrieved from GenBank, while the sequences of the other 3 isolates (JZB-PF3231, JZB-PF32 and JZB-PF41) showed over 99% identity with those of the C. fructicola strains. All the sequences were deposited in GenBank with accession number MT708987 to MT709007, MW149430 to MW149433, and MW142259 to MW142282. A multi-loci phylogenetic analysis of the concatenated sequences of ITS, TUB, CAL, ACT, GAPDH, GS and ApMat genes placed the 4 isolates described above in the C. siamense clade, while the other 3 isolates was attribute to the C. fructicola clade. Pathogenicity tests were conducted on 7 healthy 2-year-old C. chrysantha seedlings (cv. Fangpu), consisted of 21 wounded leaves made by a sterile needle, with 3 leaves per seedling. Artificial inoculations were performed by treating each seedling with 20 µl of spore suspension (106 conidia/ml) of each isolate. Leaves of seedlings treated with sterilized water under the same conditions served as controls. The experiment was repeated three times. All the seedlings were covered with plastic bags to maintain high humidity (90% RH) and placed in a greenhouse kept at 25°C with a 16 h light / 8 h dark photoperiod. After 8 days, the inoculated leaves of C. chrysantha plants developed typical dark brown or black lesions, similar to the symptoms in the field, whereas controls remained symptomless. Koch's postulates were fulfilled by re-isolation of the same fungi from symptomatic inoculated leaves, identification confirmed by morphological and molecular characteristics, respectively. C. siamense and C. fructicola have been found to cause anthracnose on Camellia sinensis (Wang et al. 2016; Shi et al. 2018). C. fructicola has also been reported to cause anthracnose on Citrus sinensis in China (Hu et al. 2019). To our knowledge, this is the first report of C. siamense and C. fructicola causing anthracnose on C. chrysantha in China.

microRNA-223 promotes autophagy to aggravate lung ischemia-reperfusion injury by inhibiting the expression of transcription factor HIF2α.

Lung ischemia-reperfusion (I/R) injury severely endangers human health, and recent studies have suggested that certain microRNAs (miRNAs) play important roles in this pathological phenomenon. The current study aimed to ascertain the ability of miR-223 to influence lung I/R injury by targeting hypoxia-inducible factor-2α (HIF2α). First, mouse models of lung I/R injury were established: during surgical procedures, pulmonary arteries and veins and unilateral pulmonary portal vessels were blocked and resuming bilateral pulmonary ventilation, followed by restoration of bipulmonary ventilation. In addition, a lung I/R injury cell model was constructed by exposure to hypoxic reoxygenation (H/R) in mouse pulmonary microvascular endothelial cells (PMVECs). Expression of miR-223, HIF2α, and ß-catenin in tissues or cells was determined by RT-qPCR and Western blot analysis. Correlation between miR-223 and HIF2α was analyzed by dual luciferase reporter gene assay. Furthermore, lung tissue injury and mouse PMVEC apoptosis was evaluated by hematoxylin and eosin (H&E), TUNEL staining, and flow cytometry. Autophagosomes in cells were detected by light chain 3 immunofluorescence assay. miR-223 was expressed at a high level while HIF2α/ß-catenin was downregulated in tissues and cells with lung I/R injury. Furthermore, miR-223 targeted and repressed HIF2α expression to downregulate ß-catenin expression. The miR-223/HIF2α/ß-catenin axis aggravated H/R injury in mouse PMVECs and lung I/R injury in mice by enhancing autophagy. Taken together, miR-223 inhibits HIF2α to repress ß-catenin, thus contributing to autophagy to complicate lung I/R injury. These findings provide a promising therapeutic target for treating lung I/R injury.

Polarization-independent high diffraction efficiency two-dimensional grating based on cylindrical hole nano arrays.

In this paper, we propose a reflective two-dimensional (2D) metal-dielectric grating based on cylindrical hole nano arrays with excellent polarization-independent high diffraction efficiency. The effects of the geometrical parameters on the polarization characteristic and diffraction efficiency are studied. Optimized results show that the (-1, 0) order diffraction efficiency of transverse electric (TE) and transverse magnetic (TM) polarizations under Littrow mounting is 98.31% and 98.05% at 780 nm incident wavelength, and the diffraction efficiency equilibrium is 99.74%, which is a significant improvement over the previously reported 2D gratings. The high efficiency in both TE and TM polarizations makes it a potential candidate as planar grating rulers for high precision multi-axis displacement measurement. Moreover, the cylindrical hole-based structure performs well in manufacturing tolerances, which provides the possibility for practical applications.

Inhibition of mitochondrial autophagy protects donor lungs for lung transplantation against ischaemia-reperfusion injury in rats via the mTOR pathway.

Impaired mitochondrial function is a key factor attributing to lung ischaemia-reperfusion (IR) injury, which contributes to major post-transplant complications. Thus, the current study was performed to investigate the role of mitochondrial autophagy in lung I/R injury and the involvement of the mTOR pathway. We established rat models of orthotopic left lung transplantation to investigate the role of mitochondrial autophagy in I/R injury following lung transplantation. Next, we treated the donor lungs with 3-MA and Rapamycin to evaluate mitochondrial autophagy, lung function and cell apoptosis with different time intervals of cold ischaemia preservation and reperfusion. In addition, mitochondrial autophagy, and cell proliferation and apoptosis of pulmonary microvascular endothelial cells (PMVECs) exposed to hypoxia-reoxygenation (H/R) were monitored after 3-MA administration or Rapamycin treatment. The cell apoptosis could be inhibited by mitochondrial autophagy at the beginning of lung ischaemia, but was rendered out of control when mitochondrial autophagy reached normal levels. After I/R of donor lung, the mitochondrial autophagy was increased until 6 hours after reperfusion and then gradually decreased. The elevation of mitochondrial autophagy was accompanied by promoted apoptosis, aggravated lung injury and deteriorated lung function. Moreover, the suppression of mitochondrial autophagy by 3-MA inhibited cell apoptosis of donor lung to alleviate I/R-induced lung injury as well as inhibited H/R-induced PMVEC apoptosis, and enhanced its proliferation. Finally, mTOR pathway participated in I/R- and H/R-mediated mitochondrial autophagy in regulation of cell apoptosis. Inhibition of I/R-induced mitochondrial autophagy alleviated lung injury via the mTOR pathway, suggesting a potential therapeutic strategy for lung I/R injury.

Streptomyces lydicus A01 affects soil microbial diversity, improving growth and resilience in tomato.

The actinomycete Streptomyces lydicus A01 promotes tomato seedling growth; however, the underlying mechanism is unclear. In this study, we investigated whether changes in soil microbial diversity, following Streptomyces lydicus A01 treatment, were responsible for the increased tomato seedling growth. Eukaryotic 18S ribosomal DNA (rDNA) sequencing showed that S. lydicus A01-treated and untreated soil shared 193 operational taxonomic units (OTUs), whereas bacterial 16S rDNA sequencing identified 1,219 shared OTUs between the treated and untreated soil. Of the 42 dominant eukaryotic OTUs, eight were significantly increased and six were significantly decreased after A01 treatment. Of the 25 dominant bacterial OTUs, 12 were significantly increased and eight were significantly decreased after A01 treatment. Most of the eukaryotes and bacteria that increased in abundance exhibited growth promoting characteristics, which were mainly predicted to be associated with mineralization of nitrogen and phosphorus, phosphate solubilization, nutrient accumulation, and secretion of auxin, whereas some were related to plant protection, such as the degradation of toxic and hazardous substances. Soil composition tests showed that S. lydicus A01 treatment enhanced the utilization of nitrogen, phosphorus, and potassium in tomato seedlings. Thus, microbial fertilizers based on S. lydicus A01 may improve plant growth, without the detriment effects of chemical fertilizers.

The Tryptophan Decarboxylase in Solanum lycopersicum.

Melatonin plays an important role in plant growth, development, and environmental stress. In this study, a systematic analysis of tomato tryptophan decarboxylase (SlTrpDC), which is the first enzyme of melatonin biosynthesis, was conducted by integrating structural features, phylogenetic relationships, an exon/intron feature, and a divergent expression profile. The results determined that the tomato genome encoded five members (SlTrpDC1-SlTrpDC5). The phylogenetic relationships indicated that gene expansion was proposed as the major mode of evolution of the TrpDC genes from the different plant algae species to the higher plants species. The analyses of the exon/intron configurations revealed that the intron loss events occurred during the structural evolution of the TrpDCs in plants. Additionally, the RNA-seq and qRT-PCR analysis revealed that the expression of the SlTrpDC3 was high in all of the tested tissues, while the SlTrpDC4 and SlTrpDC5 were not expressed. The expression patterns of the remaining two (SlTrpDC1 and SlTrpDC2) were tissue-specific, which indicated that these genes may play important roles within the different tissues. No expression difference was observed in the tomato plants in response to the biotic stresses. This study will expand the current knowledge of the roles of the TrpDC genes in tomato growth and development.

Metschnikowia persici sp. nov., A Novel Protease-Producing Yeast Species from China.

Three yeast strains, named as FHL-A, FHL-B, and FHL-C, were isolated from peach fruit surfaces collected from different regions in the North of China highly produced protease and were presented as single separate group in the genus Metschnikowia by sequence comparisons of 26S rRNA gene D1/D2 domain and internal transcribed spacer (ITS) region. BLASTn alignments on NCBI showed that the similarity of 26S rRNA gene sequences of the three strains to all sequences of other yeasts accessed into the GenBank/EMBL/DDBJ and other database was very low (≦93%). The phylogenetic tree based on the D1/D2 region of 26S rRNA gene sequences revealed that three strains are most closely related to Metschnikowia koreensis KCTC 7828T (AF257272.1) (sequence similarity: 93.0%) and Metschnikowia reukaufii CBS9709T (AJ716113.1) (sequence similarity: 93.0%). However, the strains are distinguished from M. koreensis by its non-assimilation of galactose, ribitol, and D-xylose, and by its growth at 37 °C or in vitamin-free medium, and are notably different from M. reukaufii by its non-assimilation of galactose, D-xylose, D-arabinose, and D-ribose, and by its growth at 35 °C or in vitamin-free medium. The strain FHL-B formed asci in V8 juice sporulation medium for 3 weeks. Therefore, the name Metschnikowia persici is proposed for the novel species, with FHL-B (= CBS12815T = CFCC 3578T) as the type strain.

Internal Delorme's Procedure for Treating ODS Associated With Impaired Anal Continence.

OBJECTIVE: The aim of this study was to evaluate the medium-term outcomes of internal Delorme's procedure for treating obstructed defecation syndrome (ODS) patients with impaired anal continence. PATIENTS AND METHODS: In a retrospective study, 41 ODS patients who underwent internal Delorme's procedure between 2011 and 2015 were divided into 3 subgroups according to their associated symptoms of impaired continence, as urgency, passive fecal incontinence and both, before study. Then the patients' preoperative statuses, perioperative complications, and postoperative outcomes were investigated and collected from standardized questionnaires, including Altomare ODS score, Fecal Incontinence Severity Index (FISI), Patient Assessment of Constipation-Quality of Life Questionnaire (PAC-QoL), and Fecal Incontinence Quality of Life Scale (FIQLS). All results with a 2-tailed P < .05 were considered statistically significant. RESULTS: At an average 2.8 years of follow-up, there were significant improvements ( P < .01) in Altomare ODS score, FISI, PAC-QoL, and FIQLS in all patients when comparing scores from before the operation with those at the final follow-up. Similar results were also observed in both the urgency subgroup and passive fecal incontinence subgroup, but there were no statistically significant improvements ( P > .05) in Altomare ODS score, FISI, PAC-QoL, or FIQLS in the urgency and passive fecal incontinence subgroups. Anorectal manometry showed the mean value of anal resting pressure increased 20%. Additionally, no major complications occurred. CONCLUSION: Internal Delorme's procedure is effective without major morbidity for treating ODS associated with urgency or passive fecal incontinence, but it may be less effective for treating ODS associated with both urgency and passive fecal incontinence.

Genomic Analysis of the ASMT Gene Family in Solanum lycopersicum.

Acetylserotonin methyltransferase (ASMT) is the last enzyme of melatonin biosynthesis and may play a rate-limiting role in the melatonin production of plants. In this study, systematic analysis of the ASMT gene family in tomato (Solanum lycopersicum Mill) has been presented by the integration of the structural features, phylogenetic relationships, exon/intron configuration, and expression profile during growth and development, as well as biotic stresses. The results revealed that the tomato genome encoded a minimum of 14 members, containing three probable encoded pseudogenes. Chromosome mapping indicated that the family had probably expanded via tandem duplication events. Genome-wide RNA-seq and qRT-PCR based gene expression analysis revealed that almost half of the SlASMT genes were expressed in at least one of the experimental stages studied and also showed differential accumulation. Furthermore, the tandem duplicated SlASMT genes showed differential expression levels, which indicated probable functional divergence during the course of the evolution. Finally, this study also determined that some SlASMT genes were induced by multiple pathogens. The results suggested that these genes could be involved in tomato plant response to biotic stresses.

Wogonin inhibits LPS-induced inflammatory responses in rat dorsal root ganglion neurons via inhibiting TLR4-MyD88-TAK1-mediated NF-κB and MAPK signaling pathway.

Recent studies showed that the activation of toll-like receptor 4 (TLR4) on dorsal root ganglion (DRG) neurons might underlie neuropathic and inflammatory pain states. This study was undertaken to investigate the effects of wogonin, a flavonoid with potent anti-inflammatory properties on the inflammatory reaction and TLR4 dependent pathways in lipopolysaccharide (LPS)-treated DRG neurons. Our results showed that wogonin not only inhibited the expression and interaction of TLR4, MyD88, and TAK1, but also reduced the activation of nuclear factor kappa B and mitogen-activated protein kinases pathway in LPS-treated DRG neurons. Moreover, wogonin significantly suppressed the release of pro-inflammatory mediators in LPS-induced DRG neurons, including cyclooxygenase-2, inducible nitric oxide synthases, interleukin (IL)-1ß, IL-6, and tumor necrosis factor-alpha. Our results suggested that pre-treatment with wogonin could attenuate the TLR4-mediated inflammatory response in LPS-induced DRG neurons, thus might be beneficial for the treatment of neuropathic and inflammatory pain.

1,25-Dihydroxyvitamin D promotes negative feedback regulation of TLR signaling via targeting microRNA-155-SOCS1 in macrophages.

The negative feedback mechanism is essential to maintain effective immunity and tissue homeostasis. 1,25-dihydroxyvitamin D (1,25[OH]2D3) modulates innate immune response, but the mechanism remains poorly understood. In this article, we report that vitamin D receptor signaling attenuates TLR-mediated inflammation by enhancing the negative feedback inhibition. Vitamin D receptor inactivation leads to hyperinflammatory response in mice and macrophage cultures when challenged with LPS, because of microRNA-155 (miR-155) overproduction that excessively suppresses suppressor of cytokine signaling 1, a key regulator that enhances the negative feedback loop. Deletion of miR-155 attenuates vitamin D suppression of LPS-induced inflammation, confirming that 1,25(OH)2D3 stimulates suppressor of cytokine signaling 1 by downregulating miR-155. 1,25(OH)2D3 downregulates bic transcription by inhibiting NF-κB activation, which is mediated by a κB cis-DNA element located within the first intron of the bic gene. Together, these data identify a novel regulatory mechanism for vitamin D to control innate immunity.

Transgenic Expression of Vitamin D Receptor in Gut Epithelial Cells Ameliorates Spontaneous Colitis Caused by Interleukin-10 Deficiency.

BACKGROUND: Vitamin D deficiency is common in patients with inflammatory bowel diseases. The vitamin D receptor (VDR) is a nuclear hormone receptor mediating the activity of vitamin D hormone. Our previous studies showed that intestinal epithelial VDR signaling inhibits colitis by protecting the mucosal epithelial barrier, and this activity is independent of non-epithelial immune VDR actions. Interleukin (IL)-10-deficient mouse is a chronic colitis model that develops colitis due to aberrant immune responses. Here we used IL-10 null (IL-10KO) model to assess the anti-colitic activity of epithelial VDR in the setting of an aberrant immune system. METHODS: We crossed IL-10KO mice with villin promoter-driven human (h) VDR transgenic (Tg) mice to generate IL-10KO mice that carry the hVDR transgene in intestinal epithelial cells (IL-10KO/Tg). IL-10KO and IL-10KO/Tg littermates were studied in parallel and followed for up to 25 weeks. RESULTS: By 25 weeks of age, accumulatively 79 % IL-10KO mice developed prolapse, whereas only 40 % IL-10KO/Tg mice did so (P < 0.001). Compared with IL-10KO mice, IL-10KO/Tg littermates showed markedly reduced mucosal inflammation in both small and large intestines, manifested by attenuation in immune cell infiltration and histological damage and a marked decrease in pro-inflammatory cytokine production. IL-10KO/Tg mice also showed reduced intestinal epithelial cell apoptosis as a result of diminished PUMA induction and caspase 3 activation. CONCLUSION: These observations demonstrate that targeting hVDR expression to intestinal epithelial cells is sufficient to attenuate spontaneous colitis caused by an ill-regulated immune system, confirming a critical role of the epithelial VDR signaling in blocking colitis development.