Ambroxol, a mucolytic agent, boosts<scp>HO</scp>‐1, suppresses<scp>NF‐κB</scp>, and decreases the susceptibility of the inflamed rat colon to apoptosis: A new treatment option for treating ulcerative colitis

Cavalu, Simona; Sharaf, Hossam; Saber, Sameh; Youssef, Mahmoud E.; Abdelhamid, A. M.; Mourad, Ahmed A.E.; Ibrahim, Samar; Allam, Shady; Elgharabawy, Rehab Mohamed; El‐Ahwany, Eman; Amin, Noha A.; Shata, Ahmed; Eldegla, Mai; Atef, Marina; Aboraya, Maii; Mohamed, Mayar; Anz, Niera; Elmotelb, Dina Abd; Gabr, Fayrouz; Elzablawy, Dalia; Hamada, Menna; Yehia, Ahmed; Osama, Dalia; Mohammed, Osama A.

doi:10.1096/fj.202200749r

Cited by 30 publications

(8 citation statements)

References 66 publications

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“…However, STA9090 treatment effectively reversed these effects, suggesting its potential anti-inflammatory effects through the inhibition of NFκB. It is worth noting that TNF-α is one of the key target genes regulated by NFκB [ 38 , 39 ].…”

Section: Resultsmentioning

confidence: 99%

STA9090 as a Potential Therapeutic Agent for Liver Fibrosis by Modulating the HSP90/TβRII/Proteasome Interplay: Novel Insights from In Vitro and In Vivo Investigations

Mohammed,

Abdel-Reheim,

Alamri

et al. 2023

Pharmaceuticals

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Liver fibrosis is a progressive condition characterized by the build-up of fibrous tissue resulting from long-term liver injury. Although there have been advancements in research and treatment, there is still a need for effective antifibrotic medication. HSP90 plays a crucial role in the development of fibrosis. It acts as a molecular chaperone that assists in the proper folding and stability of TβRII, potentially regulating the signaling of TGF-β1. It has been established that TβRII can be degraded through the proteasome degradation system, either via ubiquitination-dependent or -independent pathways. In the present study, STA9090 demonstrated promising effects in both in vitro and in vivo models. It reduced LDH leakage, prolonged the survival rate of hepatocytes in rats with liver fibrosis, and improved liver function. Importantly, STA9090 exerted pleiotropic effects by targeting proteins involved in limiting collagen production, which resulted in improved microscopic features of the rat livers. Our findings suggest that STA9090-induced inhibition of HSP90 leads to the degradation of TβRII, a fibrogenic client protein of HSP90, through the activation of the 20S proteasomal degradation system. We also revealed that this degradation mechanism is not dependent on the autophagy–lysosomal pathway. Additionally, STA9090 was found to destabilize HIF-1α and facilitate its degradation, leading to the reduced transcription of VEGF. Moreover, STA9090’s ability to deactivate the NFκB signaling pathway highlights its potential as an anti-inflammatory and antifibrotic agent. However, further research is necessary to fully elucidate the underlying mechanisms and fully capitalize on the therapeutic benefits of targeting HSP90 and associated pathways.

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Section: Resultsmentioning

confidence: 99%

STA9090 as a Potential Therapeutic Agent for Liver Fibrosis by Modulating the HSP90/TβRII/Proteasome Interplay: Novel Insights from In Vitro and In Vivo Investigations

Mohammed,

Abdel-Reheim,

Alamri

et al. 2023

Pharmaceuticals

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“…Tight junction proteins have been extensively studied over the past decades because they have a dual role as a barrier and fence to limit the passage of molecules and ions, thereby preventing the occurrence of some inflammatory diseases. The reduction in tight junction proteins decreased the firmness of the intestinal epithelia and elevated the permeability of the intestinal barrier, which elevated the risk of colitis occurrence [ 26 ]. Some studies exhibited that DSS treatment reduced the levels of tight junction proteins, including ZO-1, occludin, and claudin-1 [ 27 ], among which ZO-1 was the first epithelial tight junction protein identified [ 28 ], and showed a direct correlation between the actin and the transmembrane proteins [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

Mitigation of Dextran-Sodium-Sulfate-Induced Colitis in Mice through Oral Administration of Microbiome-Derived Inosine and Its Underlying Mechanisms

Guo,

Tang,

Zhang

et al. 2023

IJMS

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Background: Colonic and serum inosine are significantly reduced in patients with inflammatory bowel disease (IBD). Methods: This study aimed to explore whether microbiome-derived inosine alleviates colitis and its underlying mechanisms. Results: An inosine intervention effectively improved the clinical signs in colitis mice, suppressed inflammatory cytokines (tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and IL-1β) by regulating the nuclear factor-kappa B (NF-κB) pathway, and elevated the activities of anti-oxidative enzymes (including superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px)) by regulating the nuclear factor erythroid-2 related factor 2 (Nrf2) pathway. Additionally, the inosine intervention significantly elevated the expression of tight junction proteins (ZO-1, occudin, and claudin-1) in mice with colitis. High-throughput sequencing revealed that the inosine intervention also prevented gut microbiota disorder by increasing the abundance of beneficial bacteria (Lachnospiraceae NK4A136 group, Romboutsia, Marvinbryantia, Clostridium sensu stricto 1, and Bifidobacterium) and reducing the abundance of harmful bacteria (Pseudomonas, Acinetobacter, and Tyzzerella) in mice with colitis. Conclusions: Inosine played a significant role in mitigating colitis-related intestinal barrier injury and could potentially be used for therapy in clinical practice.

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“…The samples were stained with hematoxylin solution for 5–10 min, rinsed with tap water, differentiated with 1% acid alcohol, and counterstained with eosin solution for 1–2 min. After the samples were rinsed and dehydrated, they were cleared with xylene and mounted on microscope slides with a coverslip. , The degree of inflammation was determined by evaluating the presence of immune cells and morphological changes in corneal cells under a microscope. The inflammation was graded based on a scoring system that included 0 for no inflammation, 1 for minimal inflammation, 2 for mild inflammation, 3 for moderate inflammation, and 4 for severe inflammation.…”

Section: Experimental Sectionmentioning

confidence: 99%

New Pyrazole-Clubbed Pyrimidine or Pyrazoline Hybrids as Anti-Methicillin-Resistant Staphylococcus aureus Agents: Design, Synthesis, In Vitro and In Vivo Evaluation, and Molecular Modeling Simulation

Mansour,

El-Sherbeny,

Al-Omary

et al. 2023

ACS Omega

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Two hybrid series of pyrazole-clubbed pyrimidines 5a−c and pyrazole-clubbed pyrazoline compounds 6a,b and 7 were designed as attractive scaffolds to be investigated in vitro and in vivo for antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa. From the results of the in vitro antibacterial screening, compound 5c showed excellent activity (minimal inhibitory concentration, MIC = 521 μM) when compared with that of the reference antibiotic levofloxacin (MIC = 346 μM). The inhibition of the target dihydrofolate reductase (DHFR) enzyme by compounds 4 and 5a−c (IC 50 = 5.00 ± 0.23, 4.20 ± 0.20, 4.10 ± 0.19, and 4.00 ± 0.18 μM, respectively) was found to be better than the reference drug trimethoprim (IC 50 = 5.54 ± 0.28 μM). Molecular modeling simulation results have justified the order of activity of all the newly synthesized compounds as DHFR enzyme inhibitors, and compound 5c exhibited the best binding profile (−13.6169386 kcal/mol). Hence, the most potent inhibitor of the DHFR enzyme, 5c, was chosen to be evaluated in vivo for its activity in treating MRSA-induced keratitis in rats and that, in turn, significantly (P < 0.0001) reduced infection in rats when compared to MRSA-treated group results.

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Ambroxol, a mucolytic agent, boostsHO‐1, suppressesNF‐κB, and decreases the susceptibility of the inflamed rat colon to apoptosis: A new treatment option for treating ulcerative colitis

Cited by 30 publications

References 66 publications

STA9090 as a Potential Therapeutic Agent for Liver Fibrosis by Modulating the HSP90/TβRII/Proteasome Interplay: Novel Insights from In Vitro and In Vivo Investigations

STA9090 as a Potential Therapeutic Agent for Liver Fibrosis by Modulating the HSP90/TβRII/Proteasome Interplay: Novel Insights from In Vitro and In Vivo Investigations

Mitigation of Dextran-Sodium-Sulfate-Induced Colitis in Mice through Oral Administration of Microbiome-Derived Inosine and Its Underlying Mechanisms

New Pyrazole-Clubbed Pyrimidine or Pyrazoline Hybrids as Anti-Methicillin-Resistant Staphylococcus aureus Agents: Design, Synthesis, In Vitro and In Vivo Evaluation, and Molecular Modeling Simulation

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