A New Quinazolinone Alkaloid along with Known Compounds with Seed-Germination-Promoting Activity from Rhodiola tibetica Endophytic Fungus Penicillium sp. HJT-A-6.

A new quinazolinone alkaloid named peniquinazolinone A (1), as well as eleven known compounds, 2-(2-hydroxy-3-phenylpropionamido)-N-methylbenzamide (2), viridicatin (3), viridicatol (4), (±)-cyclopeptin (5a/5b), dehydrocyclopeptin (6), cyclopenin (7), cyclopenol (8), methyl-indole-3-carboxylate (9), 2,5-dihydroxyphenyl acetate (10), methyl m-hydroxyphenylacetate (11), and conidiogenone B (12), were isolated from the endophytic Penicillium sp. HJT-A-6. The chemical structures of all the compounds were elucidated by comprehensive spectroscopic analysis, including 1D and 2D NMR and HRESIMS. The absolute configuration at C-13 of peniquinazolinone A (1) was established by applying the modified Mosher's method. Compounds 2, 3, and 7 exhibited an optimal promoting effect on the seed germination of Rhodiola tibetica at a concentration of 0.01 mg/mL, while the optimal concentration for compounds 4 and 9 to promote Rhodiola tibetica seed germination was 0.001 mg/mL. Compound 12 showed optimal seed-germination-promoting activity at a concentration of 0.1 mg/mL. Compared with the positive drug 6-benzyladenine (6-BA), compounds 2, 3, 4, 7, 9, and 12 could extend the seed germination period of Rhodiola tibetica up to the 11th day.

Enhancing oncolytic virus efficiency with methionine and N-(3-aminoprolil)methacrylamide modified acrylamide cationic block polymer.

Oncolytic virus ablation of tumor cells has the advantages of high tumor selectivity, strong immunogenicity, and low side effects. However, the recognition and clearance of oncolytic viruses by the immune system are the main factors limiting their anti-tumor efficiency. As a highly biosafe and highly modifiable oncolytic virus vector, acrylamide can improve the long-term circulation of oncolytic viruses. Still, it is limited in its uptake efficiency by tumor cells. Herein, we constructed an N-hydroxymethyl acrylamide-b-(N-3-aminopropyl methacrylamide)-b-DMC block copolymer (NMA-b-APMA-b-DMA, NAD) as an oncolytic virus carrier, which not only improves the long-term circulation of oncolytic viruses in the body but also shows excellent stability for loading an oncolytic virus. The data shows that there was no obvious difference in the transfection effect of the NAD/Ad complex with or without neutralizing antibodies in the medium, which meant that the cationic carrier mediated by NAD/Ad had good serum stability. Only 10 micrograms of NAD carrier are needed to load the oncolytic virus, which can increase the transfection efficiency by 50 times. Cell experiments and mouse animal experiments show that NAD vectors can significantly enhance the anti-tumor effect of oncolytic viruses. We hope that this work will promote the application of acrylamide as an oncolytic virus vector and provide new ideas for methods to modify acrylamide for biomedical applications.

Camptothecin enhances the anti-tumor effect of low-dose apatinib combined with PD-1 inhibitor on hepatocellular carcinoma.

Apatinib has been shown to apply to a variety of solid tumors, including advanced hepatocellular carcinoma. Preclinical and preliminary clinical results confirmed the synergistic antitumor effects of apatinib in combination with anti-programmed death-1 (PD-1) inhibitors. In this study, we investigated camptothecin (CPT) enhances the anti-tumor effect of low-dose apatinib combined with PD-1 inhibitor on hepatocellular carcinoma. CPT combined with a PD-1 inhibitor enhances the anti-tumor effects of low-dose apatinib in hepatocellular carcinoma which was evaluated in making use of the H22 mouse model (n = 32), which was divided into four groups. Immunohistochemical staining and western blotting were used to detect nuclear factor erythroid 2-related factor 2 (Nrf2) as well as sequestosome 1 (p62), vascular endothelial growth factor A (VEGFA), vascular endothelial growth factor receptor 2 (VEGFR2), PD-1, and programmed cell death ligand 1 (PD-L1). The results showed that the average size of the tumor of the combination group (Group D) was significantly less than that of the apatinib + PD-1 inhibitor group (Group C). The expression levels of Nrf2, p62, VEGFA, VEGFR2, PD-1, and PD-L1 in the apatinib + PD-1 inhibitor group(Group C) were lower than those in the control group (Group A) (P < 0.05). The expression levels of these genes in the apatinib + PD-1 inhibitor group (Group C) were significantly lower in the combination group (Group D) (P < 0.05). There was no obvious difference in body weight and liver and kidney functions between the four groups of mice. In conclusion, CPT improves the anti-tumor effect of low-dose apatinib combined with PD-1 inhibitor on hepatocellular carcinoma.

The Fungal Diversity and Potential Pathogens Associated with Postharvest Fruit Rot of 'Huangguan' Pear (Pyrus bretschneideri) in Hebei Province, China.

Postharvest fruit rot caused by pathogens is a serious problem in the pear industry. This study investigated the fungal diversity and main pathogens and identified a new pathogen in the stored 'Huangguan' pear (Pyrus bretschneideri Rehd.), the dominant pear variety in northern China. We sampled 20 refrigeration houses from five main producing regions in Hebei Province and used Illumina sequencing technology to detect the fungal composition. Alternaria (56.3%) was the most abundant fungus, followed by Penicillium (9.2%) and Monilinia (6.2%). We also isolated and identified nine strains of Alternaria and four strains of Penicillium. Moreover, we observed a new postharvest fruit disease in 'Huangguan' pear caused by Stemphylium eturmiunum, which was confirmed by phylogenetic analysis by combining the sequences of three conserved genes, including internal transcribed spacer, gapdh, and calmodulin. This study marks the first documentation of S. eturmiunum causing fruit rot in 'Huangguan' pears, offering valuable insights for identifying and controlling this newly identified postharvest disease.

Clinical characteristics and prognosis in systemic lupus erythematosus-associated pulmonary arterial hypertension based on consensus clustering and risk prediction model.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a severe complication of systemic lupus erythematosus (SLE). This study aims to explore the clinical characteristics and prognosis in SLE-PAH based on consensus clustering and risk prediction model. METHODS: A total of 205 PAH (including 163 SLE-PAH and 42 idiopathic PAH) patients were enrolled retrospectively based on medical records at the First Affiliated Hospital of Zhengzhou University from July 2014 to June 2021. Unsupervised consensus clustering was used to identify SLE-PAH subtypes that best represent the data pattern. The Kaplan-Meier survival was analyzed in different subtypes. Besides, the least absolute shrinkage and selection operator combined with Cox proportional hazards regression model were performed to construct the SLE-PAH risk prediction model. RESULTS: Clustering analysis defined two subtypes, cluster 1 (n = 134) and cluster 2 (n = 29). Compared with cluster 1, SLE-PAH patients in cluster 2 had less favorable levels of poor cardiac, kidney, and coagulation function markers, with higher SLE disease activity, less frequency of PAH medications, and lower survival rate within 2 years (86.2% vs. 92.8%) (P < 0.05). The risk prediction model was also constructed, including older age at diagnosis (≥ 38 years), anti-dsDNA antibody, neuropsychiatric lupus, and platelet distribution width (PDW). CONCLUSIONS: Consensus clustering identified two distinct SLE-PAH subtypes which were associated with survival outcomes. Four prognostic factors for death were discovered to construct the SLE-PAH risk prediction model.

The Microbial Diversity in Relation to Postharvest Quality and Decay: Organic vs. Conventional Pear Fruit.

(1) Background: Organic food produced in environmentally friendly farming systems has become increasingly popular. (2) Methods: We used a DNA metabarcoding approach to investigate the differences in the microbial community between organic and conventional 'Huangguan' pear fruit; and (3) Results: Compared to a conventional orchard, the fruit firmness in the organic orchard had significantly lowered after 30 days of shelf-life storage at 25 °C, and the soluble solids content (SSC), titratable acid (TA), and decay index were higher. There were differences in the microbial diversity between organic and conventional orchards pears. After 30 days of storage, Fusarium and Starmerella became the main epiphytic fungi in organic fruits, while Meyerozyma was dominant in conventional fruits. Gluconobacter, Acetobacter, and Komagataeibacter were dominant epiphytic bacteria on pears from both organic and conventional orchards after a 30-day storage period. Bacteroides, Muribaculaceae, and Nesterenkonia were the main endophytic bacteria throughout storage. There was a negative correlation between fruit firmness and decay index. Moreover, the abundance of Acetobacter and Starmerella were positively correlated with fruit firmness, while Muribaculaceae was negatively correlated, implying that these three microorganisms may be associated with the postharvest decay of organic fruit; (4) Conclusions: The difference in postharvest quality and decay in organic and conventional fruits could potentially be attributed to the variation in the microbial community during storage.

Carboxyl-containing components delineation via feature-based molecular networking: A key to processing conditions of fermented soybean.

Carboxyl-containing components (CCCs) was the key chemical markers for fermented soybean, whose composition and content would be dramatically changed during the fermentation processes. To select the optimal fermented conditions, a rapid and sensitive 5-(diisopropylamino)amylamine derivatization, ultra-high performance liquid chromatography-quadrupole-time-of-flight/mass spectrometry and feature-based molecular networking method was established for determination CCCs and the developed method was successfully applied to compare the dynamic changes of CCCs under different processing conditions. A total of 120 components were identified, the optimum fermentation conditions were the temperature at 30 °C, 50% humidity, with a 2-hour steaming time. Sixteen chemical markers with significant differences were screened. Furthermore, molecular docking technology was used to verify the antiperoxidative effect of these chemical markers. Accordingly, we focused on the high-content, little-studied active CCCs rather than the low-content and well-studied flavonoids. This study was helpful for the nutraceutical development and contributed scientific basis to further exploring quality evaluation of fermented food.

Lactobacillus paracasei TK1501 fermented soybeans alleviate dextran sulfate sodium-induced colitis by regulating intestinal cell function.

BACKGROUND: Probiotic food provide health benefits by regulating intestinal floras via live bacteria, but the shelf life is short and the preservation condition is demanding due to the bacteria being fragile. Owing to these problems, we have tried to find a fermented food that is helpful for inflammatory bowel disease treatment but independent of live bacteria. In addition, the mechanisms of fermented food were investigated. Dextran sulfate sodium was used to model inflammatory bowel disease in mice, and Lactobacillus paracasei TK1501 fermented soybeans and their metabolites were used to treat inflammatory bowel disease. RESULTS: In this study, TK1501 fermented soybean alleviated colitis. However, the efficacy was associated with bacterial metabolites but not live or dead bacteria. Compositional analysis of soybean before and after fermentation shows that soy carbohydrates were used for bacteria growth and produced functional substances. Further, we display the main active ingredient was lipoteichoic acid and peptidoglycan, because lipoteichoic acid reduced the colonic macrophage and peptidoglycan may increase the mucin-2 expression. A cell experiment displayed that lipoteichoic acid could enhance the phagocytosis of macrophages. CONCLUSION: In general, TK1501 fermented soybean alleviating colitis is dependent on metabolites of TK1501, particularly lipoteichoic acid and peptidoglycan. The fermented food may have a long shelf life and lax storage condition. © 2023 Society of Chemical Industry.

Gut microbiota mediates the pharmacokinetics of Zhi-zi-chi decoction for the personalized treatment of depression.

ETHNOPHARMACOLOGICAL RELEVANCE: Zhi-zi-chi decoction (ZZCD), from "Treatise on Febrile Diseases", is a typical traditional Chinese medicine herb pair, which consists of Gardeniae Fructus (GF) and Semen Sojae Praeparatu (SSP). In clinical research, ZZCD was widely used to fight depression, remove annoyance. Many studies have reported that gut microbiota is critical target for the influence of depress through gut-brain axis, and our previously studies have found that ZZCD exhibiting antidepressant effect was through the gut-brain axis. However, the specific mechanism by which gut microbiota mediates the pharmacokinetics parameters of active compounds from ZZCD during the process of depression treatment has not yet been studied. AIM OF THE STUDY: To explore the differences in pharmacokinetics characters of bioactive iridoids from ZZCD and study the changes of gut microbiota at different stages of depression with the personalized medicine of ZZCD. MATERIALS AND METHODS: A new strategy exploring the relationship among disease phenotypes (D), intestinal microbiota (I), enzymes (E) and traits of metabolism (T) named as "DIET" was established. Firstly, a fast, selective and sensitive ultra-performance liquid chromatography coupled with tandem mass spectrometer (UPLC-MS/MS) was established and validated to quality the main bioactive compounds from ZZCD and compare the pharmacokinetics and bioavailability of different iridoids prototypes and metabolites from ZZCD between normal and chronic unpredictable mild stress rats. Subsequently, the activity of corresponding metabolic enzymes of anti-depressive compounds, ß-glucosidases and sulfotransferases, were analyzed by ρ-nitrophenyl-ß -D-glucopyranoside and sulfotransferases ELISA kits, respectively. Finally, 16S rRNA gene sequencing was adopt to analyze intestinal bacteria composition for the treatment of depression by ZZCD. RESULTS: The antidepressant effect of ZZCD was promoted due to the increased exposures and reduced eliminations of anti-depressive compounds, especially geniposide and genipin 1-gentiobioside, under the depression state. With the ZZCD treatment, the depression was improved, but the exposures of anti-depressive compounds from ZZCD gradually decreased. Meanwhile, there were the corresponding decreased trends on the activity of ß-glucosidases and sulfotransferases. With the consumption of ZZDC and the improvement of depression, the exposures of anti-depressive iridoid glycosides decreased and the activity of metabolism enzymes restored. Meanwhile, the dysbiosis of pathogenic bacteria (Bacteroidota) induced by depression was ameliorated and the probiotics (Firmicutes) at the phylum and genus level raised, the two phyla are closely related to the production of ß-glucosidase and sulfotransferases. CONCLUSIONS: It is the first proposed that ZZCD could personalized to treat depression at different stages targeting gut microbiota and gut microbiome could emerged as a potential diagnostic and therapeutic biomarker in depression.

Fruit bagging reduces the postharvest decay and alters the diversity of fruit surface fungal community in 'Yali' pear.

BACKGROUND: Fruit bagging is an effective technique for fruit protection in the orchard management. Bagging can create a micro-environment for fruit growth and affect fruit quality during storage, in which the diversity of microorganisms may play an important role. Therefore, various methods including biochemistry, analytical chemistry, and bioinformatics methods were used to reveal the influences of fruit bagging on postharvest fruit quality, physiological characters, decay and surface fungal community of 'Yali' pear fruit were investigated in this study. RESULTS: Fruit bagging significantly decreased the postharvest decay after 15 days of ambient storage. There were no significant differences in fruit firmness, titratable acid and ethylene production rate between the fruit-bagging and non-bagging group after 15 days of storage, while the soluble solids contents (SSC) and respiration rate in non-bagging fruit was significantly higher than that in fruit-bagging after 15 days of storage. Furthermore, the surface microbes of pear were collected and determined by the new generation sequencing technology. The alpha diversity of fungi in non-bagging fruit decreased significantly after 15 days of storage, while there were no significant changes in bagging fruit. Ascomycota and Basidiomycota were the two major phyla detected in the bagging fruit, and the dominant fungal genera were Alternaria (23.7%), Mycosphaerella (17.25%), Vishniacozyma (16.14%), and Aureobasidium (10.51%) after 15 days of storage. For the non-bagging pear, Ascomycota was the only phylum detected, and the dominant genera was Pichia (83.32%) after 15 days of storage. The abundance of Pichia may be regarded as the biomarker to indicate the degree of fruit decay. CONCLUSIONS: This study showed that fruit bagging could significantly reduce postharvest fruit decay and respiration rate of 'Yali' pear. Significant differences were found in fungal composition between bagging and non-bagging pear after storage for 0 or 15 days. Fruit bagging maintained the diversity of fungi on the fruit surface, increased the abundance of non-pathogenic fungi, and even antagonistic fungi such as Aureobasidium, Vishniacozyma, and Mycosphaerella. A reduction in the abundance of pathogenic fungi and incidence of postharvest decay during the storage of 'Yali' pear were also recorded. In conclusion, fruit-bagging changed the fungal diversity on fruit surface of 'Yali' pear, which had significant effect on reducing postharvest fruit decay, and thus prolong the storage period of 'Yali' pears. The future thrust of this study will focus on the isolation of fungi or bacteria from pear fruit surface and identify their roles in causing fruit decay and changing fruit quality during storage.

Mycotoxin Production and the Relationship between Microbial Diversity and Mycotoxins in Pyrus bretschneideri Rehd cv. Huangguan Pear.

Mycotoxins are generated by a series of fungal pathogens in postharvest fruit, resulting in serious health threat to consumers and great economic loss to the fruit storage industry. The microbial differences between rotten and healthy fruit during storage and their relationship with mycotoxin production have not been fully studied. In this study, differences in microbial diversity between rotten and healthy fruit after 30 days of storage at ambient temperature were investigated using high-throughput sequencing technology in 'Huangguan' pear (Pyrus bretschneideri Rehd cv. Huangguan) harvested from five different producing regions of Hebei province, China. The bacterial genus Gluconobacter was much more abundant in rotten fruit (76.24%) than that in healthy fruit (32.36%). In addition, Komagataeibacter and Acetobacter were also relatively higher in abundance in rotten fruit. In contrast, bacterial genera Pantoea, Alistipes, Muribaculaceae, Lactobacillus, and Ruminococcaceae_UCG were found to be more abundant in healthy fruit. Fungal genera including Botryosphaeria, Colletotrichum, Valsa, Alternaria, Rosellinia, Fusarium, and Trichothecium were found to be abundant in rotten fruit. The results of principal coordinate analysis (PCoA) showed that there were significant differences in the microbial diversity of different regions. PAT (patulin) was detected in all rotten fruit samples, while tenuazonic acid (TeA), alternariol (AOH), and alternariolmonomethyl ether (AME) were only detected in samples collected from one region (Weixian). Canonical correlation analysis (CCA) and Pearson correlation analysis showed that the abundance of Alistipes and Pantoea were negatively correlated with the contents of PAT, suggesting that bacterial genera Alistipes and Pantoea have potential in reducing mycotoxin production in 'Huangguan' pear.

Oligosaccharide and short-chain fatty acid: A double-edged sword in obese mice by regulating food intake and fat synthesis.

Dietary fiber has been used to prevent obesity by regulating the intestinal flora and promoting the production of short-chain fatty acids (SCFAs). However, it is insufficient to conclude the decisive role of microbiota and SCFAs by adding oligosaccharides to foods without caloric balance. In this study, the effects of oligosaccharides and their regulated microflora on the development of obesity in mice were studied by designing a high-fat diet with equal calories but different contents of oligosaccharides. Isocaloric diets demonstrated that appropriate rather than excess oligosaccharides prevent obesity by regulating appetite. Such an appetite was inhibited by oligosaccharides but promoted by SCFAs. Furthermore, promoted appetite was tightly related to decreased insulin and increased acyl-CoA binding protein, which was correlated with SCFA-induced fat degradation. Interestingly, drinking butyrate alleviated obesity even with higher calorie intake. Molecular docking demonstrated that conversion of butyrate to butyryl-CoA converted from butyrate, as a structural analog of acetyl-CoA, inhibits the activity of acetyl-CoA carboxylase. Together, these findings demonstrate that fermentable fiber supplements may have limits in obesity treatment, and we provide possible obesity therapeutic targets that inhibit bacterial fermentation or increase the ratio of butyrate/acetate.

Ozone reduces the fruit decay of postharvest winter jujube by altering the microbial community structure on fruit surface.

Microbial community structure on fruit surface plays an important role in fruit decay during postharvest storage, although the underlying mechanism has not been fully elucidated. Winter jujube (Ziziphus jujuba Miller cv. Dongzao) is a unique fruit resource with high edible and commercial value in China, while postharvest decay has always been a severe problem leading to short shelf life and poor quality of fruit. Ozone treatment is regarded as one of the most effective means to control decay and extend shelf life because of its cost-effective and eco-friendly properties. In the present study, three concentrations of ozone (2.5, 5 and 10 µL L-1) were found to reduce significantly postharvest decay of winter jujube on days 10 and 15, which were produced from Huanghua City, Hebei, China. High-throughput sequencing revealed significant changes in the bacterial and fungal communities in response to the application of ozone treatment, while Didymella, Rhizopus, Alternaria, Phialemoniopsis and Mycosphaerella were found to be the most abundant in fungi, and Methylobacterium, Pseudomonas, Pantoea, Sphingomonas and Gluconobacter being the most abundant in bacteria. Results of linear discriminant analysis (LDA) effect size (LEfSe) indicated that ozone treatments considerably reduced the abundance of Rhizopus and Gluconobacter on the surface of winter jujube fruit. Furthermore, Pearson correlation analysis showed that Rhizopus was positively correlated with Gluconobacter (r = 0.97) while negatively correlated with Didymella (r = -0.96). By predicting the metabolic function, ozone may inhibit metabolic pathways including nucleoside and nucleotide biosynthesis, amino acid biosynthesis, fatty acid and lipid degradation, respiration, and electron transfer, thereby reducing the incidence of fruit decay and maintaining the firmness of winter jujube fruit.

Dysregulation of intestinal flora: excess prepackaged soluble fibers damage the mucus layer and induce intestinal inflammation.

Soluble fiber is commonly used as a dietary supplement to improve intestinal flora, and many prepackaged products are sold in the market. However, whether these prepared soluble fibers are harmless for intestinal flora has not been systematically evaluated. Here, we assessed the dose-effect of fructooligosaccharides (FOSs) on obesity and intestinal flora using a mouse model. Gavage of low- and medium-dose FOS improved the microbiota in high-fat diet fed mice, but high-dose FOS leads to intestinal flatulence, diarrhea and flora disorders, including an increase in Akkermansia muciniphila and Clostridium difficile, which disrupt the mucus barrier and cause intestinal inflammation. Besides, a high dose of xylooligosaccharide by gavage induces symptoms similar to those of FOS in mice. These adverse effects can be alleviated by regulating intestinal flora. In addition, we experimentally proved that supplementary probiotics protect against the negative effects of FOS in obese mice. Therefore, prepackaged soluble fiber supplements need to be taken with caution, and excessive consumption of soluble fibers results in intestinal dysfunction and even induces intestinal inflammation. Combining probiotics and soluble fiber can be considered if necessary.

Dietary soybeans worsen dextran sodium sulfate-induced colitis by disrupting intestinal ecology.

Food mediates susceptibility to inflammatory bowel diseases (IBDs) associated with the microbiome. Existing studies suggest that a high-sugar and high-fat diet promotes IBDs, but whether a plant-based diet is fully harmless to IBD improvement remains unknown. In this study, for the first time, we assessed the effect of soybean and its carbohydrates on dextran sodium sulfate (DSS)-induced colitis. In a DSS-induced colitis mouse model (BALB/C WT), the oral administration of soybeans worsened colitis, which was associated with higher disease activity index, histology score and expression of pro-inflammatory cytokines, and lower expression of anti-inflammatory cytokines. Here, 16S rRNA sequencing and elimination of gut bacteria by antibiotics showed that the exacerbating colitis caused by soybeans depends on the changes in the intestinal flora. Furthermore, the gavage of soybean carbohydrates such as sucrose and raffinose-family oligosaccharides altered the intestinal microbiota and worsened inflammation. When co-cultured with macrophages (RAW 264.7), the metabolites of the disordered intestinal flora, isolated Escherichia coli and purified LPS showed high macrophage toxicity to inhibit pathogen clearance. These results indicate that the intake of soybeans and soybean carbohydrates is not conducive to recovery from IBDs based on changes in gut microbiota and metabolites affecting the activities of macrophages.

Butyrate emerges as a crucial effector of Zhi-Zi-Chi decoctions to ameliorate depression via multiple pathways of brain-gut axis.

Gut microbiota has emerged as a crucial target of gut-brain axis to influence depression. Zhi-Zi-Chi decoctions (ZZCD), as a classic oral formula in clinic, is widely applied in depression treatment nowadays. However, the underlying mechanism in the antidepressant activity of ZZCD remains unknown. A classic depression model of chronic mild unpredictable stress (CUMS) was established in rats based on the results of behavioral tests and hippocampal histomorphology. 16S rRNA sequencing analysis indicated that ZZCD could increase short-chain fatty acid-producing and anti-inflammatory bacteria and reduce inflammatory and tryptophan-metabolizing bacteria. Furthermore, ZZCD reversed the alterations of BDNF, TNF-α, pro-inflammatory cytokines and neurotransmitters in the gut, blood and brain along the brain-gut axis and restored the decrease of butyrate in cecal content caused by CUMS. Then, butyrate was utilized to validate its ameliorative effect on pathological characteristics of depressive rats. Taken together, these results show that ZZCD exhibits antidepressant effect through modulating gut microbiota to facilitate the production of butyrate, which further regulate anti-inflammation, neurotransmitters, endocrine and BDNF along the gut-brain axis. Hence, this study fills the gap of the antidepressive mechanism of ZZCD in the light of the brain-gut axis and established a multi-targets and multi-levels platform eventually for further research into the mechanism of other TCM efficacy.

Tumor markers are associated with rapidly progressive interstitial lung disease in adult-dermatomyositis.

OBJECTIVES: DM-associated rapidly progressive interstitial lung disease (DM-RP-ILD) has been the clinical conundrum. We assess the serum levels of tumor markers (TMs) in different types of ILD, and explore the diagnostic utility of TMs for DM/ADM-RP-ILD. METHODS: This was a retrospective cohort study, data including clinical and laboratory records were collected from the first affiliated hospital of Zhengzhou University from December 2015, to June 2020. Tumor markers (TMs) include CEA, CA153, CA724, CA125, and CA199. Spearman analysis, ROC, and Kaplan-Meier curve were used for data analysis. RESULTS: Total 272 patients (149 DM and 123 ADM) were enrolled, 152 (55.88%) with ILD (116 with chronic ILD, 36 with RP-ILD) and 120 (44.12%) without ILD among them. The serum levels of CEA and ferritin were significantly higher in patients with RP-ILD than in the other two groups. Serum CA125, CA199, and CA153 levels in patients with RP-ILD were higher than those without ILD. CEA levels were associated with the ferritin, KL-6 and anti-MDA5 levels, and CEA concentration was significantly negatively correlated with DLco (P = 0.016, R2 = - 0.281). CEA [AUC = 0.7, 95% CI = (0.594, 0.806)] and ferritin [AUC = 0.737, 95% CI = (0.614, 0.860)] had diagnosed value for patients developing RP-ILD. Patients with high serum CEA levels had higher mortality rate within the DM-ILD population. CONCLUSIONS: TMs and ferritin were increased in DM/ADM-RP-ILD, and serum CEA and CA153 levels can evaluate disease severity of DM. And CEA and ferritin can be used as noninvasive diagnostic biomarkers for patients with DM-RP-ILD. Key Points • Interstitial lung disease (ILD) is a serious complication of DM, and is a leading cause of mortality, especially rapidly progressive ILD. • Tumor markers as a kind of noninvasive detection can reflect the disease severity of DM, and CEA and ferritin can be used to identify patients with RP-ILD.

Sortilin deletion in the prefrontal cortex and hippocampus ameliorates depressive-like behaviors in mice via regulating ASM/ceramide signaling.

Major depressive disorder (MDD) is a common psychiatric disorder characterized by persistent mood despondency and loss of motivation. Although numerous hypotheses have been proposed, the possible pathogenesis of MDD remains unclear. Several recent studies show that a classic transporter protein, sortilin, is closely associated with depression. In the present study, we investigated the role of sortilin in MDD using a well-established rodent model of depression. Mice were subjected to chronic unpredictable mild stress (CUMS) for 6 weeks. We showed that the expression levels of sortilin were significantly increased in the prefrontal cortex and hippocampus of CUMS mice. The depressive-like behaviors induced by CUMS were alleviated by specific knockdown of sortilin in the prefrontal cortex and hippocampus. We revealed that sortilin facilitated acid sphingomyelinase (ASM)/ceramide signaling, which activated RhoA/ROCK2 signaling, ultimately causing the transformation of dendritic spine dynamics. Specific overexpression of sortilin in the prefrontal cortex and hippocampus induced depressive-like behaviors, which was mitigated by injection of ASM inhibitor SR33557 (4 µg/µL) into the prefrontal cortex and hippocampus. In conclusion, sortilin knockdown in the prefrontal cortex and hippocampus plays an important role in ameliorating depressive-like behavior induced by CUMS, which is mainly evidenced by decreasing the trafficking of ASM from the trans-Golgi network to the lysosome and reducing the ceramide levels. Our results provide a new insight into the pathology of depression, and demonstrate that sortilin may be a potential therapeutic target for MDD.

Nogo receptor impairs the clearance of fibril amyloid-ß by microglia and accelerates Alzheimer's-like disease progression.

Alzheimer's disease (AD) is characterized by the progressive accumulation of ß-amyloid (Aß)-containing amyloid plaques, and microglia play a critical role in mediating Aß clearance. Mounting evidence has confirmed that the ability of microglia in clearing Aß decreased with aging and AD progress, but the underlying mechanisms are unclear. Previously, we have demonstrated that Nogo receptor (NgR), a receptor for three axon growth inhibitors associated with myelin, can decrease adhesion and migration of microglia to fibrils Aß with aging. However, whether NgR expressed on microglia affect microglia phagocytosis of fibrils Aß with aging remains unclear. Here, we found that aged but not young microglia showed increased NgR expression and decreased Aß phagocytosis in APP/PS1 transgenic mice. NgR knockdown APP/PS1 mice showed simultaneous reduced amyloid burden and improved spatial learning and memory, which were associated with increased Aß clearance. Importantly, Nogo-P4, an agonist of NgR, enhanced the protein level of p-Smad2/3, leading to a significant transcriptional inhibition of CD36 gene expression, which in turn decreased the microglial phagocytosis of Aß. Moreover, ROCK accounted for Nogo-P4-induced activation of Smad2/3 signaling. Finally, the decreasing effect of NgR on microglial Aß uptake was confirmed in a mouse model of intra-hippocampal fAß injection. Our findings suggest that NgR may play an important role in the regulation of Aß homeostasis, and has potential as a therapeutic target for AD.