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Journal of Crohn's & Colitis Apr 2024Janus kinase [JAK] inhibitors [JAKinibs] are effective small molecule therapies for treating Crohn's disease [CD] and ulcerative colitis [UC], collectively known as... (Comparative Study)
Comparative Study
BACKGROUND
Janus kinase [JAK] inhibitors [JAKinibs] are effective small molecule therapies for treating Crohn's disease [CD] and ulcerative colitis [UC], collectively known as inflammatory bowel disease [IBD]. By preventing JAKs from phosphorylating signal transducer and activator of transcription proteins, JAKinibs disrupt cytokine signalling pathways that promote inflammation. Despite considerable overlap in the JAKs they target, first- and second-generation JAKinibs display different clinical efficacies in CD and UC.
METHODS
We conducted a comparative phosflow study of four JAKinibs [filgotinib, upadacitinib, tofacitinib, and deucravacitinib] to observe subtle mechanistic differences that may dictate their clinical behaviour. Resected mesenteric lymph node [MLN] cells from 19 patients [9 CD, 10 UC] were analysed by flow cytometry in the presence or absence of different cytokine stimuli and titrated JAKinibs.
RESULTS
We found a higher potency of the JAK 1/3-preferential inhibitor, tofacitinib, for JAK 3-dependent cytokine signalling pathways in comparison to filgotinib, but a higher potency of the JAK 1-preferential inhibitors, filgotinib and upadacitinib, for JAK 3-independent cytokine signalling pathways. Deucravacitinib, a TYK2-preferential inhibitor, demonstrated a much narrower selectivity by inhibiting only IL-10 and IFN-β pathways, albeit more potently than the other JAKinibs. Additionally, we found some differences in the sensitivity of immune cells from CD versus UC, and patients with versus without a CD-associated NOD2 polymorphism, to phosphorylate signal transducer and activator of transcriptions in response to specific cytokine stimulation.
CONCLUSIONS
Despite their similarities, differences exist in the relative potencies of different JAKinibs against distinct cytokine families, to explain their clinical efficacy.
Topics: Humans; Janus Kinase Inhibitors; Piperidines; Pyrimidines; Cytokines; Lymph Nodes; Pyrroles; Crohn Disease; Signal Transduction; Pyrrolidines; Male; Colitis, Ulcerative; Adult; Mesentery; Female; Janus Kinase 3; Heterocyclic Compounds, 3-Ring; Middle Aged; Inflammatory Bowel Diseases; Quinazolinones; Janus Kinase 1; Benzamides; Pyridines; Triazoles
PubMed: 37855324
DOI: 10.1093/ecco-jcc/jjad173 -
Proceedings. Biological Sciences Oct 2023Ratios between viruses, heterotrophic prokaryotes and chlorophyll are key indicators of microbial food structure and both virus-prokaryote and prokaryote-chlorophyll...
Ratios between viruses, heterotrophic prokaryotes and chlorophyll are key indicators of microbial food structure and both virus-prokaryote and prokaryote-chlorophyll ratios have been proposed to decrease with system productivity. However, the mechanisms underlying these responses are still insufficiently resolved and their consistency across aquatic ecosystem types requires critical evaluation. We assessed microbial community ratios in highly productive African soda-lakes and used our data from naturally hypereutrophic systems which are largely underrepresented in literature, to complement earlier across-system meta-analyses. In contrast to marine and freshwater systems, prokaryote-chlorophyll ratios in African soda-lakes did not decrease along productivity gradients. High-resolution time series from two soda-lakes indicated that this lack of response could be driven by a weakened top-down control of heterotrophic prokaryotes. Our analysis of virus-prokaryote relationships, revealed a reduction of virus-prokaryote ratios by high suspended particle concentrations in soda-lakes. This effect, likely driven by the adsorption of free-living viruses, was also found in three out of four additionally analysed marine datasets. However, the decrease of virus-prokaryote ratios previously reported in highly productive marine systems, was neither detectable in soda-lakes nor freshwaters. Hence, our study demonstrates that system-specific analyses can reveal the diversity of mechanisms that structure microbial food-webs and shape their response to productivity increases.
Topics: Ecosystem; Chlorophyll A; Prokaryotic Cells; Food Chain; Chlorophyll; Viruses; Microbiota; Lakes
PubMed: 37876193
DOI: 10.1098/rspb.2023.1531 -
Journal of Human Hypertension Feb 2024This study aimed to assess the efficacy and safety of esaxerenone (CS-3150) in treating primary hypertension. PubMed (Medline), Cochrane Central Register of Controlled... (Meta-Analysis)
Meta-Analysis Review
This study aimed to assess the efficacy and safety of esaxerenone (CS-3150) in treating primary hypertension. PubMed (Medline), Cochrane Central Register of Controlled Trials (CENTRAL), and Embase databases were searched for articles published until April 18, 2023. The outcomes included were diastolic blood pressure (DBP), systolic blood pressure (SBP), 24 h DBP, 24 h SBP, and adverse events. The meta-analysis was conducted using RevMan 5.3. This study included three trials. CS-3150 5 mg had a greater effect on lowering the SBP, DBP, 24 h SBP, and 24 h DBP than either CS-3150 2.5 mg or eplerenone 50 mg. In contrast, CS-3150 2.5 mg and eplerenone 50 mg showed no significant difference in lowering DBP, SBP, 24 h DBP, and 24 h SBP. Moreover, adverse events occurred at comparable rates in the three groups. CS-3150 (especially CS-3150 5 mg) is an effective and safe treatment for primary hypertension; which can reduce blood pressure and alleviate hypertensive symptoms.
Topics: Humans; Eplerenone; Hypertension; Blood Pressure; Essential Hypertension; Antihypertensive Agents; Pyrroles; Sulfones
PubMed: 38177694
DOI: 10.1038/s41371-023-00889-9 -
Advanced Healthcare Materials Dec 2023Developing efficient integrated diagnosis and treatment agents based on fuel-free self-movement nanomotors remains challenging in antitumor therapy. In this study, a...
Developing efficient integrated diagnosis and treatment agents based on fuel-free self-movement nanomotors remains challenging in antitumor therapy. In this study, a covalent organic framework (COF)-based biomimetic nanomotor composed of polypyrrole (PPy) core, porphyrin-COF shell, and HCT116 cancer cell membrane coating is reported. Under near-infrared (NIR) light irradiation, the obtained mPPy@COF-Por can overcome Brownian motion and achieves directional motion through self-thermophoretic force generated from the PPy core. The HCT116 cancer cell membrane coating enables the nanomotor to selectively recognize the source cell lines and reduces the bio-adhesion of mPPy@COF-Por in a biological medium, endowing with this NIR light-powered nanomotor good mobility. More importantly, such multifunctional integration allows the COF-based nanomotor to be a powerful nanoagent for cancer treatment, and the high infrared thermal imaging/photoacoustic imaging/fluorescence trimodal imaging-guided combined photothermal/photodynamic therapeutic effect on HCT116 tumor cell is successfully achieved. The results offer considerable promise for the development of COF nanomotors with integrated imaging/therapy modalities in biomedical applications.
Topics: Humans; Metal-Organic Frameworks; Polymers; Pyrroles; Precision Medicine; Neoplasms; Cell Line, Tumor
PubMed: 37557883
DOI: 10.1002/adhm.202301645 -
Journal of the American Chemical Society Jan 2024Bilirubin is the principal product of heme catabolism. High concentrations of the pigment are neurotoxic, yet slightly elevated levels are beneficial. Being a potent...
Bilirubin is the principal product of heme catabolism. High concentrations of the pigment are neurotoxic, yet slightly elevated levels are beneficial. Being a potent antioxidant, oxidative transformations of bilirubin occur in vivo and lead to various oxidized fragments. The mechanisms of their formation, intrinsic biological activities, and potential roles in human pathophysiology are poorly understood. Degradation methods have been used to obtain samples of bilirubin oxidation products for research. Here, we report a complementary, fully synthetic method of preparation. Our strategy leverages repeating substitution patterns in the parent tetracyclic pigment. Functionalized ready-to-couple γ-lactone, γ-lactam, and pyrrole monocyclic building blocks were designed and efficiently synthesized. Subsequent modular combinations, supported by metal-catalyzed borylation and cross-coupling chemistries, translated into the concise assembly of the structurally diverse bilirubin oxidation products (BOXes, propentdyopents, and biopyrrins). The discovery of a new photoisomer of biopyrrin A named lumipyrrin is reported. Synthetic bilirubin oxidation products made available in sufficient purity and quantity will support future in vitro and in vivo investigations.
Topics: Humans; Bilirubin; Oxidation-Reduction; Pyrroles; Oxidative Stress
PubMed: 38165253
DOI: 10.1021/jacs.3c11778 -
American Journal of Respiratory and... Jun 2024Pharmacological improvement of cystic fibrosis transmembrane conductance regulator (CFTR) function with elexacaftor/tezacaftor/ivacaftor (ETI) provides unprecedented...
Pharmacological Improvement of Cystic Fibrosis Transmembrane Conductance Regulator Function Rescues Airway Epithelial Homeostasis and Host Defense in Children with Cystic Fibrosis.
Pharmacological improvement of cystic fibrosis transmembrane conductance regulator (CFTR) function with elexacaftor/tezacaftor/ivacaftor (ETI) provides unprecedented improvements in lung function and other clinical outcomes in patients with cystic fibrosis (CF). However, ETI effects on impaired mucosal homeostasis and host defense at the molecular and cellular levels in the airways of patients with CF remain unknown. To investigate effects of ETI on the transcriptome of nasal epithelial and immune cells from children with CF at the single-cell level. Nasal swabs from 13 children with CF and at least one allele aged 6 to 11 years were collected at baseline and 3 months after initiation of ETI, subjected to single-cell RNA sequencing, and compared with swabs from 12 age-matched healthy children. Proportions of -positive cells were decreased in epithelial basal, club, and goblet cells, but not in ionocytes, from children with CF at baseline and were restored by ETI therapy to nearly healthy levels. Single-cell transcriptomics revealed an impaired IFN signaling and reduced expression of major histocompatibility complex classes I and II encoding genes in epithelial cells of children with CF at baseline, which was partially restored by ETI. In addition, ETI therapy markedly reduced the inflammatory phenotype of immune cells, particularly of neutrophils and macrophages. Pharmacological improvement of CFTR function improves innate mucosal immunity and reduces immune cell inflammatory responses in the upper airways of children with CF at the single-cell level, highlighting the potential to restore epithelial homeostasis and host defense in CF airways by early initiation of ETI therapy.
Topics: Humans; Cystic Fibrosis; Child; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Male; Homeostasis; Benzodioxoles; Aminophenols; Quinolones; Indoles; Drug Combinations; Quinolines; Pyrazoles; Pyrroles; Nasal Mucosa; Pyridines
PubMed: 38259174
DOI: 10.1164/rccm.202310-1836OC -
Clinical Pharmacology in Drug... Mar 2024Vonoprazan holds significant research promise for Helicobacter pylori eradication, with the goal of determining the most effective drug regimen. In this study, H. pylori...
Vonoprazan holds significant research promise for Helicobacter pylori eradication, with the goal of determining the most effective drug regimen. In this study, H. pylori patients (426) were enrolled and randomized into 3 groups: an EA14 group (20 mg of esomeprazole qid and 1000 mg of amoxicillin tid for 14 days), a VA14 group (20 mg of vonoprazan bid and 750 mg of amoxicillin qid for 14 days), and a VA10 group (20 mg of vonoprazan bid and 1000 mg of amoxicillin tid for 10 days). Key outcomes encompassed the H. pylori eradication rate, patient adverse effects, and compliance. In the EA14, VA14, and VA10 groups, H. pylori eradication rates were 89.4%, 90.1%, and 88.7% in intention-to-treat analysis, and 94.2%, 94.4%, and 94.6% in per-protocol analysis, respectively. Adverse events incidences were 14.8%, 12.7%, and 5.6%, while compliance rates were 88.7%, 90.9%, and 95.8%, respectively. Notably, the VA10 regimen demonstrated comparable H. pylori eradication rates, adverse effect incidences, and compliance levels to the EA14 and VA14 regimens.
Topics: Humans; Amoxicillin; Helicobacter pylori; Helicobacter Infections; Proton Pump Inhibitors; Metronidazole; Pyrroles; Sulfonamides
PubMed: 38197874
DOI: 10.1002/cpdd.1357 -
Aging Nov 2023Mild cognitive impairment (MCI) is a common symptom observed in people over 60 years old and is found to be aggravated by hypercholesterolemia. Severe neuroinflammation...
Mild cognitive impairment (MCI) is a common symptom observed in people over 60 years old and is found to be aggravated by hypercholesterolemia. Severe neuroinflammation induced by BBB dysfunction and monocyte infiltration might be responsible for neuron damage and cognitive impairment. Atorvastatin is a lipid-lowering drug that is widely applied for the treatment of cardiovascular diseases. However, the potential function of Atorvastatin in hypercholesterolemia-induced MCI remains uncertain. Our research will explore the potential therapeutic function of Atorvastatin in memory deficits induced by chronic hypercholesterolemia. ApoE mice were utilized to mimic the state of chronic hypercholesterolemia and were divided into four groups. Animals in the WT and ApoEgroups were orally administered with normal saline, while WT mice in the Atorvastatin group and ApoE mice in the ApoE+ Atorvastatin group were orally administered with 10 mg/kg/day Atorvastatin. Markedly increased plasma cholesterol levels reduced RI in the long-term memory test and the spatial short-term memory test, declined mobility in the open field test, and downregulated PSD-95 and BDNF were observed in ApoE mice, all of which were signally reversed by Atorvastatin. Moreover, the percentages of brain Ly6C CD45 cells and CD3 CD45 cells, as well as the blood Ly6C CD45 cells, plasma IL-12/IL-23 levels and IL-17 level were found notably increased in ApoE mice, all of which were largely repressed by Atorvastatin. Lastly, the increased BBB permeability, decreased ZO-1 and occludin levels, and reduced KLF2 level were markedly abolished by Atorvastatin. Collectively, Atorvastatin mitigated memory deficits and brain monocyte infiltration in ApoE mice.
Topics: Humans; Mice; Animals; Atorvastatin; Hypercholesterolemia; Monocytes; Heptanoic Acids; Pyrroles; Hyperlipidemias; Apolipoproteins E; Brain
PubMed: 38048213
DOI: 10.18632/aging.205217 -
Inflammatory Bowel Diseases Jul 2024Tofacitinib, as inhibitor of Janus kinases (JAK), interrupts the transmission of numerous pro-inflammatory cytokines involved in the pathogenesis of inflammatory bowel...
BACKGROUND
Tofacitinib, as inhibitor of Janus kinases (JAK), interrupts the transmission of numerous pro-inflammatory cytokines involved in the pathogenesis of inflammatory bowel diseases (IBD). Therefore, tofacitinib provides a potent option to treat ulcerative colitis (UC). Besides the anti-inflammatory potential, inhibition of widespread JAKs carries the risk of side effects. Macrophages are involved in the form of different subtypes in inflammation, wound healing, and even coagulation. This study aimed to explore the balanced use of tofacitinib in M1-like as well as M2-like macrophages of healthy donors and patients with IBD.
METHODS
Monocytes of healthy donors and patients with chronic courses of IBD were obtained from blood samples. Macrophage colony-stimulating factor (M-CSF)-derived macrophages were treated with tofacitinib (1 µM, 5 µM, 10 µM) and polarized with either lipopolysaccharide and interferon (IFN)-γ towards M1-like-phenotype or with interleukin (IL)-4 towards M2-like-phenotype. ELISA and flow cytometry were used to evaluate cytokine levels and surface molecules.
RESULTS
Tofacitinib had a modulating effect on M1-like macrophages whereby the effect on pro-inflammatory cytokines (TNF-α, IL-6, IL-1β, IL-12, IL-23) was less pronounced than the induction of anti-inflammatory IL-10. However, during M2-like polarization tofacitinib impaired the development of the corresponding phenotype becoming evident through decreased IL-10 levels and CD206 expression in treated macrophages. In both phenotypes, tofacitinib strongly downregulated the expression of immunostimulatory molecules (CD80, CD86, CD83, CD40). Furthermore, a dose-dependent correlation between treatment with tofacitinib and expressed tissue factor was noticed.
CONCLUSIONS
Tofacitinib influences both polarizations (M1/M2) and the expression of tissue factor in a dose-dependent manner.
Topics: Humans; Piperidines; Pyrimidines; Macrophages; Pyrroles; Thromboplastin; Cytokines; Adult; Healthy Volunteers; Male; Inflammatory Bowel Diseases; Female; Protein Kinase Inhibitors; Case-Control Studies; Cells, Cultured; Middle Aged
PubMed: 38142236
DOI: 10.1093/ibd/izad290 -
Acta Biomaterialia Sep 2023Nitric oxide (NO) is a crucial gaseous medium for tumor growth and progression, but it may also cause mitochondrial disorder and DNA damage by drastically increasing its...
Nitric oxide (NO) is a crucial gaseous medium for tumor growth and progression, but it may also cause mitochondrial disorder and DNA damage by drastically increasing its concentration in tumor. Due to its challenging administration and unpredictable release, NO based gas therapy is difficult to eliminate malignant tumor at low safe doses. To address these issues, herein, we develop a multifunctional nanocatalyst called Cu-doped polypyrrole (CuP) as an intelligent nanoplatform (CuP-B@P) to deliver the NO precursor BNN6 and specifically release NO in tumors. Under the aberrant metabolic environment of tumors, CuP-B@P catalyzes the conversion of antioxidant GSH into GSSG and excess HO into ·OH through Cu/Cu cycle, which results in oxidative damage to tumor cells and the concomitant release of cargo BNN6. More importantly, after laser exposure, nanocatalyst CuP can absorb and convert photons into hyperthermia, which in turn, accelerates the aforesaid catalytic efficiency and pyrolyzes BNN6 into NO. Under the synergistic effect of hyperthermia, oxidative damage, and NO burst, almost complete tumor elimination is achieved in vivo with negligible toxicity to body. Such an ingenious combination of NO prodrug and nanocatalytic medicine provides a new insight into the development of NO based therapeutic strategies. STATEMENT OF SIGNIFICANCE: A hyperthermia-responsive NO delivery nanoplatform (CuP-B@P) based on Cu-doped polypyrrole was designed and fabricated, in which CuP catalyzed the conversion of HO and GSH into ·OH and GSSG to induce intratumoral oxidative damage. After laser irradiation, hyperthermia ablation and responsive release of NO further coupled with oxidative damage to eliminate malignant tumors. This versatile nanoplatform provides new insights into the combined application of catalytic medicine and gas therapy.
Topics: Humans; Polymers; Pyrroles; Nitric Oxide; Phototherapy; Hyperthermia, Induced; Hydrogen Peroxide; Glutathione Disulfide; Neoplasms; Catalysis; Cell Line, Tumor; Nanoparticles
PubMed: 37302733
DOI: 10.1016/j.actbio.2023.06.002