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The Journal of Pharmacology and... Jun 2024Nonsteroidal anti-inflammatory drugs (NSAIDs) possess anti-inflammatory, antipyretic, and analgesic properties and are among the most commonly used drugs. Although the...
Nonsteroidal anti-inflammatory drugs (NSAIDs) possess anti-inflammatory, antipyretic, and analgesic properties and are among the most commonly used drugs. Although the cause of NSAID-induced gastric ulcers is well understood, the mechanism behind small intestinal ulcers remains elusive. In this study, we examined the mechanism through which indomethacin (IM), a prominent NSAID, induces small intestinal ulcers, both in vitro and in vivo. In IEC6 cells, a small intestinal epithelial cell line, IM treatment elevated levels of LC3-II and p62. These expression levels remained unaltered after treatment with chloroquine or bafilomycin, which are vacuolar ATPase (V-ATPase) inhibitors. IM treatment reduced the activity of cathepsin B, a lysosomal protein hydrolytic enzyme, and increased the lysosomal pH. There was a notable increase in subcellular colocalization of LC3 with Lamp2, a lysosome marker, post IM treatment. The increased lysosomal pH and decreased cathepsin B activity were reversed by pretreatment with rapamycin (Rapa) or glucose starvation, both of which stabilize V-ATPase assembly. To validate the in vitro findings in vivo, we established an IM-induced small intestine ulcer mouse model. In this model, we observed multiple ulcerations and heightened inflammation following IM administration. However, pretreatment with Rapa or fasting, which stabilize V-ATPase assembly, mitigated the IM-induced small intestinal ulcers in mice. Coimmunoprecipitation studies demonstrated that IM binds to V-ATPase in vitro and in vivo. These findings suggest that IM induces small intestinal injury through lysosomal dysfunction, likely due to the disassembly of lysosomal V-ATPase caused by direct binding. Moreover, Rapa or starvation can prevent this injury by stabilizing the assembly. SIGNIFICANCE STATEMENT: This study elucidates the largely unknown mechanisms behind small intestinal ulceration induced by indomethacin and reveals the involvement of lysosomal dysfunction via vacuolar ATPase disassembly. The significance lies in identifying potential preventative interventions, such as rapamycin treatment or glucose starvation, offering pivotal insights that extend beyond nonsteroidal anti-inflammatory drugs-induced ulcers to broader gastrointestinal pathologies and treatments, thereby providing a foundation for novel therapeutic strategies aimed at a wide array of gastrointestinal disorders.
Topics: Animals; Indomethacin; Lysosomes; Vacuolar Proton-Translocating ATPases; Sirolimus; Mice; Male; Rats; Anti-Inflammatory Agents, Non-Steroidal; Cathepsin B; Mice, Inbred C57BL; Cell Line; Intestine, Small; Ulcer
PubMed: 38834354
DOI: 10.1124/jpet.123.001981 -
International Immunopharmacology Jul 2024Systemic sclerosis (SSc) is a devastating autoimmune illness with a wide range of clinical symptoms, including vascular abnormalities, inflammation, and persistent and...
Systemic sclerosis (SSc) is a devastating autoimmune illness with a wide range of clinical symptoms, including vascular abnormalities, inflammation, and persistent and progressive fibrosis. The disease's complicated pathophysiology makes it difficult to develop effective therapies, necessitating research into novel therapeutic options. Molecular hybridization is a strategy that can be used to develop new drugs that act on two or multiple targets and represents an interesting option to be explored for the treatment of complex diseases. We aimed to evaluate the effects of a hybrid mutual prodrug of ibuprofen and acetaminophen (IBPA) in peripheral blood mononuclear cells (PBMC) isolated from SSc patients, and in an in vivo model of SSc induced in BALB/c mice by intradermal injections of hypochlorous acid (HOCl) for 6 weeks. The mice were treated at the same time with daily intraperitoneal injections of IBPA (40 mg/kg). Pulmonary and skin fibrosis as well as immune responses were evaluated. IBPA significantly decreased the release of cytokines in PBMC culture supernatants from SSc patients after stimulation with phytohemagglutinin-M (IL-2, IL-4, IL-6, IL-10, IL-13, IL-17A, TNF and IFN-γ).In HOCl-induced SSc, IBPA treatment prevented dermal and pulmonary fibrosis, in addition to reducing CD4 + T and B cells activation and reversing the M2 polarization of macrophages in spleen cells, and inhibiting IFN-γ secretion in splenocyte cultures. These results show the anti-inflammatory and antifibrotic effects of IBPA in SSc and highlight the therapeutic potential of this mutual prodrug, providing support for future studies.
Topics: Animals; Humans; Prodrugs; Mice, Inbred BALB C; Acetaminophen; Female; Scleroderma, Systemic; Ibuprofen; Cytokines; Leukocytes, Mononuclear; Fibrosis; Disease Models, Animal; Mice; Male; Middle Aged; Inflammation; Cells, Cultured; Skin; Hypochlorous Acid; Adult
PubMed: 38833846
DOI: 10.1016/j.intimp.2024.112344 -
Saudi Medical Journal Jun 2024
Topics: Humans; Colorectal Neoplasms; Aspirin; Disease Progression; Anti-Inflammatory Agents, Non-Steroidal
PubMed: 38830654
DOI: No ID Found -
Annals of Internal Medicine Jun 2024Kamel H, Longstreth WT Jr, Tirschwell DL, et al; ARCADIA Investigators. JAMA. 2024;331:573-581. 38324415. (Randomized Controlled Trial)
Randomized Controlled Trial
Kamel H, Longstreth WT Jr, Tirschwell DL, et al; ARCADIA Investigators. JAMA. 2024;331:573-581. 38324415.
Topics: Humans; Pyridones; Pyrazoles; Aspirin; Factor Xa Inhibitors; Secondary Prevention; Atrial Fibrillation; Recurrence; Male; Stroke; Platelet Aggregation Inhibitors; Female; Ischemic Stroke; Aged
PubMed: 38830225
DOI: 10.7326/ANNALS-24-00436-JC -
Annals of Internal Medicine Jun 2024Hong SJ, Lee SJ, Suh Y, et al; T-PASS (Ticagrelor Monotherapy in Patients Treated With New-Generation Drug-Eluting Stents for Acute Coronary Syndrome) Investigators.... (Randomized Controlled Trial)
Randomized Controlled Trial
Hong SJ, Lee SJ, Suh Y, et al; T-PASS (Ticagrelor Monotherapy in Patients Treated With New-Generation Drug-Eluting Stents for Acute Coronary Syndrome) Investigators. Circulation. 2024;149:562-573. 37878786.
Topics: Ticagrelor; Humans; Acute Coronary Syndrome; Drug-Eluting Stents; Dual Anti-Platelet Therapy; Platelet Aggregation Inhibitors; Aspirin; Percutaneous Coronary Intervention; Male; Female; Middle Aged; Treatment Outcome
PubMed: 38830214
DOI: 10.7326/ANNALS-24-00207-JC -
Pharmacoepidemiology and Drug Safety Jun 2024Medications prescribed to older adults in US skilled nursing facilities (SNF) and administrations of pro re nata (PRN) "as needed" medications are unobservable in...
PURPOSE
Medications prescribed to older adults in US skilled nursing facilities (SNF) and administrations of pro re nata (PRN) "as needed" medications are unobservable in Medicare insurance claims. There is an ongoing deficit in our understanding of medication use during post-acute care. Using SNF electronic health record (EHR) datasets, including medication orders and barcode medication administration records, we described patterns of PRN analgesic prescribing and administrations among SNF residents with hip fracture.
METHODS
Eligible participants resided in SNFs owned by 11 chains, had a diagnosis of hip fracture between January 1, 2018 to August 2, 2021, and received at least one administration of an analgesic medication in the 100 days after the hip fracture. We described the scheduling of analgesics, the proportion of available PRN doses administered, and the proportion of days with at least one PRN analgesic administration.
RESULTS
Among 24 038 residents, 57.3% had orders for PRN acetaminophen, 67.4% PRN opioids, 4.2% PRN non-steroidal anti-inflammatory drugs, and 18.6% PRN combination products. The median proportion of available PRN doses administered per drug was 3%-50% and the median proportion of days where one or more doses of an ordered PRN analgesic was administered was 25%-75%. Results differed by analgesic class and the number of administrations ordered per day.
CONCLUSIONS
EHRs can be leveraged to ascertain precise analgesic exposures during SNF stays. Future pharmacoepidemiology studies should consider linking SNF EHRs to insurance claims to construct a longitudinal history of medication use and healthcare utilization prior to and during episodes of SNF care.
Topics: Humans; Hip Fractures; Electronic Health Records; Female; Aged; Male; Aged, 80 and over; United States; Analgesics; Skilled Nursing Facilities; Medicare; Subacute Care; Acetaminophen
PubMed: 38825963
DOI: 10.1002/pds.5846 -
International Heart Journal 2024This study aimed to investigate the molecular mechanisms underlying the protective effects of cyclooxygenase (cox) inhibitors against myocardial hypertrophy.Rat H9c2...
This study aimed to investigate the molecular mechanisms underlying the protective effects of cyclooxygenase (cox) inhibitors against myocardial hypertrophy.Rat H9c2 cardiomyocytes were induced by mechanical stretching. SD rats underwent transverse aortic constriction to induce pressure overload myocardial hypertrophy. Rats were subjected to echocardiography and tail arterial pressure in 12W. qPCR and western blot were used to detect the expression of Notch-related signaling. The inflammatory factors were tested by ELISA in serum, heart tissue, and cell culture supernatant.Compared with control, levels of pro-inflammatory cytokines IL-6, TNF-α, and IL-1β were increased and anti-inflammatory cytokine IL-10 was reduced in myocardial tissues and serum of rat models. Levels of Notch1 and Hes1 were reduced in myocardial tissues. However, cox inhibitor treatment (aspirin and celecoxib), the improvement of exacerbated myocardial hypertrophy, fibrosis, dysfunction, and inflammation was parallel to the activation of Notch1/Hes1 pathway. Moreover, in vitro experiments showed that, in cardiomyocyte H9c2 cells, application of ~20% mechanical stretching activated inflammatory mediators (IL-6, TNF-α, and IL-1β) and hypertrophic markers (ANP and BNP). Moreover, expression levels of Notch1 and Hes1 were decreased. These changes were effectively alleviated by aspirin and celecoxib.Cox inhibitors may protect heart from hypertrophy and inflammation possibly via the Notch1/Hes1 signaling pathway.
Topics: Animals; Receptor, Notch1; Rats; Transcription Factor HES-1; Rats, Sprague-Dawley; Signal Transduction; Celecoxib; Aspirin; Male; Myocytes, Cardiac; Cyclooxygenase Inhibitors; Cardiomegaly; Disease Models, Animal
PubMed: 38825493
DOI: 10.1536/ihj.23-614 -
Journal of Biotechnology Aug 2024Solanum xanthocarpum fruits are used in the treatment of cough, fever, and heart disorders. It possesses antipyretic, hypotensive, antiasthmatic, aphrodisiac and...
Solanum xanthocarpum fruits are used in the treatment of cough, fever, and heart disorders. It possesses antipyretic, hypotensive, antiasthmatic, aphrodisiac and antianaphylactic properties. In the present study, 24 elicitors (both biotic and abiotic) were used to enhance the production of glycoalkaloids in cell cultures of S. xanthocarpum. Four concentrations of elicitors were added into the MS culture medium. The maximum accumulation (5.56-fold higher than control) of demissidine was induced by sodium nitroprusside at 50 mM concentration whereas the highest growth of cell biomass (4.51-fold higher than control) stimulated by systemin at 30 mM concentration. A total of 17 genes of biosynthetic pathways of glycoalkaloids were characterized from the cells of S. xanthocarpum. The greater accumulation of demissidine was confirmed with the expression analysis of 11 key biosynthetic pathway enzymes e.g., acetoacetic-CoA thiolase, 3- hydroxy 3-methyl glutaryl synthase, β-hydroxy β-methylglutaryl CoA reductase, mevalonate kinase, farnesyl diphosphate synthase, squalene synthase, squalene epoxidase, squalene-2,3- epoxide cyclase, cycloartenol synthase, UDP-glucose: solanidine glucosyltransferase and UDP-rhamnose: solanidine rhamno-galactosyl transferase. The maximum expression levels of UDP-rhamnose: solanidine rhamno-galactosyl transferase gene was recorded in this study.
Topics: Solanum; Biosynthetic Pathways; Gene Expression Regulation, Plant; Alkaloids; Plant Proteins; Solanaceous Alkaloids
PubMed: 38825191
DOI: 10.1016/j.jbiotec.2024.05.008 -
Journal of Medicinal Chemistry Jun 2024The concept of ferroptosis inhibition has gained growing recognition as a promising therapeutic strategy for addressing a wide range of diseases. Here, we present the...
The concept of ferroptosis inhibition has gained growing recognition as a promising therapeutic strategy for addressing a wide range of diseases. Here, we present the discovery of four series of -aminophenol derivatives as potential ferroptosis inhibitors beginning with the endogenous substance 3-hydroxyanthranilic acid (3-HA) by employing quantum chemistry techniques, in vitro and in vivo assays. Our findings reveal that these -aminophenol derivatives exhibit unique intra-H bond interactions, compelling -amines to achieve enhanced alignment with the aromatic π-system, thereby expanding their activity. Notably, compounds from all four series display remarkable activity against RSL3-induced ferroptosis, showcasing an activity 100 times more than that of 3-HA. Furthermore, these compounds also demonstrate robust in vivo efficacy in protecting mice from kidney ischemia-reperfusion injury and acetaminophen-induced hepatotoxicity. In summary, we provide four distinct series of active scaffolds that significantly expand the chemical space of ferroptosis inhibitors, serving as valuable insights for future structural modifications.
Topics: Animals; Aminophenols; Ferroptosis; Mice; Lipid Peroxidation; Humans; Structure-Activity Relationship; Acetaminophen; Reperfusion Injury; Male; Drug Discovery; Mice, Inbred C57BL
PubMed: 38822802
DOI: 10.1021/acs.jmedchem.4c00600 -
Journal of Translational Medicine May 2024Acetaminophen (APAP)-induced liver injury (AILI) is a pressing public health concern. Although evidence suggests that Bifidobacterium adolescentis (B. adolescentis) can...
Acetaminophen (APAP)-induced liver injury (AILI) is a pressing public health concern. Although evidence suggests that Bifidobacterium adolescentis (B. adolescentis) can be used to treat liver disease, it is unclear if it can prevent AILI. In this report, we prove that B. adolescentis significantly attenuated AILI in mice, as demonstrated through biochemical analysis, histopathology, and enzyme-linked immunosorbent assays. Based on untargeted metabolomics and in vitro cultures, we found that B. adolescentis generates microbial metabolite hypaphorine. Functionally, hypaphorine inhibits the inflammatory response and hepatic oxidative stress to alleviate AILI in mice. Transcriptomic analysis indicates that Cry1 expression is increased in APAP-treated mice after hypaphorine treatment. Overexpression of Cry1 by its stabilizer KL001 effectively mitigates liver damage arising from oxidative stress in APAP-treated mice. Using the gene expression omnibus (GEO) database, we verified that Cry1 gene expression was also decreased in patients with APAP-induced acute liver failure. In conclusion, this study demonstrates that B. adolescentis inhibits APAP-induced liver injury by generating hypaphorine, which subsequently upregulates Cry1 to decrease inflammation and oxidative stress.
Topics: Animals; Acetaminophen; Chemical and Drug Induced Liver Injury; Liver; Mice, Inbred C57BL; Male; Bifidobacterium adolescentis; Humans; Oxidative Stress; Mice; Gene Expression Regulation; Pyridines
PubMed: 38822329
DOI: 10.1186/s12967-024-05312-6