Paeonol interferes with lupus nephritis by regulating M1/M2 polarization of macrophages.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease of unknown etiology. It is marked by the production of pathogenic autoantibodies and the deposition of immune complexes. Lupus nephritis (LN) is a prevalent and challenging clinical complications of SLE. Cortex Moutan contains paeonol as its main effective component. In this study, using the animal model of SLE induced by R848, it was found that paeonol could alleviate the lupus-like symptoms of lupus mouse model induced by R848 activating TLR7, reduce the mortality and ameliorate the renal damage of mice. In order to explore the mechanism of paeonol on lupus nephritis, we studied the effect of paeonol on the polarization of Raw264.7 macrophages in vitro. The experimental results show that paeonol can inhibit the polarization of macrophages to M1 and promote their polarization to M2, which may be related to the inhibition of MAPK and NF-κB signaling pathways. Our research provides a new insight into paeonol in the treatment of lupus nephritis, which is of great importance for the treatment of systemic lupus erythematosus and its complications.

Hinge-like paper-based dual-channel enzyme-free ratiometric fluorescent microfluidic platform for simultaneous visual detection of carbaryl and glyphosate.

On-site multi-pesticide residues detection is particularly urgent and challenging. Here, we fabricated an enzyme-free ratiometric fluorescent detection system in combination with a hinge-like dual-channel 3D microfluidic paper analytical device (3D µPAD) for simultaneous visual detection of carbaryl and glyphosate. Blue-emission 1-naphthol (Em. 470 nm) was hydrolyzed from carbaryl, while yellow-emission 2,3-diaminophenazine (Em. 570 nm) was produced with the aid of Cu2+ for glyphosate sensing. Inner-filter effect between 1-naphthol or 2,3-diaminophenazine and green-emission carbon dots (Em. 510 nm) realized two ratiometric fluorescent detection systems. Remarkable color variation of green-blue for carbaryl (50.00-1100 µΜ) and yellow-green for glyphosate (5.00-600 µΜ) were observed on a dual-channel 3D µPAD without crosstalk. Their detection limits were 1.11 and 0.63 µΜ, respectively. The strategy realized simultaneous visual detection of carbaryl and glyphosate in food/herbal with excellent accuracy (spiked recoveries, 91.00-107.2%), high precision (RSD ≤ 8.43%), and superior selectivity.

Mutant p53 leads to low-grade IFN-I-induced inflammation and impairs cGAS-STING signalling in mice.

Type I interferons (IFN-Is) are a class of proinflammatory cytokines produced in response to viruses and environmental stimulations, resulting in chronic inflammation and even carcinogenesis. However, the connection between IFN-I and p53 mutation is poorly understood. Here, we investigated IFN-I status in the context of mutant p53 (p53N236S , p53S). We observed significant cytosolic double-stranded DNA (dsDNA) derived from nuclear heterochromatin in p53S cells, along with an increased expression of IFN-stimulated genes. Further study revealed that p53S promoted cyclic GMP-AMP synthase (cGAS) and IFN-regulatory factor 9 (IRF9) expression, thus activating the IFN-I pathway. However, p53S/S mice were more susceptible to herpes simplex virus 1 infection, and the cGAS-stimulator of IFN genes (STING) pathway showed a decline trend in p53S cells in response to poly(dA:dT) accompanied with decreased IFN-ß and IFN-stimulated genes, whereas the IRF9 increased in response to IFN-ß stimulation. Our results illustrated the p53S mutation leads to low-grade IFN-I-induced inflammation via consistent low activation of the cGAS-STING-IFN-I axis, and STAT1-IRF9 pathway, therefore, impairs the protective cGAS-STING signalling and IFN-I response encountered with exogenous DNA attack. These results suggested the dual molecular mechanisms of p53S mutation in inflammation regulation. Our results could be helping in further understanding of mutant p53 function in chronic inflammation and provide information for developing new therapeutic strategies for chronic inflammatory diseases or cancer.

CaCl2 treatment effectively delays postharvest senescence of passion fruit.

This study aimed to systematically investigate the changes in peel color, physicochemical characteristics, textural properties, and peel ultrastructure between CaCl2-treated and water-soaked passion fruit under short-term storage at room temperature (20 °C) for eight days. The fruit peel was further analyzed and compared for the differences in calmodulin (CaM) gene expression between the two groups. The data were analyzed using principal component analysis. The results confirmed that CaCl2 treatment effectively maintained the appearance and color of passion fruit, inhibited peel browning, and improved fruit quality. The treatment had an effect on maintaining the physiological properties of passion fruit parenchyma, effectively delayed the passion fruit senescence, and kept the structural integrity of the fruit peel. The relative expression of PeCaM gene in the CaCl2-treated fruit peels was higher than that of the control peels. The Ca2+ stimulated the relative expression of the PeCaM gene, which delayed the senescence of passion fruit.

SMPD1 expression profile and mutation landscape help decipher genotype-phenotype association and precision diagnosis for acid sphingomyelinase deficiency.

BACKGROUND: Acid sphingomyelinase deficiency (ASMD) disorder, also known as Niemann-Pick disease (NPD) is a rare genetic disease caused by mutations in SMPD1 gene, which encodes sphingomyelin phosphodiesterase (ASM). Except for liver and spleen enlargement and lung disease, two subtypes (Type A and B) of NDP have different onset times, survival times, ASM activities, and neurological abnormalities. To comprehensively explore NPD's genotype-phenotype association and pathophysiological characteristics, we collected 144 NPD cases with strict quality control through literature mining. RESULTS: The difference in ASM activity can differentiate NPD type A from other subtypes, with the ratio of ASM activity to the reference values being lower in type A (threshold 0.045 (4.45%)). Severe variations, such as deletion and insertion, can cause complete loss of ASM function, leading to type A, whereas relatively mild missense mutations generally result in type B. Among reported mutations, the p.Arg3AlafsX76 mutation is highly prevalent in the Chinese population, and the p.R608del mutation is common in Mediterranean countries. The expression profiles of SMPD1 from GTEx and single-cell RNA sequencing data of multiple fetal tissues showed that high expressions of SMPD1 can be observed in the liver, spleen, and brain tissues of adults and hepatoblasts, hematopoietic stem cells, STC2_TLX1-positive cells, mesothelial cells of the spleen, vascular endothelial cells of the cerebellum and the cerebrum of fetuses, indicating that SMPD1 dysfunction is highly likely to have a significant effect on the function of those cell types during development and the clinicians need pay attention to these organs or tissues as well during diagnosis. In addition, we also predicted 21 new pathogenic mutations in the SMPD1 gene that potentially cause the NPD, signifying that more rare cases will be detected with those mutations in SMPD1. Finally, we also analysed the function of the NPD type A cells following the extracellular milieu. CONCLUSIONS: Our study is the first to elucidate the effects of SMPD1 mutation on cell types and at the tissue level, which provides new insights into the genotype-phenotype association and can help in the precise diagnosis of NPD.

Prognostic value of PNN in prostate cancer and its correlation with therapeutic significance.

Prostate cancer (PCa) is the most common malignancy. New biomarkers are in demand to facilitate the management. The role of the pinin protein (encoded by PNN gene) in PCa has not been thoroughly explored yet. Using The Cancer Genome Atlas (TCGA-PCa) dataset validated with Gene Expression Omnibus (GEO) and protein expression data retrieved from the Human Protein Atlas, the prognostic and diagnostic values of PNN were studied. Highly co-expressed genes with PNN (HCEG) were constructed for pathway enrichment analysis and drug prediction. A prognostic signature based on methylation status using HCEG was constructed. Gene set enrichment analysis (GSEA) and the TISIDB database were utilised to analyse the associations between PNN and tumour-infiltrating immune cells. The upregulated PNN expression in PCa at both transcription and protein levels suggests its potential as an independent prognostic factor of PCa. Analyses of the PNN's co-expression network indicated that PNN plays a role in RNA splicing and spliceosomes. The prognostic methylation signature demonstrated good performance for progression-free survival. Finally, our results showed that the PNN gene was involved in splicing-related pathways in PCa and identified as a potential biomarker for PCa.

The genome of single-petal jasmine (Jasminum sambac) provides insights into heat stress tolerance and aroma compound biosynthesis.

Jasmine [Jasminum sambac (L.) Aiton] is a commercially important cultivated plant species known for its fragrant flowers used in the perfume industry, medicine and cosmetics. In the present study, we obtained a draft genome for the J. sambac cultivar 'Danbanmoli' (JSDB, a single-petal phenotype). We showed that the final genome of J. sambac was 520.80 Mb in size (contig N50 = 145.43 kb; scaffold N50 = 145.53 kb) and comprised 35,363 genes. Our analyses revealed that the J. sambac genome has undergone only an ancient whole-genome duplication (WGD) event. We estimated that the lineage that has given rise to J. sambac diverged from the lineage leading to Osmanthus fragrans and Olea europaea approximately 31.1 million years ago (Mya). On the basis of a combination of genomic and transcriptomic analyses, we identified 92 transcription factors (TFs) and 206 genes related to heat stress response. Base on a combination of genomic, transcriptomic and metabolomic analyses, a range of aroma compounds and genes involved in the benzenoid/phenylpropanoid and terpenoid biosynthesis pathways were identified. In the newly assembled J. sambac genome, we identified a total of 122 MYB, 122 bHLH and 69 WRKY genes. Our assembled J. sambac JSDB genome provides fundamental knowledge to study the molecular mechanism of heat stress tolerance, and improve jasmine flowers and dissect its fragrance.

Melatonin treatment improves postharvest quality and regulates reactive oxygen species metabolism in "Feizixiao" litchi based on principal component analysis.

Postharvest quality of litchi reduces rapidly during storage at room temperature. This study aimed to investigate the effect of melatonin treatment on postharvest quality and oxidative stress markers of litchi fruit during cold storage. The "Feizixiao" litchi was treated with melatonin solution concentrations of 0.2 and 0.6 mmol·L-1 and then stored at 4°C for 12 days. The results confirmed that the melatonin treatment effectively maintained the appearance and color of the litchi fruit, suppressed the peel browning, and improved the litchi quality. The treatment also significantly enhanced the levels of endogenous melatonin, antioxidant components (total phenolics, flavonoids, and anthocyanin), and antioxidant enzyme activities of the fruit. It also inhibited the other oxidative stress markers, such as O 2 - , H2O2, MDA, and protein carbonyl content, and upregulated the expressions of antioxidant and Msr-related genes. Correlation and principal component analyses further confirmed that the melatonin treatment effectively delayed the fruit senescence by enhancing the antioxidant enzyme activities and modulating peel browning and reactive oxygen species metabolism of the litchi fruit via regulating gene expression of the related enzymes (SOD and PPO). These findings suggested that the exogenous application of melatonin to litchi during the postharvest is an ideal way to preserve the fruit quality and delay fruit senescence.

Comparative physiology and transcriptome analysis reveals that chloroplast development influences silver-white leaf color formation in Hydrangea macrophylla var. maculata.

BACKGROUND: Hydrangea macrophylla var. Maculata 'Yinbianxiuqiu' (YB) is an excellent plant species with beautiful flowers and leaves with silvery white edges. However, there are few reports on its leaf color characteristics and color formation mechanism. RESULTS: The present study compared the phenotypic, physiological and transcriptomic differences between YB and a full-green leaf mutant (YM) obtained from YB. The results showed that YB and YM had similar genetic backgrounds, but photosynthesis was reduced in YB. The contents of pigments were significantly decreased at the edges of YB leaves compared to YM leaves. The ultrastructure of chloroplasts in the YB leaves was irregular. Transcriptome profiling identified 7,023 differentially expressed genes between YB and YM. The expression levels of genes involved in photosynthesis, chloroplast development and division were different between YB and YM. Quantitative real-time PCR showed that the expression trends were generally consistent with the transcriptome data. CONCLUSIONS: Taken together, the formation of the silvery white leaf color of H. macrophylla var. maculata was primarily due to the abnormal development of chloroplasts. This study facilitates the molecular function analysis of key genes involved in chloroplast development and provides new insights into the molecular mechanisms involved in leaf coloration in H. macrophylla.

Biochemistry and transcriptome analyses reveal key genes and pathways involved in high-aluminum stress response and tolerance in hydrangea sepals.

Hydrangea [Hydrangea macrophylla (Thunb.) Ser.] is a high aluminum-tolerant ornamental plant species, which has a specific characteristic of color change, ie. some cultivars' floral color will change from red to blue or blue-violet planted in acidic soil containing aluminum. This study aims to understand the complex molecular mechanisms of floral color change under Al stress, through comparative biochemistry and transcriptome analyses between an Al3+-sensitive cultivar 'Bailer' and insensitive cultivar 'Ruby' under Al-stress. The results of biochemistry analysis showed that 'Bailer' displayed higher contents of Al3+ and delphinium-3-O-glucoside than that of 'Ruby' after Al2(SO4)3 treating. Meanwhile, the transcriptome analysis of different tissues identified 12,321 differentially expressed genes (DEGs) in 'Bailer' and 6,703 in 'Ruby'. Transcriptome analysis showed that changes in genes' expression pattern in several genes and pathways [such as including metal transporters, reactive oxygen species (ROS) scavenging enzyme, plant hormone signal transduction and favonoid biosynthesis pathway] were the key contributors to the Al3+-sensitive cultivar 'Bailer'. Besides, gene co-expression network analysis (WGCNA) demonstrated that five hub genes, including ABC transporters (TRINITY_DN1053_c0_g1, TRINITY_DN3377_c0_g2), cationic amino acid transporter (TRINITY_DN9684_c0_g2), oligopeptide transporter (TRINITY_DN1147_c0_g2) and flavonol synthase (TRINITY_DN15902_c0_g1), played vital roles in the networks regulating Al tolerance in hydrangea. Furthermore, HmABCI17's (TRINITY_DN1053_c0_g1) expression enhanced Al tolerance in yeast. The conclusions of this study are helpful to elucidate the differences and molecular mechanisms of different hydrangea cultivars on Al tolerance, and provide new insights into molecular assisted-screening for breeding blue flowers in hydrangea and other ornamental plants.

Identification of aluminum-activated malate transporters (ALMT) family genes in hydrangea and functional characterization of HmALMT5/9/11 under aluminum stress.

Hydrangea (Hydrangea macrophylla (Thunb.) Ser.) is a famous ornamental plant species with high resistance to aluminum (Al). The aluminum-activated malate transporter (ALMT) family encodes anion channels, which participate in many physiological processes, such as Al tolerance, pH regulation, stomatal movement, and mineral nutrition. However, systematic studies on the gene family have not been reported in hydrangea. In this study, 11 candidate ALMT family members were identified from the transcriptome data for hydrangea, which could be divided into three clusters according to the phylogenetic tree. The protein physicochemical properties, phylogeny, conserved motifs and protein structure were analyzed. The distribution of base conservative motifs of HmALMTs was consistent with that of other species, with a highly conserved WEP motif. Furthermore, tissue-specific analysis showed that most of the HmALMTs were highly expressed in the stem under Al treatment. In addition, overexpression of HmALMT5, HmALMT9 and HmALMT11 in yeasts enhanced their tolerance to Al stress. Therefore, the above results reveal the functional role of HmALMTs underlying the Al tolerance of hydrangea. The present study provides a reference for further research to elucidate the functional mechanism and expression regulation of the ALMT gene family in hydrangea.

An integrated transcriptomic and proteomic approach to dynamically study the mechanism of pollen-pistil interactions during jasmine crossing.

Jasmine (Jasminum sambac Aiton, Oleaceae) flowers are widely consumed in many countries for their tea-making, medicinal and ornamental properties. To improve the quality and yield of flowers, it is very important to carry out cross-breeding between different petal types of jasmine. However, because of the difficulty of sexual reproduction, there is no report on the success of jasmine crosses. In this paper, single- and double-petal jasmine plants were crossed artificially. The stigmas of single-petal plants post pollination, including those at 0 h after pollination (CK), 1 h after pollination (T1) and 6 h after pollination (T2), were sequenced by transcriptomic combined with proteomic analyses. A total of 178,098 gene products were assembled. Simultaneously, a total of 2337 protein species were identified. Some regulatory gene products and functional protein species were identified that may be involved in the process of pollen-pistil interactions. These findings suggest that the identified differentially expressed gene products and differentially accumulated protein species may play vital roles in jasmine plants in response to pollen-pistil interactions, providing important genetic resources for further functional dissection of the molecular mechanisms of these interactions. SIGNIFICANCE: These results have important scientific significance to take effective measures to overcome pre-fertilization barriers and to guide the cross breeding of jasmine. Further, they can also be used for reference in other plant breeding with the same fertilization barriers.

Multi-omics approaches identify SF3B3 and SIRT3 as candidate autophagic regulators and druggable targets in invasive breast carcinoma.

Autophagy is a critical cellular homeostatic mechanism, and its dysfunction is linked to invasive breast carcinoma (BRCA). Recently, several omics methods have been applied to explore autophagic regulators in BRCA; however, more reliable and robust approaches for identifying crucial regulators and druggable targets remain to be discovered. Thus, we report here the results of multi-omics approaches to identify potential autophagic regulators in BRCA, including gene expression (EXP), DNA methylation (MET) and copy number alterations (CNAs) from The Cancer Genome Atlas (TCGA). Newly identified candidate genes, such as SF3B3, TRAPPC10, SIRT3, MTERFD1, and FBXO5, were confirmed to be involved in the positive or negative regulation of autophagy in BRCA. SF3B3 was identified firstly as a negative autophagic regulator, and siRNA/shRNA-SF3B3 were shown to induce autophagy-associated cell death in in vitro and in vivo breast cancer models. Moreover, a novel small-molecule activator of SIRT3, 1-methylbenzylamino amiodarone, was discovered to induce autophagy in vitro and in vivo. Together, these results provide multi-omics approaches to identify some key candidate autophagic regulators, such as the negative regulator SF3B3 and positive regulator SIRT3 in BRCA, and highlight SF3B3 and SIRT3 as new druggable targets that could be used to fill the gap between autophagy and cancer drug development.

Cytosolic dsDNA is a novel senescence marker associated with pyroptosis activation.

Cellular senescence has become a research focus because of its dual roles in ageing and tumorigenesis. The biomarkers of senescence are essential for detecting senescent cells and understanding the ageing process and its regulation. Here, we identify cytosolic double-stranded DNA (dsDNA) as a novel sensitive biomarker for cellular senescence of mouse embryonic fibroblasts (MEFs) in response to common types of stimuli, including replicative stress, genetic modification and oxidative stress. We found that the accumulation of cytosolic dsDNA was positively correlated with the senescence process in MEFs and was detectable earlier than senescence-associated ß-galactosidase (SA-ß-Gal) staining, which is the current gold standard for senescence detection. Due to the immunogenicity of dsDNA, we further investigated the stimulation of two dsDNA sensors, cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) (cGAMP) synthase (cGAS) and absent in melanoma-2 (AIM2). The results showed that the cGAS protein level did not significantly change upon senescence stimulation, while AIM2 expression was significantly upregulated in senescent cells. Surprisingly, we found that ageing-related cytosolic dsDNA induced significant pyroptosis activation in the senescent MEFs. These data reveal novel easy-to-detect biomarker for cellular senescence. The activation of downstream immunological response pathways might add new experimental evidence for inflammatory ageing.

Preparation of three-dimensional palygorskite based carrier.

Palygorskite is a kind of crystalline hydrated magnesium aluminum silicate mineral with micro-fibrous morphology. Due to the large specific surface area, moderate cationic exchange capacity and pronounced adsorption properties, it has been widely used in many fields. In order to enhance the loading capacity and adjust the microstructure of palygorskite (Pal) crystal, series of three-dimensional palygorskite carriers (3D Pal) with different pore size were fabricated through grafting from or grafting onto method. Due to the functional and cross-linked molecules act as upholder reagents, the specific surface of individual palygorskite is fully utilized and the load capacity is greatly improved. The porosity and pore size of 3D palygorskite based carrier also can be regulated by the length of organic molecular chain segments. The successful preparation of 3D Pal-based carrier provides a new way for surface grafting, modification or preparing 3D carrier of palygorskite and other minerals.•The developed method allows fabricating three-dimensional palygorskite based carriers by covalent bonding method.•The pore size of the as-prepared carriers can be conveniently adjusted by length of the bonded molecular chain.

The triggers of the cGAS-STING pathway and the connection with inflammatory and autoimmune diseases.

Cyclic GMP-AMP synthase (cGAS) is a cytosolic nucleic acid sensor that can bind to dsDNA. It maintains an autoinhibited state in the absence of cytosolic dsDNA, while when activated, it in turn activates its adaptor protein STING, ultimately triggering a cascade that produces inflammatory cytokines and type I interferons (IFNs). With further research, additional types of nucleic acids have been found to be activators of the cGAS-STING pathway. The cGAS-STING pathway can provide protection or resistance against infections; however, improper or overactivation might cause severe inflammatory pathologies, including autoimmunity. This article systematically reviews the latest research progress on the axis, including categorical pathway triggers, the connection with autoimmune disease and drug therapy progress.

Integrating multiple omics data for the discovery of potential Beclin-1 interactions in breast cancer.

Breast cancer has been reported as one of the most frequently diagnosed malignant diseases and the leading cause of cancer death in women all around the world. Furthermore, this complicated cancer is divided into multiple subtypes which present different clinical symptoms and need correspondingly directed therapy. We took BECN1, a core gene in autophagy performing a tumor inhibitory effect, as a starting point. The study in this paper aims to identify genes related to breast cancer and its multiple subtypes by integrating multiple omics data using the least absolute shrinkage and selection operator (LASSO), which is a statistical method that can integrate more than two types of omics data. All the data is obtained from The Cancer Genome Atlas (TCGA) platform which stores clinical and molecular tumor data. The model constructed is based on three kinds of data including mRNA-gene expression with a dependent variable level, DNA methylation and copy number alterations as independent variables. Finally, we propose four subnets of four subtypes of breast cancer, and consider as a result of microarray analysis that AFF3 is associated with BECN1 in breast cancer, and may be a potential therapeutic target. This finding may provide some potential targeted therapeutics for the four different subtypes of breast cancer at the genetic level. In conclusion, finding out the major role Beclin-1 plays in breast cancer subtypes is of great value. The results obtained are instructive for further research and may provide excellent results in clinical applications, as well as testing in animal experiments, and may also indicate a new method to perform bioinformatics analysis.

Systematic network-based discovery of a Fam20C inhibitor (FL-1607) with apoptosis modulation in triple-negative breast cancer.

Family with sequence similarity 20, member C (Fam20C) is a physiological Golgi casein kinase that phosphorylates multiple secreted proteins. Recently, it has been reported that Fam20C can be identified as a novel kinase target for therapeutic development. Thus, inhibition of Fam20C will be a potential therapeutic strategy to prevent tumor cell progression and metastasis. In our study, based upon the systems-biology network, molecular modeling and molecular dynamics (MD) simulations, we discovered a novel Fam20C inhibitor (FL-1607) with potent anti-proliferative effects on triple-negative breast cancer (TNBC) cells. Subsequently, we found that this Fam20C inhibitor could induce apoptosis and inhibit cell migration in MDA-MB-468 cells. Together, these findings would provide a new clue to the exploration of more novel Fam20C inhibitors for future TNBC therapy.