Indoloquinazoline alkaloids with cardiomyocyte protective activity against cold ischemic injury from Aspergillus clavatonanicus.

The arthropod-associated fungi have been demonstrated to be a remarkable producer of structurally captivating and bioactive secondary metabolites for drug discovery. In this study, eleven new indoloquinazoline alkaloids, namely aspergilloids A-K (1-11), along with five known congeners (12-16), were obtained from fungus Aspergillus clavatonanicus, which was isolated from the gut of a centipede collected in our Tongji campus. All these compounds were rarely defined by a 6/5/5 indolone ring system in conjugation with a five-membered spiral ring (1-5 and 10-16) or an opening five-membered spiral ring (6-9). Their structures were elucidated by widespread spectroscopic analyses, mainly including HRESIMS and 1D and 2D NMR data, single-crystal X-ray diffraction, and electronic circular dichroism (ECD) data analyses. The cardiomyocyte protective activity assay revealed that compounds 1, 2, 5, 12-14, and 16 ameliorated cold ischemic injury at 48 h post cold ischemia (CI), and compounds 1, 5, and 14 prevented cold ischemia induced Ser9 dephosphorylation of GSK3ß at 12 h post CI. Our current study highlights indoloquinazoline alkaloids as the first class of natural cardiomyocyte protective agents against cold ischemic injury, which furnishes promising lead molecules for the development of new cardioprotectants in heart transplantation medicine.

The Bioinformatical Identification of Potential Biomarkers in Heart Failure Diagnosis and Treatment.

Background: Heart failure (HF) is defined as the inability of the heart's systolic and diastolic function to properly discharge blood flow from the veins to the heart. The goal of our research is to look into the possible mechanism that causes HF. Methods: The GSE5406 database was used for screening the differentially expressed genes (DEGs). Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Protein-Protein Interaction (PPI) network were applied to analyze DEGs. Besides, cell counting Kit-8 (CCK-8) was conducted to observe the knockdown effect of hub genes on cell proliferation. Results: Finally, 377 upregulated and 461 downregulated DEGs came out, enriched in the extracellular matrix organization and gap junction. According to GSEA results, Hoft cd4 positive alpha beta memory t cell bcg vaccine age 18-45 yo id 7 dy top 100 deg ex vivo up, Sobolev t cell pandemrix age 18-64 yo 7 dy dn, and so on were significantly related to gene set GSE5406. 7 hub genes, such as COL1A1, UBB, COL3A1, HSP90AA1, MYC, STAT3 and MAPK1, were selected from PPI networks. CCK-8 indicated silencing of STAT3 promoted the proliferation of H9C2 cells and silencing of UBB inhibited the proliferation of H9C2 cells. Conclusion: Our analysis reveals that COL1A1, UBB, COL3A1, HSP90AA1, MYC, STAT3, and MAPK1 might promote the progression of HF and become the biomarkers for diagnosis and treatment of HF.

Influence of Gut Microbiota and Trimethylamine N-Oxide in Patients with Coronary Heart Disease.

In the current study, the gut microbiota of patients with and without coronary heart disease was compared and the relationship between gut microbiota distribution, intending to reveal the role of gut microbiota in the coronary atherosclerosis process, was investigated.This study included 50 patients diagnosed with coronary heart disease (CHD) who received conventional coronary angiography or computed tomography angiography and 50 patients with CHD at Changshu No. 2 People's Hospital, Suzhou, China, from May 2020 to January 2021. Trimethylamine N-oxide (TMAO) level was tested and feces were collected, the DNA of the gut microbiota was extracted, and the distribution by 16SrRNA gene sequencing was obtained from the two groups of patients.Plasma TMAO concentrations were significantly higher in patients with CHD (P < 0.001). In the CHD group, 22 patients with multivessel disease had a higher level of TMAO compared with the 28 patients who had the single-vessel disease (P < 0.001). No difference in the gut microbiota diversity was noted between the two groups (P < 0.001). Patients with CHD had a significantly lower proportion of Bacteroidetes phyla and more proportion of Epsilonbacteraeota phyla. At the genus level, patients with CHD had an increased abundance of Enterococcus, whereas healthy controls had significantly higher levels of Streptococcus. Phylogenetic Investigation of Communities by Reconstruction of Unobserved States 2 analysis found that, in the KEGG ORTHOLOGY, the level of choline trimethylamine-lyase gene expression correlated with TMAO production was higher in the fecal microbiome of the CHD group (P < 0.05).Gut microbiota and its product were expected to become a diagnostic marker and a new target for preventing CHD.

Hollow Carbon Spheres with Abundant Micropores for Enhanced CO2 Adsorption.

The interest in the design and controllable fabrication of hollow carbon spheres (HCSs) emanates from their tremendous potential applications in adsorption, energy conversion and storage, and catalysis. However, the effective synthesis of uniform HCSs with high surface area and abundant micropores remains a challenge. In this work, HCSs with tunable microporous shells were rationally synthesized via the hard-template method using resorcinol (R) and formaldehyde (F) as a carbon precursor. HCSs with a very high surface area (1369 m2/g) and abundant micropores (0.53 cm3/g) can be obtained with the assistance of additional inorganic silanes (TEOS) simultaneously with the carbon source (RF). Interestingly, the extra-abundant micropores showed favorable adsorption for CO2, resulting in a 1.5 times increase in the CO2 adsorption capacity compared to that of normal HCSs under the same conditions. Meanwhile, these HCSs hold potential for use in the separation of gases such as CO2 and N2.

Morphinan and isoquinoline alkaloids from the tuberous roots of Stephania cepharantha.

A new morphinan alkaloid (6S, 9S, 13 R, 14S)-6-O-acetyl-7,8-Didehydro-4-hydroxy-3,7-dimethoxymorphinan-6-ol (1), and a new naturally occurring cularine alkaloid (S)-2, 3, 12, 12a-tetrahydro-5, 6, 9, 10-tetramethoxy-1-methyl-1H-[1]benzoxepino[2, 3, 4-ij]isoquinoline(5), along with four known alkaloids were isolated from the roots of Stephania cepharantha. The structures of these compounds were elucidated based on spectroscopic data analyses. Cytotoxic activities of the compounds against three human cancer cell lines (A549, MCF-7 and SW480) were also evaluated.

Generation of indole derivatives by an endophytic fungus Chaetomium sp. through feeding 1,2-dimethylindole.

Through feeding 1,2-dimethylindole, two new bisindoles, chaetoindolone E and F (1 and 2) and five known indole derivatives (3-7) were isolated from the cultures of an endophytic fungus Chaetomium sp. The structures of these compounds were elucidated based on HR-MS, NMR and single-crystal X-ray crystallography. Compounds 1 and 2 were undescribed before, compounds 3-7 were first reported from natural sources, and NMR spectrums of compounds 4 and 5 were first reported. The cytotoxity of the bisindole compounds (1-3) was also tested.

Alkaloids from Aconitum carmichaelii Alleviates DSS-Induced Ulcerative Colitis in Mice via MAPK/NF-κB/STAT3 Signaling Inhibition.

Fuzi (Aconitum carmichaelii Debx) has been traditionally used for the treatment of ulcerative colitis (UC) in China for thousands of years. The total alkaloids of A. carmichaelii (AAC) have been considered as the main medicinal components of fuzi, whereas its underlying anti-UC mechanisms remain elusive. In the present study, the dextran sulfate sodium (DSS)-induced UC mice model, which was consistent with the symptoms and pathological features of human UC, was established to comprehensively evaluate the anti-UC effects of AAC. The results indicated that AAC effectively improved the weight loss, disease activity index (DAI), spleen hyperplasia, and colon shortening, and thus alleviated the symptoms of UC mice. Meanwhile, AAC not only inhibited the MPO enzyme and the abnormal secretion of inflammatory cytokines (TNF-α, IL-1ß, IL-6, IFN-γ, and IL-17A) and suppressed the overexpression of inflammatory mediators (TNF-α, IL-1ß, and IL-6) of mRNA but also reduced the phosphorylation of p38 MAPK, ERK, and JNK, and the protein expressions of NF-κB, IκB-α, STAT3, and JAK2 in the colon tissue. Furthermore, the LC-MS/MS quantitative determination suggested that the three low toxic monoester alkaloids were higher in both contents and proportion than that of the three high toxic diester alkaloids. Additionally, molecular docking was hired to investigate the interactions between alkaloid-receptor complexes, and it suggested the three monoester alkaloids exhibited higher binding affinities with the key target proteins of MAPK, NF-κB, and STAT3. Our finding showcased the noteworthy anti-UC effects of AAC based on the MAPK/NF-κB/STAT3 signaling pathway, which would provide practical and edge-cutting background information for the development and utilization of A. carmichaelii as a potential natural anti-UC remedy.

A new diketopiperazine from an endophytic fungus Aspergillus aculeatus F027.

A new diketopiperazine cyclo-(L-Phe-N-ethyl-L-Glu) (1), along with two known diketopiperazines cyclo-(L-Pro-L-Leu) (2) and cyclo-(L-Pro-L-Phe) (3) were isolated from the cultures of an endophytic fungus Aspergillus aculeatus F027. The structures of these compounds were elucidated based on spectroscopic data. The configurations of these compounds were determined by advanced Marfey's analysis. Antibacterial activity of the diketopiperazines against Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa were also evaluated.Supplemental data for this article can be accessed at https://doi.org/10.1080/14786419.2019.1677652.

A Traditional Chinese Medicine Formula Danshen Baibixiao Ameliorates Imiquimod-Induced Psoriasis-Like Inflammation in Mice.

Background: Danshen Baibixiao (DB) is a traditional Chinese medicine formula, which has been used to treat psoriasis for decades. Although DB shows good efficacy in clinical practice, the pharmacological effects and underlying mechanisms of DB remain elusive. This study aimed to evaluate the anti-psoriatic effects of DB and explore its underlying mechanisms in an imiquimod (IMQ)-induced psoriasis-like mouse model. Materials and methods: DB was orally administered on IMQ-induced psoriatic mice. Psoriasis area severity index (PASI) was used to evaluate the severity of the inflammation in skin, and histological changes were evaluated by hematoxylin and eosin (H and E) staining. Levels of inflammatory cytokines, such as tumor necrosis factor α (TNF-α), interleukin (IL)-17A, IL-23, IL-6, IL-1ß and IL-22 in serum were assessed by enzyme-linked immunosorbent assay (ELISA). mRNA expressions of IL-17A, IL-23, IL-6 and IL-22 were determined by real-time polymerase chain reaction (PCR). Expression levels of proteins related to NF-κB, STAT3 and MAPKs signaling pathways were measured by western blotting (WB). Results: DB significantly ameliorated the psoriatic symptoms in IMQ-induced mice. The serum levels of inflammatory cytokines (TNF-α, IL-17A, IL-23, IL-6, IL-1ß and IL-22) were decreased, and mRNA expressions of IL-17A, IL-23, IL-6 and IL-22 in skin tissues were down-regulated. Moreover, WB analysis indicated that DB inhibited the activation of NF-κB, STAT3 and MAPKs signaling pathways. Conclusion: This study confirms the anti-psoriatic activity of DB in IMQ-induced psoriasis-like mice. The possible mechanism may relate to the activities of regulating the IL-23/TH-17 axis and suppressing the activation of NF-κB, STAT3 and MAPKs signaling pathways.

Identification of Key Genes Involved in Acute Myocardial Infarction by Comparative Transcriptome Analysis.

BACKGROUND: Acute myocardial infarction (AMI) is regarded as an urgent clinical entity, and identification of differentially expressed genes, lncRNAs, and altered pathways shall provide new insight into the molecular mechanisms behind AMI. MATERIALS AND METHODS: Microarray data was collected to identify key genes and lncRNAs involved in AMI pathogenesis. The differential expression analysis and gene set enrichment analysis (GSEA) were employed to identify the upregulated and downregulated genes and pathways in AMI. The protein-protein interaction network and protein-RNA interaction analysis were utilized to reveal key long noncoding RNAs. RESULTS: In the present study, we utilized gene expression profiles of circulating endothelial cells (CEC) from 49 patients of AMI and 50 controls and identified a total of 552 differentially expressed genes (DEGs). Based on these DEGs, we also observed that inflammatory response-related genes and pathways were highly upregulated in AMI. Mapping the DEGs to the protein-protein interaction (PPI) network and identifying the subnetworks, we found that OMD and WDFY3 were the hub nodes of two subnetworks with the highest connectivity, which were found to be involved in circadian rhythm and organ- or tissue-specific immune response. Furthermore, 23 lncRNAs were differentially expressed between AMI and control groups. Specifically, we identified some functional lncRNAs, including XIST and its antisense RNA, TSIX, and three lncRNAs (LINC00528, LINC00936, and LINC01001), which were predicted to be interacting with TLR2 and participate in Toll-like receptor signaling pathway. In addition, we also employed the MMPC algorithm to identify six gene signatures for AMI diagnosis. Particularly, the multivariable SVM model based on the six genes has achieved a satisfying performance (AUC = 0.97). CONCLUSION: In conclusion, we have identified key regulatory lncRNAs implicated in AMI, which not only deepens our understanding of the lncRNA-related molecular mechanism of AMI but also provides computationally predicted regulatory lncRNAs for AMI researchers.

Intestinal anti-inflammatory effects of fuzi-ganjiang herb pair against DSS-induced ulcerative colitis in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Fuzi and ganjiang are widely used as traditional Chinese medicines (TCM) in China, Korea, Japan, and many other southeast Asian countries for treating ulcerative colitis (UC), emesis and heart failure for more than 1800 years. However, the underlying mechanism of fuzi, ganjiang and fuzi-ganjiang herb pair is still unclear. In our study, we explored the therapeutic effects of fuzi, ganjiang and fuzi-ganjiang herb pair against dextran sulfate sodium (DSS)-induced UC in mice model, along with the relevant mechanism. MATERIALS AND METHODS: The contents of each marker compound in fuzi decoction (FD), ganjiang decoction (GD) and fuzi-ganjiang decoction (FGD) were determined using LC-MS/MS. During the experiment, bodyweight changes in each group were monitored every 5 days. On the day of sacrifice, colonic length, disease activity index (DAI) and spleen weight were also evaluated and histopathological examination was performed through hematoxylin & eosin (H&E) staining. The levels of myeloperoxidase (MPO) and inflammatory cytokines in colon tissues were determined by enzyme-linked immunosorbent assay (ELISA), and then the relative mRNA productions of inflammatory mediators, such as MPO, inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 were measured by real-time polymerase chain reaction (PCR). Involvement of MAPK, STAT3 and NF-κB signaling pathways in the pathogenesis of UC was determined in each group using Western Blot (WB) analysis. RESULTS: Compared with fuzi and ganjiang single decoction, the content of the alkaloids derived from fuzi (especially the diester alkaloid with strong toxicity, hypaconitine) in fuzi-ganjiang herb pair decoction was reduced. Additionally, the 6-gingerol, which was not found in ganjiang single decoction, was retained in fuzi-ganjiang herb pair decoction. FD, GD, and FGD significantly restored the bodyweight reduction, colon shortening, DAI elevation, splenomegaly and histological score in DSS-induced UC mice. Furthermore, except for the failure of low dosage of ganjiang decoction (GD-L) on IL-17A, all FD, GD and FGD significantly inhibited the production of MPO and inflammatory cytokines, such as IFN-γ, TNF-α, IL-1ß, IL-6, IL-10 and IL-17A, and suppressed the relative expression of inflammatory mediators, such as MPO, iNOS and COX-2 mRNA in colon tissues of DSS-induced mice. According to WB analysis, fuzi, ganjiang and fuzi-ganjiang combination inhibited the activation of MAPK, NF-κB and STAT3 signaling pathways. CONCLUSIONS: Our study demonstrated that fuzi, ganjiang and fuzi-ganjiang combination possess prominent anti-inflammatory activities against DSS-induced UC mice; the involved mechanism may be related to inhibition the activation of MAPK, NF-κB, and STAT3 signaling pathways.

Nanoassemblies constructed from bimodal mesoporous silica nanoparticles and surface-coated multilayer pH-responsive polymer for controlled delivery of ibuprofen.

The pH-sensitive poly(D-A) grafted amine-functionalized bimodal mesoporous silica (D-A/BMMs) was prepared by a facile method used as a drug delivery vehicle. They exhibited superior properties such as good dispersion in aqueous medium, high drug loading efficiency, improved stability and high drug release rates. Meanwhile, its structural features and performances in a controlled delivery of ibuprofen (IBU) were systematically investigated by using XRD, N2 adsorption and desorption, SEM, TEM, FT-IR, elemental analysis and TG techniques. The results demonstrated that the obtained nanocomposite presented a flexible control over drug release by controlling the grafting amount of D-A onto the mesopores surface of aminated BMMs. The cumulative percent release of IBU from D-A/BMMs was found to be much higher at pH 7.4 than at pH 2.0. The release rate was very slow in an acidic medium but became faster in a neutral medium, owing to hydrogen bonding in an acidic medium and electrostatic repulsion between negatively charged carboxyl groups in an alkaline medium.

"Graft to" Synthesis and Ibuprofen-Loading Performance of pH-Sensitive PMAA-Silica Hybrid Nanoparticles with Controlled Bimodal Mesopores.

Bimodal mesoporous silicas (BMMs) have been proved to be a good drug-loaded carrier. However, it did not provide stimuli sensitivity or controlled release performance yet. In the present work, a "smart" mesoporous silica-based pH-dependent [poly(methacrylic acid)]-silica hybrid nanoparticles (P/NN-BMMs) drug delivery system was developed and evaluated with ibuprofen (IBU) as a model drug. P/NN-BMMs were prepared by coating poly(methacrylic acid) (PMAA) onto amino-modified surface of BMMs via the "graft to" strategy. The structure and texture of resultant hybrid nanoparticles were determined with X-ray diffraction, scanning electron microscopy, transmission electron microscopy, Fourier transform infrared, thermogravimetric analysis, N2 sorption isotherms, and elemental analysis. The PMAA acts as a molecular switch to achieve controlled drug release and the amount of grafted-PMAA can remarkably affect its performance. The drug-loading rate is decreased markedly with the increasing of the amount of grafted-PMAA, meanwhile, the drug-loading kinetics on P/NN-BMMs fits Korsmeyer-Peppas model. In addition, the drug-release amount from drug-loaded P/NN-BMMs is pH dependent, showing an increasing tendency with the increase of pH value.