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Bioelectrochemistry (Amsterdam,... Feb 2024Polypyrrole (Ppy) is an electroconductive polymer used in various applications, including in vitro experiments with cell cultures under electrical stimulation (ES). Ppy... (Review)
Review
Polypyrrole (Ppy) is an electroconductive polymer used in various applications, including in vitro experiments with cell cultures under electrical stimulation (ES). Ppy can be applied in various forms and most importantly, it is biocompatible with cells. Ppy specifically directs ES to cells, which makes Ppy a potential polymer for the development of novel technologies for targeted tissue regeneration. The high potential of ES in combination with different Ppy-based systems, such as hydrogels, scaffolds, or Ppy-layers is advantageous to stimulate cellular differentiation towards neurogenic, cardiac, muscle, and osteogenic lineages. Different in-house devices and the principles of ES application used to stimulate cellular functions are reviewed and summarized. The focus of this review is to observe the most relevant studies and their in-house techniques regarding the application of Ppy-based materials for the use of bone, neural, cardiac, and muscle tissue regeneration under ES. Different types of Ppy materials, such as Ppy particles, layers/films, membranes, and 3D-shaped synthetic and natural scaffolds, as well as combining Ppy with different active molecules are reviewed.
Topics: Polymers; Pyrroles; Cell Line; Electric Stimulation
PubMed: 37847982
DOI: 10.1016/j.bioelechem.2023.108585 -
Endocrinology Feb 2024Endometriosis is a common and debilitating disease, affecting ∼170 million women worldwide. Affected patients have limited therapeutic options such as hormonal...
Endometriosis is a common and debilitating disease, affecting ∼170 million women worldwide. Affected patients have limited therapeutic options such as hormonal suppression or surgical excision of the lesions, though therapies are often not completely curative. Targeting receptor tyrosine kinases (RTKs) could provide a nonhormonal treatment option for endometriosis. We determined that 2 RTKs, macrophage-colony stimulating factor 1 receptor (CSF1R) and mast/stem cell growth factor receptor KIT (KIT), are overexpressed in endometriotic lesions and could be novel nonhormonal therapeutic targets for endometriosis. The kinase activity of CSF1R and KIT is suppressed by pexidartinib, a small molecule inhibitor that was recently approved by the US Food and Drug Administration. Using immunohistochemistry, we detected CSF1R and KIT in endometriotic tissues obtained from peritoneal lesions, colorectal lesions, and endometriomas. Specifically, we show that KIT is localized to the epithelium of the lesions, while CSF1R is expressed in the stroma and macrophages of the endometriotic lesions. Given the high epithelial expression of CSF1R and KIT, 12Z endometriotic epithelial cells were used to evaluate the efficacy of dual CSF1R and KIT inhibition with pexidartinib. We found that pexidartinib suppressed activation in 12Z cells of JNK, STAT3, and AKT signaling pathways, which control key proinflammatory and survival networks within the cell. Using quantitative real-time polymerase chain reaction, we determined that pexidartinib suppressed interleukin 8 (IL8) and cyclin D1 (CCND1) expression. Lastly, we demonstrated that pexidartinib decreased cell growth and viability. Overall, these results indicate that pexidartinib-mediated CSF1R and KIT inhibition reduces proinflammatory signaling and cell viability in endometriosis.
Topics: Humans; Female; Endometriosis; Cell Survival; Signal Transduction; Receptor Protein-Tyrosine Kinases; Aminopyridines; Pyrroles
PubMed: 38227801
DOI: 10.1210/endocr/bqae003 -
ACS Chemical Biology Mar 2024Elucidating the mechanism of action (MoA) of antibacterial natural products is crucial to evaluating their potential as novel antibiotics. Marinopyrroles,...
Elucidating the mechanism of action (MoA) of antibacterial natural products is crucial to evaluating their potential as novel antibiotics. Marinopyrroles, pentachloropseudilin, and pentabromopseudilin are densely halogenated, hybrid pyrrole-phenol natural products with potent activity against Gram-positive bacterial pathogens like . However, the exact way they exert this antibacterial activity has not been established. In this study, we explore their structure-activity relationship, determine their spatial location in bacterial cells, and investigate their MoA. We show that the natural products share a common MoA based on membrane depolarization and dissipation of the proton motive force (PMF) that is essential for cell viability. The compounds show potent protonophore activity but do not appear to destroy the integrity of the cytoplasmic membrane via the formation of larger pores or interfere with the stability of the peptidoglycan sacculus. Thus, our current model for the antibacterial MoA of marinopyrrole, pentachloropseudilin, and pentabromopseudilin stipulates that the acidic compounds insert into the membrane and transport protons inside the cell. This MoA may explain many of the deleterious biological effects in mammalian cells, plants, phytoplankton, viruses, and protozoans that have been reported for these compounds.
Topics: Animals; Anti-Bacterial Agents; Pyrroles; Hydrocarbons, Chlorinated; Biological Products; Microbial Sensitivity Tests; Mammals
PubMed: 38377384
DOI: 10.1021/acschembio.3c00773 -
Journal of Ayub Medical College,... 2023Helicobacter pylori (H. pylori) is a gram-negative bacterium which usually resides in the mucoid lining of the stomach and may cause different gastric pathologies e.g.,... (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy And Cost-Effectiveness, Comparison Of 7-Days Vonoprazan Versus 14-Days Esomeprazole Based Triple Therapies For Treating Helicobacter Pylori Infection In Pakistani Population: A Randomized Clinical Trial.
BACKGROUND
Helicobacter pylori (H. pylori) is a gram-negative bacterium which usually resides in the mucoid lining of the stomach and may cause different gastric pathologies e.g., Gastritis, peptic ulcer disease, adenocarcinoma of the gastric system and mucoid associated lymphoma (MALT). The Objective was to compare the effect of 7-days Vonoprazan based triple therapy and 14-days Esomeprazole based triple therapy on eradication rate, compliance and cost effectiveness in Helicobacter pylori infected patients.
METHODS
This clinical trial was performed in the Department of Pharmacology Army Medical College, National University of Medical Sciences (NUMS) in collaboration with the Gastroenterology Department, Pak Emirates Military Hospital (PEMH) Rawalpindi from December 2022 to March 2023. A total of one hundred and twenty-two patients with dyspepsia symptoms and yielding lab results positive for Helicobacter pylori by stool antigen test were enrolled in the study. They were randomly allocated into two groups. The Esomeprazole group received 14 days of triple therapy orally with Esomeprazole 20 mg twice a day; Amoxicillin 1000 mg twice a day; and Levofloxacin 500 mg one time a day. The comparative Vonoprazan group was given 7-days triple therapy orally with Vonoprazan 20 mg twice a day; Amoxicillin 1000 mg twice a day; and Levofloxacin 500 mg one time a day. Eradication success was evaluated by stool antigen test four weeks later, as counted from the start of treatment. compliance and cost-effectiveness of both therapies were also assessed.
RESULTS
The eradication rate was (95.1%) in the Vonoprazan group with 58 out of 61 patients negative for H. pylori and (93.1%) in Esomeprazole group with 54 patients out of 58 yielding a negative result demonstrating p-value of 0.64. Compliance was 95.0% in the Esomeprazole group with p-value of 0.07. Cost effective ratio for Vonoprazan triple therapy was lower (731.8PKR) than the Esomeprazole group.
CONCLUSION
One two-week Vonoprazan regimen demonstrated improved eradication rate, good compliance, and better tolerability in patients with less cost and a half duration of treatment in comparison with two weeks Esomeprazole regimen, attesting that one week Vonoprazan therapy is more cost efficacious in producing better results.
Topics: Humans; Amoxicillin; Anti-Bacterial Agents; Cost-Benefit Analysis; Cost-Effectiveness Analysis; Drug Therapy, Combination; Esomeprazole; Helicobacter Infections; Helicobacter pylori; Levofloxacin; Pakistan; Pyrroles; Sulfonamides; Treatment Outcome
PubMed: 38406904
DOI: 10.55519/JAMC-S4-12110 -
Cephalalgia : An International Journal... Aug 2023Atogepant is an oral, small-molecule, calcitonin gene-related peptide receptor antagonist for the preventive treatment of episodic migraine. (Randomized Controlled Trial)
Randomized Controlled Trial
Patient-reported migraine-specific quality of life, activity impairment and headache impact with once-daily atogepant for preventive treatment of migraine in a randomized, 52-week trial.
BACKGROUND
Atogepant is an oral, small-molecule, calcitonin gene-related peptide receptor antagonist for the preventive treatment of episodic migraine.
METHODS
In this 52-week, multicenter, randomized, open-label trial, adults with 4-14 monthly migraine days received atogepant 60 mg once-daily or standard care. Health outcome endpoints collected from participants randomized to atogepant included change from baseline in Migraine-Specific Quality of Life Questionnaire version 2.1 (MSQ v2.1) Role Function-Restrictive (RFR), Role Function-Preventive (RFP) and Emotional Function (EF) domain scores, change in Activity Impairment in Migraine-Diary (AIM-D) Performance of Daily Activities (PDA) and Physical Impairment (PI) domain scores, and change in Headache Impact Test-6 (HIT-6) total score.
RESULTS
Of 744 randomized participants, 521 received atogepant 60 mg in the modified intent-to-treat population. Least-squares mean changes from baseline in MSQ-RFR score were 30.02 (95% confidence interval = 28.16-31.87) at week 12 and 34.70 (95% confidence interval = 32.74-36.66) at week 52. Improvements were also observed in other MSQ domains, AIM-D PDA, PI and HIT-6 total scores. A ≥5-point improvement from baseline in HIT-6 score was observed in 59.9% of participants at week 4 and 80.8% of participants at week 52.
CONCLUSION
Over 52 weeks, atogepant 60 mg once-daily was associated with sustained improvements in quality of life and reductions in activity impairment and headache impact. NCT03700320.
Topics: Humans; Quality of Life; Piperidines; Pyridines; Pyrroles; Spiro Compounds; Calcitonin Gene-Related Peptide Receptor Antagonists; Migraine Disorders; Patient Reported Outcome Measures; Drug Administration Schedule
PubMed: 37638400
DOI: 10.1177/03331024231190296 -
Alimentary Pharmacology & Therapeutics Dec 2023
Topics: Humans; Proton Pump Inhibitors; Gastroesophageal Reflux; Pyrroles; Sulfonamides
PubMed: 37986593
DOI: 10.1111/apt.17766 -
ACS Applied Materials & Interfaces Sep 2023Effective repair and functional recovery of large peripheral nerve deficits are urgent clinical needs. A biofunctional electroactive scaffold typically acts as a...
Effective repair and functional recovery of large peripheral nerve deficits are urgent clinical needs. A biofunctional electroactive scaffold typically acts as a "bridge" for the repair of large nerve defects. In this study, we constructed a biomimetic piezoelectric and conductive aligned polypyrrole (PPy)/polydopamine (PDA)/poly-l-lactic acid (PLLA) electrospun fibrous scaffold to improve the hydrophilicity and cellular compatibility of PLLA and restore the weakened piezoelectric effect of PDA, which is beneficial in promoting Schwann cell differentiation and dorsal root ganglion neuronal extension and alignment. The aligned PPy/PDA/PLLA fibrous scaffold bridged the sciatic nerve of Sprague-Dawley rats with a 10 mm deficit, prevented autotomy, and promoted nerve regeneration and functional recovery, thereby activating the calcium and AMP-activated protein kinase signaling pathways. Therefore, electroactive fibrous scaffolds exhibit great potential for neural tissue regeneration.
Topics: Rats; Animals; Rats, Sprague-Dawley; Polymers; Pyrroles; Nerve Regeneration; Sciatic Nerve
PubMed: 37606339
DOI: 10.1021/acsami.3c09237 -
Clinical Gastroenterology and... Jun 2024Previous studies confirm vonoprazan-amoxicillin effectiveness for Helicobacter pylori. This study aims to investigate vonoprazan with varying amoxicillin dose and... (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy and Safety of Vonoprazan-Amoxicillin Dual Regimen With Varying Dose and Duration for Helicobacter pylori Eradication: A Multicenter, Prospective, Randomized Study.
BACKGROUND & AIMS
Previous studies confirm vonoprazan-amoxicillin effectiveness for Helicobacter pylori. This study aims to investigate vonoprazan with varying amoxicillin dose and duration.
METHODS
This multicenter, prospective, randomized controlled, noninferiority trial enrolled patients with treatment naive H pylori infection from 5 clinical centers. Eligible participants were randomly assigned to H-VA-10 (vonoprazan 20 mg twice a day (b.i.d.) + amoxicillin 750 mg 4 times a day, 10 days), L-VA-10 (vonoprazan 20 mg b.i.d. + amoxicillin 1000 mg b.i.d, 10 days), and H-VA-14 (vonoprazan 20 mg b.i.d + amoxicillin 750 mg 4 times a day, 14 days) in a 1:1:1 ratio. The eradication rate was assessed using the C-urea breath test at least 28 days after treatment.
RESULTS
Of the 623 eligible patients, 516 patients were randomized. In both the intention-to-treat and per-protocol analyses, eradication rates were comparable between H-VA-10 and H-VA-14 groups (86.6% vs 89.5% and 90.9% vs 94.5%, P = .021 and .013 for noninferiority, respectively). However, eradication rates were significantly lower in the L-VA-10 group than the H-VA-14 group (79.7% vs 89.5% and 82.0% vs 94.5%, P = .488 and .759, respectively). Rates of study withdrawal, loss to follow-up, and adverse events were similar across study groups.
CONCLUSIONS
H-VA-10 and H-VA-14 regimens provide satisfactory efficacy for H pylori infection, and the L-VA-10 regimen was inferior.
CLINICALTRIALS
gov number: NCT05719831.
Topics: Humans; Sulfonamides; Helicobacter Infections; Male; Female; Middle Aged; Pyrroles; Prospective Studies; Amoxicillin; Helicobacter pylori; Anti-Bacterial Agents; Drug Therapy, Combination; Treatment Outcome; Aged; Adult; Proton Pump Inhibitors; Drug Administration Schedule
PubMed: 38309492
DOI: 10.1016/j.cgh.2024.01.022 -
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