Super enhancer related gene ANP32B promotes the proliferation of acute myeloid leukemia by enhancing MYC through histone acetylation.

BACKGROUND: Acute myeloid leukemia (AML) is a malignancy of the hematopoietic system, and childhood AML accounts for about 20% of pediatric leukemia. ANP32B, an important nuclear protein associated with proliferation, has been found to regulate hematopoiesis and CML leukemogenesis by inhibiting p53 activity. However, recent study suggests that ANP32B exerts a suppressive effect on B-cell acute lymphoblastic leukemia (ALL) in mice by activating PU.1. Nevertheless, the precise underlying mechanism of ANP32B in AML remains elusive. RESULTS: Super enhancer related gene ANP32B was significantly upregulated in AML patients. The expression of ANP32B exhibited a negative correlation with overall survival. Knocking down ANP32B suppressed the proliferation of AML cell lines MV4-11 and Kasumi-1, along with downregulation of C-MYC expression. Additionally, it led to a significant decrease in H3K27ac levels in AML cell lines. In vivo experiments further demonstrated that ANP32B knockdown effectively inhibited tumor growth. CONCLUSIONS: ANP32B plays a significant role in promoting tumor proliferation in AML. The downregulation of ANP32B induces cell cycle arrest and promotes apoptosis in AML cell lines. Mechanistic analysis suggests that ANP32B may epigenetically regulate the expression of MYC through histone H3K27 acetylation. ANP32B could serve as a prognostic biomarker and potential therapeutic target for AML patients.

Benzene-Linked Polymeric Carbon Nitride for Enhanced Photocatalytic Hydrogen Production.

Cross-linking with functional molecular species in polymeric carbon nitride (PCN) could offer a positive strategy that tunes its molecular structure with excellent conductivity to improve photocatalytic activity. Herein, the benzene ring-cross-linked photocatalyst is obtained via the polymerization of urea, melamine, and trimesic acid. Benzene ring-cross-linked PCN narrows the band gap and augments the push-pull effect of carriers, thus enhancing visible light harvesting and transfer easiness of photogenerated electron/hole pairs. Notably, the amount of trimesic acid was optimized during the benzene ring-cross-linked photocatalyst preparation (marked as 01T/A-CN, 02T/A-CN, and 03T/A-CN). Among them, 02T/A-CN photocatalyst achieved an excellent hydrogen production rate of 1931 µmol/h·g, which is higher than that of CN under visible light and beyond most reported. Theoretical calculations further confirmed that the introduction of benzene ring significantly reduces the band gap of PCN, bringing the delocalized electron, a longer intramolecular electron transition distance, and molecular bending. All those factors made benzene ring-cross-linked PCN with improved photocatalytic hydrogen production under visible light irradiation.

Adverse events and efficacy of second-round CAR-T cell therapy in relapsed pediatric B-ALL.

OBJECTIVE: Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment approach for pediatric patients suffering from relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). However, there was a paucity of data on the challenges associated with second-round CAR-T therapy in this population. METHODS: Medical records of nine pediatric patients who received second-round CAR-T therapy in a single center from June 2019 to May 2023 were analyzed. Throughout the course of the clinical trial, we evaluated adverse events including CRS, CRES, infections, hematologic toxicity, and organ injury, as well as CAR-T responses. RESULTS: Except for one patient who chose CART therapy due to testicular relapse, the remaining patients had indications for CAR-T therapy due to relapse with bone marrow alone or combined with other site. There were no difference between the transfusion dose of CART1 and CART2. No differences of incidence and grade of CRS was found between the first-round CAR-T therapy (CART1) and second-round CAR-T therapy (CART2). Additionally, we found that the incidence of CRES was higher for CART1(3/9,33.3%) than CART2(1/9,11.1%). Our findings revealed that there were no differences of IL-2, IL-4, IL-6, IL-10, IFN-γ, and TNF-α between CART1 and CART2, but the peak level of IL-17A was significantly higher in patients receiving CART1 compared to those receiving CART2 (p = .011). Early and late infection rates after CART1 were higher than CART2. Based on the dynamic changes of ANC, hemoglobin and platelet, ANC, and platelet were reduced obviously post CART. It seems that the incidences of severe thrombocytopenia and severe anemia were higher in the CART1 group compared to CART2. The MRD-negative CR rates for CART1 and CART2 are 100% and 44.4%, respectively (p = .029). All patients experienced events (relapse, chemotherapy, transplantation, or death) after receiving CART2, including one died, three discharged automatically, and the remaining five patients survived. CONCLUSION: Although the remission rate of CART2 is not as high as the CART1 due to the severity of the disease, its safety regarding CRS, CRES, infections, and organ injury is still excellent. Therefore, CART2 remains a viable option for treating pediatric relapsed B-ALL.

Mitoguardin Regulates Mitochondrial Fusion through MitoPLD and Is Required for Neuronal Homeostasis.

Mitochondria undergo frequent morphological changes through fission and fusion. Mutations in core members of the mitochondrial fission/fusion machinery are responsible for severe neurodegenerative diseases. However, the mitochondrial fission/fusion mechanisms are poorly understood. We found that the loss of a mitochondrial protein encoding gene, mitoguardin (miga), leads to mitochondrial defects and neurodegeneration in fly eyes. Mammals express two orthologs of miga: Miga1 and Miga2. Both MIGA1 and MIGA2 form homotypic and heterotypic complexes on the outer membrane of the mitochondria. Loss of MIGA results in fragmented mitochondria, whereas overexpression of MIGA leads to clustering and fusion of mitochondria in both fly and mammalian cells. MIGA proteins function downstream of mitofusin and interact with MitoPLD to stabilize MitoPLD and facilitate MitoPLD dimer formation. Therefore, we propose that MIGA proteins promote mitochondrial fusion by regulating mitochondrial phospholipid metabolism via MitoPLD.

Fu'cupping Physical Permeation-enhancing Techniques Enhances the Therapeutic Efficacy of Corydalis yanhusuo Gel Plaster.

Corydalis yanhusuo(YHS), a traditional Chinese medicine, is widely used to treat various pains, and its active ingredient is alkaloids. This study aimed to develop a new type of transdermal gel plaster containing the extract of Corydalis yanhusuo. Studies have shown that Fu'cupping physical permeation-enhancing techniques(FCPT) can promote the penetration of alkaloids and improve the efficacy of drugs. A transdermal gel plaster containing the extract of YHS was prepared and optimized using an orthogonal experimental design. The skin permeation ability of the gel plaster was studied in vitro, while the anti-inflammatory and analgesic effects of the prepared patch alone or with FCPT were evaluated in a rat model. The formulation of a gel plaster containing YHS extract was successfully prepared, with an optimized composition consisting of glycerin (15 g), sodium polyacrylate (2 g), silicon dioxide (0.3 g), ethanol (2 g), aluminum oxide (0.1 g), citric acid (0.05 g), the YHS extract (3 g) and water (15 g). The cumulative transdermal permeation of dehydrocorydaline, corypalmine, tetrahydropalmatine, and corydaline in 24 h was estimated to be, respectively, 569.7±63.2, 74.5±13.7, 82.4±17.2, and 38.9±8.1 µg/cm2. The in vitro diffusion dehydrocorydaline and corydaline followed the zero order kinetics profile, while that of corypalmine and tetrahydropalmatine followed a Higuchi equation. The prepared gel plaster significantly reduced paw swelling, down regulated inflammatory cytokines, and mitigated pain induced by mechanical or chemical stimuli. FCPT further improved the anti-inflammatory and analgesic effects of the patch. The combined application of FCPT and the alkaloid gel plaster may be effective against inflammation and pain.

Refractory hepatosplenic T-cell lymphoma was successfully treated with salvage allogeneic hematopoietic stem cell transplantation combined with enhanced myeloablative preconditioning.

This study aims to evaluate the clinical benefit of salvage allogeneic hematopoietic stem cell transplantation (allo-HSCT) in combination with enhanced myeloablative preconditioning in the treatment of refractory liver and spleen T-cell lymphomas. A retrospective analysis was performed on three patients (with refractory liver and spleen T-cell lymphomas) who have been treated with salvage allo-HSCT combined with enhanced myeloablative preconditioning. One of three patients had a liver biopsy; the other two underwent bone marrow analysis using morphology, immunology, cytogenetics, and molecular biology. All three patients were resistant to chemotherapy and with a high tumor load, so a new total body irradiation/splenic region irradiation/GEM/CLAG/ATG preconditioning regimen was conducted and followed with salvage HSCT. Two patients received haploidentical-donor hematopoietic stem cell transplants, and one received an unrelated full-donor hematopoietic stem cell transplant. The three patients survived disease-free until May 2021. Clinically, hepatosplenic T-cell lymphoma (HSTCL) is rare, with a poor prognosis and chemotherapy response. Based on the present study's encouraging clinical results, salvage allo-HSCT in conjunction with an enhanced myeloablative preconditioning regiment may be an effective and safe treatment for HSTCL.

The effect of tomato and lycopene on clinical characteristics and molecular markers of UV-induced skin deterioration: A systematic review and meta-analysis of intervention trials.

Lycopene as a natural antioxidant that have been studied for ultraviolet radiation (UVR) photo protection and is one of the most effective carotenoids to scavenge reactive oxygen species (ROS). This review aims to summarize the protective effect of tomato and lycopene on skin photo damage and skin photoaging in healthy subjects by reviewing the existing population intervention experiments. A total of five electronic databases including PubMed, Scopus, EBSCO, Web of Science and Cochrane Library were searched from inceptions to January 2021 without any restriction. Out of 19336 publications identified, 21 fulfilled the inclusion criteria and were meta-analysis. Overall, interventions supplementing tomato and lycopene were associated with significant reductions in Δa*, MMP-1, ICAM-1 and skin pigmentation; while tomato and lycopene supplementation were associated with significant increase in MED, skin thickness and skin density. Based on the results of this systematic review and meta-analysis, supplementation with tomato and lycopene could reduce skin erythema formation and improve the appearance and pigmentation of the skin, thereby preventing light-induced skin photodamage and skin photoaging. Lycopene-rich products could be used as endogenous sun protection and may be a potential nutraceutical for sun protection.

Fermented foods and metabolic outcomes in diabetes and prediabetes: A systematic review and meta-analysis of randomized controlled trials.

Several randomized controlled trials (RCTs) have investigated the effects of fermented foods on metabolic outcomes in adult patients suffering from diabetes and prediabetes. However, the results of these RCTs are conflicting. This systematic review and meta-analysis was carried out on data from RCTs to evaluate the effects of fermented foods in patients with diabetes and prediabetes. The PubMed, Web of Science, Embase, the Cochrane Library and Scopus databases were searched up to 21 June, 2022. English-language RCTs of fermented foods consumption were included which gave metabolic outcomes on body composition, glucose control, insulin sensitivity, lipid profile, as well as blood pressure. Eighteen RCTs met the inclusion criteria and 843 participants were included in the final analysis. The pooled results showed a significant reduction of fasting blood glucose (FBG), the homeostatic model assessment of insulin resistance (HOMA-IR), total cholesterol (TC), low density lipid cholesterol (LDL-C) and diastolic blood pressure (DBP) in the intervention group versus the control group. The results of this research showed that fermented foods have the potential to improve some metabolic outcomes, including FBG, HOMA-IR, TC, LDL-C, and DBP in patients with diabetes and prediabetes.

Characterization and molecular evolution analysis of Periploca forrestii inferred from its complete chloroplast genome sequence.

Periploca forrestii, a medicinal plant of the family Apocynaceae, is known as an effective and widely used clinical prescription for the treatment of rheumatoid diseases. In this study, we de novo sequenced and assembled the completement chloroplast (cp) genome of P. forrestii based on combined Oxford Nanopore PromethION and Illumina data. The cp genome was 153 724 bp in length and had four subregions. Moreover, an 84 433 bp large single-copy and a 17 731 bp small single-copy were separated by 25 780 bp inverted repeats (IRs). The cp genome included 132 genes with 18 duplicates in the IRs. A total of 45 repeat structures and 183 simple sequence repeats were detected. Codon usage showed a bias toward A/T-ending codons. A comparative study of Apocynaceae revealed that an IR expansion occurred on P. forrestii. The Ka/Ks values of eight species of Apocynaceae suggested that positive selection was exerted on the psaI and ycf2 genes, which might reflect specific adaptions to the P. forrestii particular growth environment. Phylogenetic analysis indicated that Periplocoideae was a sister to Asclepiadoideae, forming a monophyletic group in the family Apocynaceae. This study provided an important P. forrestii genomic resource for future evolutionary studies and the phylogenetic reconstruction of the family Apocynaceae.

Omega-3 Polyunsaturated Fatty Acid Eicosapentaenoic Acid or Docosahexaenoic Acid Improved Ageing-Associated Cognitive Decline by Regulating Glial Polarization.

Neuroinflammation induced by microglial and astrocyte polarizations may contribute to neurodegeneration and cognitive impairment. Omega (n)-3 polyunsaturated fatty acids (PUFAs) have anti-inflammatory and neuroprotective effects, but conflicting results were reported after different n-3 PUFA treatments. This study examined both the change in glial polarizations in ageing rats and the differential effects of two omega-3 PUFAs. The results showed that both PUFAs improved spatial memory in ageing rats, with docosahexaenoic acid (DHA) being more effective than eicosapentaenoic acid (EPA). The imbalance between microglial M1/M2 polarizations, such as up-regulating ionized calcium binding adaptor molecule 1 (IBA1) and down-regulating CD206 and arginase-1 (ARG-1) was reversed in the hippocampus by both n-3 PUFAs, while the DHA effect on CD206 was stronger. Astrocyte A1 polarization presented increasing S100B and C3 but decreasing A2 parameter S100A10 in the ageing brain, which were restored by both PUFAs, while DHA was more effective on S100A10 than EPA. Consistent with microglial M1 activation, the concentration of pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1ß and IL-6 were significantly increased, which were attenuated by DHA, while EPA only suppressed IL-6. In correlation with astrocyte changes, brain-derived neurotrophic factor precursor was increased in ageing rats, which was more powerfully down-regulated by DHA than EPA. In summary, enhanced microglial M1 and astrocytic A1 polarizations may contribute to increased brain pro-inflammatory cytokines, while DHA was more powerful than EPA to alleviate ageing-associated neuroimmunological changes, thereby better-improving memory impairment.

Isolation and Identification of a Novel Anti-Dry Eye Peptide from Tilapia Skin Peptides Based on In Silico, In Vitro, and In Vivo Approaches.

Tilapia skin is a great source of collagen. Here, we aimed to isolate and identify the peptides responsible for combating dry eye disease (DED) in tilapia skin peptides (TSP). In vitro cell DED model was used to screen anti-DED peptides from TSP via Sephadex G-25 chromatography, LC/MS/MS, and in silico methods. The anti-DED activity of the screened peptide was further verified in the mice DED model. TSP was divided into five fractions (TSP-I, TSP-II, TSP-III, TSP-IV, and TSP-V), and TSP-II exerted an effective effect for anti-DED. A total of 131 peptides were identified using LC/MS/MS in TSP-II, and NGGPSGPR (NGG) was screened as a potential anti-DED fragment in TSP-II via in silico methods. In vitro, NGG restored cell viability and inhibited the expression level of Cyclooxygenase-2 (COX-2) protein in Human corneal epithelial cells (HCECs) induced by NaCl. In vivo, NGG increased tear production, decreased tear ferning score, prevented corneal epithelial thinning, alleviated conjunctival goblet cell loss, and inhibited the apoptosis of corneal epithelial cells in DED mice. Overall, NGG, as an anti-DED peptide, was successfully identified from TSP, and it may be devoted to functional food ingredients or medicine for DED.

Estimations and Control of Julia Sets of the SIS Model Perturbed by Noise.

The estimations and control of Julia sets of the SIS(susceptible-infectious-susceptible) model under noise perturbation are studied. At first, a discrete SIS model is introduced, and the effects of additive and multiplicative noises on the fractal characteristics of the SIS model are discussed. Then, estimations of the Julia sets of the SIS model under additive and multiplicative noise perturbations are given, respectively. At last, the feedback control method is used to set appropriate controllers to realize control of the Julia set, and the influence of noise on the Julia set of the SIS model is reduced. The reason why this method is effective is also explained.

Scientific planning of urban cordon sanitaire for desired queuing time.

The outbreak of the COVID-19 pandemic disrupted ofur normal life. Many cities enforced a cordon sanitaire as a countermeasure to protect densely inhabited areas. Travelers can only cross the cordon after being checked. To minimize the waiting time in the queue, this paper proposes a method to determine the scientific planning of urban cordon sanitaire for desired queuing time, which is a significant problem that has not been explored. A novel two-stage optimization model is proposed where the first stage is the transportation system equilibrium problem to predict traffic inflow, and the second stage is the queuing network design problem to determine the allocation of test stations. This method aims to minimize the total health infrastructure investment for the desired maximum queuing time. Note that queuing theory is used to represent the queuing phenomenon at each urban entrance. A heuristic algorithm is designed to solve the proposed model where the Method of Successive Averages (MSA) is adopted for the first stage, and the Genetic Algorithm (GA) with elite strategy is adopted for the second stage. An experimental study with sensitivity analysis is conducted to demonstrate the effectiveness of the proposed methods. The results show that the methods can find a good heuristic optimal solution. This research is helpful for policymakers to determine the optimal investment and planning of cordon sanitaire for disease prevention and control, as well as other criminal activities such as drunk driving, terrorists, and smuggling.

Evaluation of tumour heterogeneity by 18F-fluoroestradiol PET as a predictive measure in breast cancer patients receiving palbociclib combined with endocrine treatment.

BACKGROUND: Predictive biomarkers are needed to identify oestrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER + /HER2-) metastatic breast cancer (MBC) patients who would likely benefit from cyclin-dependent kinase 4 and 6 inhibitors combined with endocrine therapy. Therefore, we performed an exploratory study to evaluate the tumour heterogeneity parameters based on 16α-18F-fluoro-17ß-oestradiol (18F-FES)-PET imaging as a potential marker to predict progression-free survival (PFS) in MBC patients receiving palbociclib combined with endocrine therapy. METHODS: Fifty-six ER + MBC patients underwent 18F-FES-PET/CT before the initiation of palbociclib. 18F-FES uptake was quantified and expressed as the standardized uptake value (SUV). Interlesional heterogeneity was qualitatively identified according to the presence or absence of 18F-FES-negative lesions. Intralesional heterogeneity was measured by the SUV-based heterogeneity index (HI = SUVmax/SUVmean). Association with survival was evaluated using the Cox proportional hazards model. RESULTS: A total of 551 metastatic lesions were found in 56 patients: 507 lesions were identified as 18F-FES-positive, 38 lesions were distributed across 10 patients without 18F-FES uptake, and the remaining 6 were liver lesions. Forty-three patients obtained a clinical benefit, and 13 developed progressive disease (PD) within 24 weeks. Nine out of 10 patients with an 18F-FES-negative site developed PD, and the median PFS was only 2.4 months. Among 46 patients with only 18F-FES-positive lesions, only four patients had PD, and the median PFS was 23.6 months. There were statistically significant differences between the two groups (P < 0.001). For the subgroup of patients with only 18F-FES-positive lesions, low FES-HI patients experienced substantially longer PFS times than those with high FES-HI (26.5 months vs. 16.5 months, P = 0.004). CONCLUSIONS: 18F-FES-PET may provide a promising method for identifying and selecting candidate ER + /HER2- MBC patients who would most likely benefit from palbociclib combined with endocrine treatment and could serve as a predictive marker for treatment response. Trial registration NCT04992156, Date of registration: August 5, 2021 (retrospectively registered).

Transcriptional regulation of proanthocyanidin biosynthesis pathway genes and transcription factors in Indigofera stachyodes Lindl. roots.

BACKGROUND: Proanthocyanidins (PAs) have always been considered as important medicinal value component. In order to gain insights into the PA biosynthesis regulatory network in I. stachyodes roots, we analyzed the transcriptome of the I. stachyodes in Leaf, Stem, RootI (one-year-old root), and RootII (two-year-old root). RESULTS: In this study, a total of 110,779 non-redundant unigenes were obtained, of which 63,863 could be functionally annotated. Simultaneously, 75 structural genes that regulate PA biosynthesis were identified, of these 6 structural genes (IsF3'H1, IsANR2, IsLAR2, IsUGT72L1-3, IsMATE2, IsMATE3) may play an important role in the synthesis of PAs in I. stachyodes roots. Furthermore, co-expression network analysis revealed that 34 IsMYBs, 18 IsbHLHs, 15 IsWRKYs, 9 IsMADSs, and 3 IsWIPs hub TFs are potential regulators for PA accumulation. Among them, IsMYB24 and IsMYB79 may be closely involved in the PA biosynthesis in I. stachyodes roots. CONCLUSIONS: The biosynthesis of PAs in I. stachyodes roots is mainly produced by the subsequent pathway of cyanidin. Our work provides new insights into the molecular pathways underlying PA accumulation and enhances our global understanding of transcriptome dynamics throughout different tissues.

Pedobacter mucosus sp. nov., isolated from a soil sample of glacier foreland in Austre Lovénbreen, Arctic.

A rod-shaped, Gram-stain-negative, non-motile and aerobic bacterium, designated Q8-18T, was isolated from soil of glacier foreland in Austre Lovénbreen, Arctic, and subjected to a polyphasic taxonomic study. Strain Q8-18T grew optimally at 20 °C, pH 5.0-8.0 and in the presence of 0-1.0 % (w/v) NaCl. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain Q8-18T belonged to the family Sphingobacteriaceae. Strain Q8-18T showed the highest sequence similarity to Pedobacter mendelii CCM 8685T (96.8%), Pedobacter lithocola CCM 8691T (96.8%), Pedobacter roseus CL-GP80T (96.7%), Pedobacter changchengzhani E01020T (96.7%), Pedobacter alluvionis DSM 19624T (96.6%), Pedobacter jejuensis THG-DR3T (96.3%), Pedobacter ginsengiterrae DCY49T (95.9%) and Pedobacter jamesrossensis CCM 8689T (95.9%). A whole genome-level comparison of strain Q8-18T with P. roseus CL-GP80T, P. changchengzhani E01020T, P. alluvionis DSM 19624T and Pedobacter heparinus LMG 10339T revealed average nucleotide identity values of 77.0, 76.0, 77.0 and 70.4%, respectively. The only respiratory isoprenoid quinone was menaquinone-7. The polar lipid profile of strain Q8-18T was found to contain one phosphatidylethanolamine, eight unidentified aminolipids, one aminophospholipids and five unidentified lipids. The G+C content of the genomic DNA was determined to be 35.4 mol%. The main fatty acids were summed feature 3 (comprising C16 : 1 ω7c and/or C16 : 1 ω6c), iso-C15 : 0 and anteiso-C15 : 0. On the basis of the evidence presented in this study, a novel species of the genus Pedobacter, Pedobacter mucosus sp. nov., is proposed, with the type strain Q8-18T (=CCTCC AB 2020009T=KCTC 82636T).

Neonatal outcomes after neuraminidase inhibitor use during pregnancy: A meta-analysis of cohort studies.

AIM: Influenza infection poses a severe threat to pregnant mothers, and antiviral treatment is recommended. However, the safety of neuraminidase-inhibitor antiviral medications during pregnancy has not been well described. METHODS: A systematic review and meta-analysis were performed to evaluate the adverse neonatal outcomes associated with exposure to neuraminidase inhibitors during pregnancy. The PubMed, Embase and Cochrane Library databases were searched to identify potential studies for inclusion. RESULTS: Nine cohort studies that estimated adverse neonatal outcomes associated with exposure to neuraminidase-inhibitor medication during pregnancy were included. Exposure to a neuraminidase inhibitor during pregnancy was not associated with an increased risk of congenital malformation (odds ratio [OR] 0.9, 95% confidence interval [CI] 0.72-1.12, P = .341), low Apgar score (OR 0.96, 95% CI 0.77-1.2, P = .733) or preterm birth (OR 0.99, 95% CI 0.89-1.09, P = .771) compared with no exposure. However, exposure to a neuraminidase inhibitor was associated with a reduced risk of low birth weight (OR 0.79, 95% CI 0.68-0.92, P = .002) and giving birth to a small-for-gestational-age infant (OR 0.78, 95% CI 0.69-0.88, P < .001). Further analyses limited to oseltamivir exposure were consistent with the overall results. CONCLUSION: Exposure to neuraminidase-inhibitor medication during pregnancy does not appear to be associated with adverse neonatal outcomes. We recommend further studies to investigate this association, which will help clinicians determine whether to prescribe a neuraminidase inhibitor during pregnancy.

Integrated multi-omics analysis and microbial recombinant protein system reveal hydroxylation and glycosylation involving nevadensin biosynthesis in Lysionotus pauciflorus.

BACKGROUND: Karst-adapted plant, Lysionotus pauciflours accumulates special secondary metabolites with a wide range of pharmacological effects for surviving in drought and high salty areas, while researchers focused more on their environmental adaptations and evolutions. Nevadensin (5,7-dihydroxy-6,8,4'-trimethoxyflavone), the main active component in L. pauciflours, has unique bioactivity of such as anti-inflammatory, anti-tubercular, and anti-tumor or cancer. Complex decoration of nevadensin, such as hydroxylation and glycosylation of the flavone skeleton determines its diversity and biological activities. The lack of omics data limits the exploration of accumulation mode and biosynthetic pathway. Herein, we integrated transcriptomics, metabolomics, and microbial recombinant protein system to reveal hydroxylation and glycosylation involving nevadensin biosynthesis in L. pauciflours. RESULTS: Up to 275 flavonoids were found to exist in L. pauciflorus by UPLC-MS/MS based on widely targeted metabolome analysis. The special flavone nevadensin (5,7-dihydroxy-6,8,4'-trimethoxyflavone) is enriched in different tissues, as are its related glycosides. The flavonoid biosynthesis pathway was drawn based on differential transcripts analysis, including 9 PAL, 5 C4H, 8 4CL, 6 CHS, 3 CHI, 1 FNSII, and over 20 OMTs. Total 310 LpCYP450s were classified into 9 clans, 36 families, and 35 subfamilies, with 56% being A-type CYP450s by phylogenetic evolutionary analysis. According to the phylogenetic tree with AtUGTs, 187 LpUGTs clustered into 14 evolutionary groups (A-N), with 74% being E, A, D, G, and K groups. Two LpCYP82D members and LpUGT95 were functionally identified in Saccharomyces cerevisiae and Escherichia coli, respectively. CYP82D-8 and CYP82D-1 specially hydroxylate the 6- or 8-position of A ring in vivo and in vitro, dislike the function of F6H or F8H discovered in basil which functioned depending on A-ring substituted methoxy. These results refreshed the starting mode that apigenin can be firstly hydroxylated on A ring in nevadensin biosynthesis. Furthermore, LpUGT95 clustered into the 7-OGT family was verified to catalyze 7-O glucosylation of nevadensin accompanied with weak nevadensin 5-O glucosylation function, firstly revealed glycosylation modification of flavones with completely substituted A-ring. CONCLUSIONS: Metabolomic and full-length transcriptomic association analysis unveiled the accumulation mode and biosynthetic pathway of the secondary metabolites in the karst-adapted plant L. pauciflorus. Moreover, functional identification of two LpCYP82D members and one LpUGT in microbe reconstructed the pathway of nevadensin biosynthesis.

Interleukin-10 Attenuates Behavioral, Immune and Neurotrophin Changes Induced by Chronic Central Administration of Interleukin-1ß in Rats.

BACKGROUND: Activated microglia can trigger pro-inflammatory cytokine releases and neuroinflammation, which may inhibit astrocytes to produce neurotrophins and anti-inflammatory factors. Both eventually lead to neuron apoptosis or death. Furthermore, effective antidepressant or anti-dementia treatments can reduce pro-inflammatory cytokines, while enhance interleukin (IL)-10 production. However, the underline mechanism by which IL-10 modulates glial cell function, hence improves cognitive impairment or depression-like behavior is unknown. This study evaluated whether and how IL-10 attenuated chronic IL-1ß administration-induced behavioral changes and the possible involved mechanisms. METHODS: Rats received intracerebroventricular injection of IL-1ß and/or IL-10 for 14 days. Then animal memory and depression-like behavior, pro-inflammatory cytokines, glial activities, expression of brain-derived neurotrophic factor (BDNF), Trk B, p75, and apoptosis-related genes were studied. RESULTS: Compared to controls, significantly increased latent time and swimming distance in the Morris-water-maze, decreased sucrose consumption, and decreased locomotor and center zone entries in the open-field were found in rats administrated with IL-1ß. These changes were associated with the reduction of GFAP expression, and concentrations of BDNF and anti-inflammatory cytokine IL-10, but the increase in the expressions of CD11b, TrkB, p75, and Caspase-3, the ratio of Bax/Bcl-2, and the concentrations of IL-1ß, tumor necrosis factor-α, and IL-6. IL-10 treatment markedly attenuated IL-1ß-induced above changes, except for the expressions of neurotrophin receptors. CONCLUSION: IL-10-improved behavioral changes may be through suppressing microglia activity and inflammation, while restoring astrocyte function and BDNF expression.

The Emerging Evidence for a Protective Role of Fucoidan from Laminaria japonica in Chronic Kidney Disease-Triggered Cognitive Dysfunction.

This study aimed to explore the mechanism of fucoidan in chronic kidney disease (CKD)-triggered cognitive dysfunction. The adenine-induced ICR strain CKD mice model was applied, and RNA-Seq was performed for differential gene analysis between aged-CKD and normal mice. As a result, fucoidan (100 and 200 mg kg-1) significantly reversed adenine-induced high expression of urea, uric acid in urine, and creatinine in serum, as well as the novel object recognition memory and spatial memory deficits. RNA sequencing analysis indicated that oxidative and inflammatory signaling were involved in adenine-induced kidney injury and cognitive dysfunction; furthermore, fucoidan inhibited oxidative stress via GSK3ß-Nrf2-HO-1 signaling and ameliorated inflammatory response through regulation of microglia/macrophage polarization in the kidney and hippocampus of CKD mice. Additionally, we clarified six hallmarks in the hippocampus and four in the kidney, which were correlated with CKD-triggered cognitive dysfunction. This study provides a theoretical basis for the application of fucoidan in the treatment of CKD-triggered memory deficits.