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Digestive Diseases (Basel, Switzerland) 2021Refractory reflux esophagitis (RRE), unresponsive to conventional proton-pump inhibitors (PPIs), is a complication in esophagectomy with gastric pull-up. Vonoprazan...
BACKGROUND
Refractory reflux esophagitis (RRE), unresponsive to conventional proton-pump inhibitors (PPIs), is a complication in esophagectomy with gastric pull-up. Vonoprazan (VPZ), a novel potassium-competitive acid blocker, has been available in Japan since 2015. Here, we investigated the efficacy of VPZ on PPI-resistant RRE after esophagectomy with gastric pull-up.
METHODS
This was a single-center retrospective study. We used the revised Los Angeles (r-LA) classification based on the Los Angeles classification and the modified Los Angeles classification to evaluate abnormal forms of mucosal breaks such as lateral spreading consistently. Patients who underwent esophagectomy with gastric pull-up and had RRE grade B-D as per the r-LA classification, despite using standard-dose PPIs or double dose of rabeprazole, were included. Sixteen patients who switched to VPZ (20 mg/day) and 14 patients who continued PPIs were assigned to the VPZ and PPI groups, respectively. Endoscopic observations were reviewed by 3 endoscopists using the r-LA classification to ensure consistent diagnosis, while the treatment arm and patient information were blinded to evaluators. We defined mucosal breaks that improved by at least one grade after treatment as improved mucosa and recovery to grade M or N as mucosal healing.
RESULTS
The percentage of patients with improved mucosa in the VPZ and PPI groups was 81.3 and 14.3%, respectively (p < 0.001). The rate of mucosal healing was 68.8 and 7.1%, respectively (p = 0.001).
CONCLUSION
VPZ significantly improved PPI-resistant RRE after esophagectomy with gastric pull-up.
Topics: Esophagectomy; Esophagitis, Peptic; Humans; Proton Pump Inhibitors; Pyrroles; Retrospective Studies; Sulfonamides; Treatment Outcome
PubMed: 33567428
DOI: 10.1159/000515146 -
Marine Drugs Mar 2023The JAK/STAT3 signaling pathway is aberrantly hyperactivated in many cancers, promoting cell proliferation, survival, invasiveness, and metastasis. Thus, inhibitors...
The JAK/STAT3 signaling pathway is aberrantly hyperactivated in many cancers, promoting cell proliferation, survival, invasiveness, and metastasis. Thus, inhibitors targeting JAK/STAT3 have enormous potential for cancer treatment. Herein, we modified derivatives by introducing the isothiouronium group, which can improve the antitumor activity of the compounds. We performed a high-throughput screen of 3157 compounds and identified compounds , , and , which contain a pyrrole [2,3-c] azepine structure linked to an isothiouronium group through different lengths of carbon alkyl chains and significantly inhibited JAK/STAT3 activities. Further results showed that compound exhibited the optimal antiproliferative activity and was a pan-JAKs inhibitor capable of inhibiting constitutive and IL-6-induced STAT3 activation. In addition, compound influenced STAT3 downstream gene expression (Bcl-xl, C-Myc, and Cyclin D1) and induced the apoptosis of A549 and DU145 cells in a dose-dependent manner. The antitumor effects of were further demonstrated in an in vivo subcutaneous tumor xenograft experiment with DU145 cells. Taken together, we designed and synthesized a novel small molecule JAKs inhibitor targeting the JAK/STAT3 signaling pathway, which has predicted therapeutic potential for JAK/STAT3 overactivated cancer treatment.
Topics: Humans; Isothiuronium; Cell Line, Tumor; Signal Transduction; Cell Proliferation; Apoptosis; Azepines; Pyrroles; STAT3 Transcription Factor
PubMed: 37103357
DOI: 10.3390/md21040218 -
PloS One 2022Coal is the largest non-renewable energy as well as an important basic energy and industrial raw material. Thus, correctly understanding the molecular structure...
Coal is the largest non-renewable energy as well as an important basic energy and industrial raw material. Thus, correctly understanding the molecular structure characteristics of coal has important theoretical value for realizing carbon neutralization. In this work, we clarified the molecular structure characteristics of anthracite, where the organic matter in anthracite was characterized and analyzed by industrial/elemental analysis, FTIR, XPS, XRD and solid 13C NMR. The ratio of bridge carbon to the perimeter carbon of anthracite was 0.38, and the degree of condensation in the aromatic structure was high. Nitrogen in coal primarily exists in the form of pyridine and pyrrole. Based on the information on functional group composition, the carbon skeleton structure, and surface element composition, a molecular structure model of Yangquan anthracite could be constructed, where the molecular formula was C208H162O12N4. This study may serve as a reference for researchers in this field to consult and refer to the construction ideas and methods of molecular structure models of different coal samples.
Topics: Carbon; Coal; Models, Molecular; Molecular Structure; Nitrogen; Pyridines; Pyrroles
PubMed: 36170645
DOI: 10.1371/journal.pone.0275108 -
Journal of the American Chemical Society Jun 2024Reactive functional groups, such as -nitrosamines, impart unique bioactivities to the natural products in which they are found. Recent work has illuminated enzymatic...
Reactive functional groups, such as -nitrosamines, impart unique bioactivities to the natural products in which they are found. Recent work has illuminated enzymatic -nitrosation reactions in microbial natural product biosynthesis, motivating interest in discovering additional metabolites constructed using such reactivity. Here, we use a genome mining approach to identify over 400 cryptic biosynthetic gene clusters (BGCs) encoding homologues of the -nitrosating biosynthetic enzyme SznF, including the BGC for chalkophomycin, a Cu-binding metabolite that contains a -type diazeniumdiolate and -hydroxypyrrole. Characterizing chalkophomycin biosynthetic enzymes reveals previously unknown enzymes responsible for -hydroxypyrrole biosynthesis, including the first prolyl--hydroxylase, and a key step in the assembly of the diazeniumdiolate-containing amino acid graminine. Discovery of this pathway enriches our understanding of the biosynthetic logic employed in constructing unusual heteroatom-heteroatom bond-containing functional groups, enabling future efforts in natural product discovery and biocatalysis.
Topics: Pyrroles; Multigene Family; Streptomyces
PubMed: 38810110
DOI: 10.1021/jacs.4c04712 -
Marine Drugs Jul 2022Twelve new and four known alkaloids including five different structural scaffolds were isolated from the sponge collected in the South China Sea. Compound is the first...
Twelve new and four known alkaloids including five different structural scaffolds were isolated from the sponge collected in the South China Sea. Compound is the first identified precursor metabolite of the classic 5/7/5 tricyclic skeleton with unesterified guanidine and carboxyl groups, compounds - and - belong to the spongiacidin-type pyrrole imidazole alkaloids (PIAs). - and -configurations of the spongiacidin-type PIAs often appeared concomitantly and were distinguished by the chemical shift analysis of C NMR spectra. The structures of all twelve new compounds were determined by NMR, MS, and ECD analysis combined with single-crystal data of compounds , , and . In the aldose reductase (ALR2) inhibitory assay, six 5/7/5 tricyclic compounds (-, -) displayed significant activities. Compounds and , as the representative members of spongiacidin-PIAs, demonstrated their ALR2-targeted activities in SPR experiments with K values of 12.5 and 6.9 µM, respectively.
Topics: Alkaloids; Animals; Magnetic Resonance Spectroscopy; Molecular Structure; Porifera; Pyrroles
PubMed: 35877747
DOI: 10.3390/md20070454 -
Marine Drugs Dec 2018Two new sceptrin derivatives (,) and eight structurally-related known bromopyrrole-bearing alkaloids were isolated from the tropical sponge . By a combination of...
Two new sceptrin derivatives (,) and eight structurally-related known bromopyrrole-bearing alkaloids were isolated from the tropical sponge . By a combination of spectroscopic methods, the new compounds, designated dioxysceptrin () and ageleste C (), were determined to be structural analogs of each other that differ at the imidazole moiety. Dioxysceptrin was also found to exist as a mixture of α-amido epimers. The sceptrin alkaloids exhibited weak cytotoxicity against cancer cells. Compounds and also moderately exhibited anti-angiogenic and isocitrate lyase-inhibitory activities, respectively.
Topics: Agelas; Alkaloids; Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Biological Products; Cell Line, Tumor; Drug Screening Assays, Antitumor; Enzyme Assays; Human Umbilical Vein Endothelial Cells; Humans; Isocitrate Lyase; Pyrroles; Stereoisomerism
PubMed: 30563015
DOI: 10.3390/md16120513 -
Molecules (Basel, Switzerland) Mar 2016In recent years, several synthetic strategies aiming at the peripheral functionalization of porphyrins were developed. Particularly interesting are those involving the... (Review)
Review
In recent years, several synthetic strategies aiming at the peripheral functionalization of porphyrins were developed. Particularly interesting are those involving the modification of β-pyrrolic positions leading to pyrrole-modified porphyrins containing four-, five-, six- or seven-membered heterocycles. Azeteoporphyrins, porpholactones and morpholinoporphyrins are representative examples of such porphyrinoids. These porphyrin derivatives have recently gained an increasing interest due to their potential application in PDT, as multimodal imaging contrast agents, NIR-absorbing dyes, optical sensors for oxygen, cyanide, hypochlorite and pH, and in catalysis.
Topics: Catalysis; Contrast Media; Humans; Molecular Structure; Multimodal Imaging; Porphyrins; Pyrroles
PubMed: 27005605
DOI: 10.3390/molecules21030320 -
Toxins Oct 2021Pyrrolizidine alkaloids (PAs) with 1,2-unsaturated necine base are hepatotoxic phytotoxins. Acute PA intoxication is initiated by the formation of adducts between...
Pyrrolizidine alkaloids (PAs) with 1,2-unsaturated necine base are hepatotoxic phytotoxins. Acute PA intoxication is initiated by the formation of adducts between PA-derived reactive pyrrolic metabolites with cellular proteins. The present study aimed to investigate the correlation between the formation of hepatic pyrrole-protein adducts and occurrence of PA-induced liver injury (PA-ILI), and to further explore the use of such adducts for rapidly screening the hepatotoxic potency of natural products which contain PAs. Aqueous extracts of (containing one PA: monocrotaline) and (containing two PAs: senecionine and seneciphylline) were orally administered to rats at different doses for 24 h to investigate PA-ILI. Serum alanine aminotransferase (ALT) activity, hepatic glutathione (GSH) level, and liver histological changes of the treated rats were evaluated to assess the severity of PA-ILI. The levels of pyrrole-protein adducts formed in the rats' livers were determined by a well-established spectrophotometric method. The biological and histological results showed a dose-dependent hepatotoxicity with significantly different toxic severity among groups of rats treated with herbal extracts containing different PAs. Both serum ALT activity and the amount of hepatic pyrrole-protein adducts increased in a dose-dependent manner. Moreover, the elevation of ALT activity correlated well with the formation of hepatic pyrrole-protein adducts, regardless of the structures of different PAs. The findings revealed that the formation of hepatic pyrrole-protein adducts-which directly correlated with the elevation of serum ALT activity-was a common insult leading to PA-ILI, suggesting a potential for using pyrrole-protein adducts to screen hepatotoxicity and rank PA-containing natural products, which generally contain multiple PAs with different structures.
Topics: Alanine Transaminase; Animals; Asteraceae; Chemical and Drug Induced Liver Injury; Crotalaria; Liver; Male; Plant Extracts; Proteins; Pyrroles; Pyrrolizidine Alkaloids; Rats, Sprague-Dawley; Rats
PubMed: 34679016
DOI: 10.3390/toxins13100723 -
Chemistry (Weinheim An Der Bergstrasse,... May 2020The degradation of chlorophyll, the omnipresent green pigment, has been investigated intensively over the last 30 years resulting in many elucidated tetrapyrrolic...
The degradation of chlorophyll, the omnipresent green pigment, has been investigated intensively over the last 30 years resulting in many elucidated tetrapyrrolic degradation products. With a comparison to the degradation of the structurally similar heme, we hereby propose a novel additional chlorophyll degradation mechanism to mono- and dipyrrolic products. This is the first proof of the occurrence of a family of mono- and dipyrrols in leaves that are previously only known as heme degradation products. This product family is also found in spit and feces of herbivores with specific metabolomic patterns reflecting the origin of the samples. Based on chromatographic and mass spectrometric evidence as well as on mechanistic considerations we also suggest several tentative new degradation products. One of them, dihydro BOX A, was fully confirmed as a novel natural product by synthesis and comparison of its spectroscopic data.
Topics: Chlorophyll; Herbivory; Plant Leaves; Plants; Pyrroles
PubMed: 31971638
DOI: 10.1002/chem.201905236 -
Marine Drugs Apr 2020is an opportunistic pathogen using virulence factors and biofilm regulated by quorum sensing (QS) systems to infect patients and protect itself from environmental...
is an opportunistic pathogen using virulence factors and biofilm regulated by quorum sensing (QS) systems to infect patients and protect itself from environmental stress and antibiotics. Interfering with QS systems is a novel approach to combat infections without killing the bacteria, meaning that it is much harder for bacteria to develop drug resistance. A marine fungus sp. Z148 with anti-QS activity was obtained from Jiaozhou Bay, China. Cladodionen, a novel QS inhibitor, was isolated from the extracts of this fungus. Cladodionen had a better inhibitory effect than pyocyanin on the production of elastase and rhamnolipid. It also inhibited biofilm formation and motilities. The mRNA expressions of QS-related genes, including receptor proteins (), autoinducer synthases () and virulence factors () were down-regulated by cladodionen. Molecular docking analysis showed that cladodionen had better binding affinity to LasR and PqsR than natural ligands. Moreover, the binding affinity of cladodionen to LasR was higher than to PqsR. Cladodionen exhibits potential as a QS inhibitor against , and its structure-activity relationships should be further studied to illustrate the mode of action, optimize its structure and improve anti-QS activity.
Topics: Animals; Anti-Bacterial Agents; Aquatic Organisms; Bays; China; Cladosporium; Pseudomonas aeruginosa; Pyrans; Pyrroles; Quorum Sensing
PubMed: 32290259
DOI: 10.3390/md18040205