The cytochrome P4501A1 (CYP1A1) inhibitor bergamottin enhances host tolerance to multidrug-resistant Vibrio vulnificus infection DOI Creative Commons

Ruo-Bai Qiao,

Weihong Dai,

Wei Li

et al.

Chinese Journal of Traumatology, Journal Year: 2024, Volume and Issue: 27(5), P. 295 - 304

Published: July 3, 2024

Vibrio vulnificus (V. Vulnificus) infection is characterized by rapid onset, aggressive progression, and challenging treatment. Bacterial resistance poses a significant challenge for clinical anti-infection treatment thus the subject of research. Enhancing host tolerance represents novel prevention strategy to improve patient survival. Our team initially identified cytochrome P4501A1 (CYP1A1) as an important target owing its negative modulation body's tolerance. This study explored superior effects CYP1A1 inhibitor bergamottin compared antibiotic combination therapy on survival mice infected with multidrug-resistant V. Vulnificus protection their vital organs. An increasing concentration gradient method was used induce development. We established lethal model in C57BL/6J male evaluated effect mouse A mild mice, serum levels creatinine, urea nitrogen, aspartate aminotransferase, alanine aminotransferase were determined using enzyme-linked immunosorbent assay evaluate liver kidney function. The morphological changes induced presence organs hematoxylin eosin staining tissues. bacterial growth curve organ load determination whether has direct antibacterial Vulnificus. Quantification inflammatory factors expression tissues real-time quantitative polymerase chain reaction performed factor levels. Western blot analysis IκBα, phosphorylated p65, p65 protein human hepatocellular carcinomas-2 kidney-2 cell lines nuclear kappa-B signaling pathway. One-way ANOVA Kaplan-Meier statistical analysis. In Vulnificus, prolonged (p = 0.014), reduced creatinine 0.002), nitrogen 0.030), 0.029), 0.003) levels, protected cellular morphology Bergamottin inhibited interleukin (IL)-1β, IL-6, tumor necrosis (TNF)-α (IL-1β: p 0.010, IL-6: 0.029, TNF-α: 0.025) IL-1β, TNF-α 0.011, 0.037) 0.016, 0.008) did not affect proliferation or peritoneal lavage fluid 0.225), 0.186), 0.637). enhances infection. can serve reference guide development strategies

Language: Английский

Therapeutic Targeting of NF-κB in Acute Lung Injury: A Double-Edged Sword DOI Creative Commons
Michelle Warren Millar,

Fabeha Fazal,

Arshad Rahman

et al.

Cells, Journal Year: 2022, Volume and Issue: 11(20), P. 3317 - 3317

Published: Oct. 21, 2022

Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is a devastating disease that can be caused by variety of conditions including pneumonia, sepsis, trauma, and most recently, COVID-19. Although our understanding the mechanisms ALI/ARDS pathogenesis resolution has considerably increased in recent years, mortality rate remains unacceptably high (~40%), primarily due to lack effective therapies for ALI/ARDS. Dysregulated inflammation, as characterized massive infiltration polymorphonuclear leukocytes (PMNs) into airspace associated damage capillary-alveolar barrier leading pulmonary edema hypoxemia, major hallmark Endothelial cells (ECs), inner lining blood vessels, are important cellular orchestrators PMN lung. Nuclear factor-kappa B (NF-κB) plays an essential role rendering endothelium permissive adhesion transmigration reach inflammatory site. Thus, targeting NF-κB provides attractive approach mitigate PMN-mediated vascular injury, not only ALI/ARDS, but other diseases well which EC dysfunction pathogenic mechanism. This review discusses regulation context inflammation evaluates potential problems it therapy

Language: Английский

Citations

86
Small molecules in the treatment of COVID-19 DOI Creative Commons
Sibei Lei, Xiaohua Chen, Jieping Wu

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: Dec. 5, 2022

Abstract The outbreak of COVID-19 has become a global crisis, and brought severe disruptions to societies economies. Until now, effective therapeutics against are in high demand. Along with our improved understanding the structure, function, pathogenic process SARS-CoV-2, many small molecules potential anti-COVID-19 effects have been developed. So far, several antiviral strategies were explored. Besides directly inhibition viral proteins such as RdRp M pro , interference host enzymes including ACE2 proteases, blocking relevant immunoregulatory pathways represented by JAK/STAT, BTK, NF-κB, NLRP3 pathways, regarded feasible drug development. development treat achieved strategies, computer-aided lead compound design screening, natural product discovery, repurposing, combination therapy. Several representative remdesivir paxlovid proved or authorized emergency use countries. And candidates entered clinical-trial stage. Nevertheless, due epidemiological features variability issues it is necessary continue exploring novel COVID-19. This review discusses current findings for treatment. Moreover, their detailed mechanism action, chemical structures, preclinical clinical efficacies discussed.

Language: Английский

Citations

82
Modulation of redox-sensitive transcription factors with polyphenols as pathogenetically grounded approach in therapy of systemic inflammatory response DOI Creative Commons
V.О. Kostenko, O. Ye. Akimov, O.M. Gutnik

et al.

Heliyon, Journal Year: 2023, Volume and Issue: 9(5), P. e15551 - e15551

Published: April 16, 2023

One of the adverse outcomes acute inflammatory response is progressing to chronic stage or transforming into an aggressive process, which can develop rapidly and result in multiple organ dysfunction syndrome. The leading role this process played by Systemic Inflammatory Response that accompanied production pro- anti-inflammatory cytokines, phase proteins, reactive oxygen nitrogen species.The purpose review highlights both recent reports results authors' own research encourage scientists new approaches differentiated therapy various SIR manifestations (low- high-grade systemic phenotypes) modulating redox-sensitive transcription factors with polyphenols evaluate saturation pharmaceutical market appropriate dosage forms tailored for targeted delivery these compounds.Redox-sensitive such as NFκB, STAT3, AP1 Nrf2 have a mechanisms formation low- phenotypes variants SIR. These phenotypic underlie pathogenesis most dangerous diseases internal organs, endocrine nervous systems, surgical pathologies, post-traumatic disorders.The use individual chemical compounds class polyphenols, their combinations be effective technology Administering natural oral very beneficial management number low-grade phenotype. associated phenotype requires medicinal phenol preparations manufactured parenteral administration.

Language: Английский

Citations

56
The Immunopathogenesis of a Cytokine Storm: The Key Mechanisms Underlying Severe COVID-19 DOI Creative Commons

Luka Hiti,

Tijana Markovič,

Mitja Lainščak

et al.

Cytokine & Growth Factor Reviews, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

A cytokine storm is marked by excessive pro-inflammatory release, and has emerged as a key factor in severe COVID-19 cases - making it critical therapeutic target. However, its pathophysiology was poorly understood, which hindered effective treatment. SARS-CoV-2 initially disrupts angiotensin signalling, promoting inflammation through ACE-2 downregulation. Some patients' immune systems then fail to shift from innate adaptive immunity, suppressing interferon responses leading pyroptosis neutrophil activation. This amplifies tissue damage inflammation, creating loop. The result the disruption of Th1/Th2 Th17/Treg balances, lymphocyte exhaustion, extensive blood clotting. Cytokine treatments include glucocorticoids suppress system, monoclonal antibodies neutralize specific cytokines, JAK inhibitors block receptor signalling. most treatment options for mitigating infection remain vaccines preventive measure antiviral drugs early stages infection. article synthesizes insights into dysregulation COVID-19, offering framework better understand storms improve monitoring, biomarker discovery, strategies other conditions involving storms.

Language: Английский

Citations

7
COVID-19 in the Initiation and Progression of Atherosclerosis DOI Creative Commons
Vignesh Chidambaram,

Amudha Kumar,

Murrium I. Sadaf

et al.

JACC Advances, Journal Year: 2024, Volume and Issue: 3(8), P. 101107 - 101107

Published: July 17, 2024

The incidence of atherosclerotic cardiovascular disease is increasing globally, especially in low- and middle-income countries, despite significant efforts to reduce traditional risk factors. Premature subclinical atherosclerosis has been documented association with several viral infections. magnitude the recent COVID-19 pandemic highlighted need understand between SARS-CoV-2 atherosclerosis. This review examines various pathophysiological mechanisms, including endothelial dysfunction, platelet activation, inflammatory immune hyperactivation triggered by infection, specific attention on their roles initiating promoting progression lesions. Additionally, it addresses pathogenic mechanisms which post-acute phase may contribute development vascular disease. Understanding overlap these syndromes enable novel therapeutic strategies. We further explore for guidelines closer follow-up often-overlooked evidence among patients COVID-19, particularly those cardiometabolic

Language: Английский

Citations

9
Emerging regulatory mechanisms and functions of biomolecular condensates: implications for therapeutic targets DOI Creative Commons
Soyoung Jeon, Yong‐Duck Chung, Jae‐Sung Lim

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: Jan. 6, 2025

Cells orchestrate their processes through complex interactions, precisely organizing biomolecules in space and time. Recent discoveries have highlighted the crucial role of biomolecular condensates-membrane-less assemblies formed condensation proteins, nucleic acids, other molecules-in driving efficient dynamic cellular processes. These condensates are integral to various physiological functions, such as gene expression intracellular signal transduction, enabling rapid finely tuned responses. Their ability regulate signaling pathways is particularly significant, it requires a careful balance between flexibility precision. Disruption this can lead pathological conditions, including neurodegenerative diseases, cancer, viral infections. Consequently, emerged promising therapeutic targets, with potential offer novel approaches disease treatment. In review, we present recent insights into regulatory mechanisms by which influence pathways, roles health disease, strategies for modulating condensate dynamics approach. Understanding these emerging principles may provide valuable directions developing effective treatments targeting aberrant behavior diseases.

Language: Английский

Citations

1
Role of Angiotensin II in Cardiovascular Diseases: Introducing Bisartans as a Novel Therapy for Coronavirus 2019 DOI Creative Commons
Jordan Swiderski, Laura Kate Gadanec, Vasso Apostolopoulos

et al.

Biomolecules, Journal Year: 2023, Volume and Issue: 13(5), P. 787 - 787

Published: May 2, 2023

Cardiovascular diseases (CVDs) are the main contributors to global morbidity and mortality. Major pathogenic phenotypes of CVDs include development endothelial dysfunction, oxidative stress, hyper-inflammatory responses. These have been found overlap with pathophysiological complications coronavirus disease 2019 (COVID-19). identified as major risk factors for severe fatal COVID-19 states. The renin–angiotensin system (RAS) is an important regulatory in cardiovascular homeostasis. However, its dysregulation observed CVDs, where upregulation angiotensin type 1 receptor (AT1R) signaling via II (AngII) leads AngII-dependent CVDs. Additionally, interaction between spike protein acute respiratory syndrome 2 angiotensin-converting enzyme downregulation latter, resulting RAS. This favors AngII/AT1R toxic pathways, providing a mechanical link pathology COVID-19. Therefore, inhibiting through blockers (ARBs) has indicated promising therapeutic approach treatment Herein, we review role AngII We also provide future direction potential implication novel class ARBs called bisartans, which speculated contain multifunctional targeting towards

Language: Английский

Citations

21
SARS-CoV-2 ORF3a positively regulates NF-κB activity by enhancing IKKβ-NEMO interaction DOI Creative Commons
Ying Nie,

Lumin Mou,

Qizhou Long

et al.

Virus Research, Journal Year: 2023, Volume and Issue: 328, P. 199086 - 199086

Published: March 13, 2023

Coronavirus disease 2019 (COVID-19) is a global pandemic caused by SARS-CoV-2 infection. Patients with severe COVID-19 exhibit robust induction of proinflammatory cytokines, which are closely associated the development acute respiratory distress syndrome. However, underlying mechanisms NF-κB activation mediated infection remain poorly understood. Here, we screened genes and found that ORF3a induces cytokines activating pathway. Moreover, interacts IKKβ NEMO enhances interaction IKKβ-NEMO, thereby positively regulating activity. Together, these results suggest may play pivotal roles in pathogenesis provide novel insights into between host immune responses

Language: Английский

Citations

14
Diabetes as one of the long-term COVID-19 complications: from the potential reason of more diabetic patients’ susceptibility to COVID-19 to the possible caution of future global diabetes tsunami DOI Open Access

Yasamin Sharbatdar,

Ronak Mousavian,

Seyed Mostafa Noorbakhsh Varnosfaderani

et al.

Inflammopharmacology, Journal Year: 2023, Volume and Issue: 31(3), P. 1029 - 1052

Published: April 20, 2023

Language: Английский

Citations

13
On fine particulate matter and COVID-19 spread and severity: An in vitro toxicological plausible mechanism DOI Creative Commons
Sara Marchetti, Maurizio Gualtieri, Andrea Pozzer

et al.

Environment International, Journal Year: 2023, Volume and Issue: 179, P. 108131 - 108131

Published: Aug. 11, 2023

COVID-19 pandemic had a significant impact on global public health. The spread of the disease was related to high transmissibility SARS-CoV-2 virus but incidence and mortality rate suggested possible relationship with environmental factors. Air pollution has been hypothesized play role in transmission resulting severity disease. Here we report plausible vitro toxicological mode action by which fine particulate matter (PM2.5) could promote higher infection PM2.5 promotes 1.5 fold over-expression angiotensin 2 converting enzyme (ACE2) is exploited viral particles enter human lung alveolar cells (1.5 increase RAB5 protein) increases their inflammatory state (IL-8 NF-kB protein expression). Our results provide basis for further exploring synergy between biological threats air pollutants ask deeper understanding how quality influence new pandemics future.

Language: Английский

Citations

11