Serotonin 5HT2A receptor antagonism mediated anti-inflammatory and anti-fibrotic effect in adriamycin-induced CKD in rats

Kaur, Gagandeep; Krishan, Pawan

doi:10.1007/s00210-020-01826-0

Cited by 14 publications

(5 citation statements)

References 44 publications

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“…It is important to note that, unlike psilocybin and 4-AcO-DMT, ketanserin is a 5-HT2A antagonist. While ketanserin has been shown to inhibit inflammation by reducing IL-6 and ameliorate kidney fibrosis by decreasing TGF-beta and collagen production [ 5 , 35 ], ketanserin demonstrated a moderate ability to reduce COX-2 levels (−1.7×). Our data suggest that selective 5-HT2A agonists (psilocybin) are stronger anti-inflammatory agents than antagonists, specifically ketanserin ( Table 1 ).…”

Section: Discussionmentioning

confidence: 99%

“…While synergy between ketanserin and eugenol or capsaicin is intriguing, their clinical use is contraindicated due to the known adverse effects of ketanserin. Nevertheless, the anti-inflammatory effects seen through 5-HT2A receptor antagonism are known to be mediated through both MEK/ERK to reduce nitrosative stress [ 54 ] and have been shown to inhibit IL-6 production as well [ 35 , 54 , 55 ]. As MEK/ERK both regulate IL-6 production through Stat3 signaling [ 56 ], this is likely how ketanserin can further reduce IL-6 expression when ketanserin is combined with TRP ligands that are not known to interact with the MEK/ERK/STAT3/IL-6 pathway.…”

Section: Discussionmentioning

confidence: 99%

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Anti-Inflammatory Effects of Serotonin Receptor and Transient Receptor Potential Channel Ligands in Human Small Intestinal Epithelial Cells

Robinson,

Li,

Wang

et al. 2023

CIMB

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Intestinal inflammation and dysbiosis can lead to inflammatory bowel diseases (IBD) and systemic inflammation, affecting multiple organs. Developing novel anti-inflammatory therapeutics is crucial for preventing IBD progression. Serotonin receptor type 2A (5-HT2A) ligands, including psilocybin (Psi), 4-Acetoxy-N,N-dimethyltryptamine (4-AcO-DMT), and ketanserin (Ket), along with transient receptor potential (TRP) channel ligands like capsaicin (Cap), curcumin (Cur), and eugenol (Eug), show promise as anti-inflammatory agents. In this study, we investigated the cytotoxic and anti-inflammatory effects of Psi, 4-AcO-DMT, Ket, Cap, Cur, and Eug on human small intestinal epithelial cells (HSEIC). HSEIC were exposed to tumor necrosis factor (TNF)-α and interferon (IFN)-γ for 24 h to induce an inflammatory response, followed by treatment with each compound at varying doses (0–800 μM) for 24 to 96 h. The cytotoxicity was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and protein expression by Western blot (WB) analysis. As single treatments, Psi (40 μM), Cur (0.5 μM), and Eug (50 μM) significantly reduced COX-2 levels without cytotoxic effects. When combined, Psi (40 μM) and Cur (0.5 μM) exhibited synergy, resulting in a substantial decrease in COX-2 protein levels (−28× fold change), although the reduction in IL-6 was less pronounced (−1.6× fold change). Psi (20 μM) and Eug (25 μM) demonstrated the most favorable outcomes, with significant decreases in COX-2 (−19× fold change) and IL-6 (−10× fold change) protein levels. Moreover, the combination of Psi and Eug did not induce cytotoxic effects in vitro at any tested doses. This study is the first to explore the anti-inflammatory potential of psilocybin and 4-AcO-DMT in the intestines while highlighting the potential for synergy between the 5-HT2A and TRP channel ligands, specifically Psi and Eug, in alleviating the TNF-α/IFN-γ-induced inflammatory response in HSEIC. Further investigations should evaluate if the Psi and Eug combination has the therapeutic potential to treat IBD in vivo.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Anti-Inflammatory Effects of Serotonin Receptor and Transient Receptor Potential Channel Ligands in Human Small Intestinal Epithelial Cells

Robinson,

Li,

Wang

et al. 2023

CIMB

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“…PAI-1, which promotes fibrosis through inhibition of MMP activation, is also a factor that promotes TGF-β1 synthesis, while its expression is enhanced by TGF-β1 [ 104 ]. Enhanced serotonin signaling mediated by 5-hydroxytryptamine receptors resulting in increased transcription of TGF-β1 has been identified in some fibrotic diseases [ 105 , 106 ]. TGF-β1 is synthesized in a linked state with latency-associated polypeptide (LAP), then forms a complex with latent TGF-β-binding protein (LTBP) or a leucine-rich repeat containing (LRRC) protein, and is subsequently released outside the cell [ 107 ].…”

Section: Core Signaling Pathways and Their Crosstalk Involved In Deve...mentioning

confidence: 99%

Molecular Mechanisms and Risk Factors Related to the Pathogenesis of Peyronie’s Disease

Mitsui

Yamabe

Hori

et al. 2023

IJMS

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Peyronie’s disease (PD) is a benign condition caused by plaque formation on the tunica albuginea of the penis. It is associated with penile pain, curvature, and shortening, and contributes to erectile dysfunction, which worsens patient quality of life. In recent years, research into understanding of the detailed mechanisms and risk factors involved in the development of PD has been increasing. In this review, the pathological mechanisms and several closely related signaling pathways, including TGF-β, WNT/β-catenin, Hedgehog, YAP/TAZ, MAPK, ROCK, and PI3K/AKT, are described. Findings regarding cross-talk among these pathways are then discussed to elucidate the complicated cascade behind tunica albuginea fibrosis. Finally, various risk factors including the genes involved in the development of PD are presented and their association with the disease summarized. The purpose of this review is to provide a better understanding regarding the involvement of risk factors in the molecular mechanisms associated with PD pathogenesis, as well as to provide insight into disease prevention and novel therapeutic interventions.

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“…Real-time polymerase chain reaction was performed on Roche Light Cycler 480II for relative quantification of PDE-4A, B, D isoforms expression. Relative gene expression was calculated by double delta Ct (2-ΔΔct) method and was normalized to GAPDH as standard gene [29].…”

Section: Quantitative Gene Expression Analysis Of Different Pde-4 Iso...mentioning

confidence: 99%

Roflumilast improves resolution of sepsis‐induced acute kidney injury by retarding late phase renal interstitial immune cells infiltration and leakage in urinary sediments

Gupta

Pandey

et al. 2021

Fundamemntal Clinical Pharma

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Some evidence has demonstrated that both inflammation and immune cell dysregulation are coincident at late phase (post 24 h) of sepsis. The present study was designed to determine the pathological role of hyperinflammation and renal immune cells mobilization during late phase of sepsis induced acute kidney injury (S-AKI) and tests the pharmacological effects of PDE-4 inhibitor on these events. Sepsis was induced by cecal ligation puncture and renal function, oxidative-inflammatory stress biomarkers were assessed after 24 h. PDE-4 inhibitor was administered for 7 days prior to induction of S-AKI. Renal immune cells infiltration during sepsis was analyzed by H&E staining and papanicolaou staining method was used for detecting leukocytes and cast in urinary sediments, periodic acid schiff (PAS) staining was used for detection of brush border loss. AKI developed 24 h post sepsis insult as depicted by increase in serum creatinine, blood urea nitrogen (BUN), renal oxidative stress, and elevated inflammatory biomarkers levels. Moreover, septic rats displayed increased bacterial load, renal expression of phosphodiesterase-4B, 4D isoforms, enhanced vascular permeability, caspase-3 and myeloperoxidase activity, electrolyte imbalance, reduced Na + K + ATPase activity, declined cAMP levels, increased interstitial leukocyte infiltration, and leakage in urinary sediments along with histological alterations. Pre-treatment with roflumilast at high dose completely prevented the various AKI associated manifestations in septic rats. Renal hyper-inflammation and leukocyte infiltration was detected in late phase of S-AKI. Roflumilast pre-treatment resolved sepsis induced renal dysfunction and histological damage by suppressing late phase renal immune cells invasion and anti-inflammatory effects mediated by upregulation of renal cAMP levels.

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Serotonin 5HT2A receptor antagonism mediated anti-inflammatory and anti-fibrotic effect in adriamycin-induced CKD in rats

Cited by 14 publications

References 44 publications

Anti-Inflammatory Effects of Serotonin Receptor and Transient Receptor Potential Channel Ligands in Human Small Intestinal Epithelial Cells

Anti-Inflammatory Effects of Serotonin Receptor and Transient Receptor Potential Channel Ligands in Human Small Intestinal Epithelial Cells

Molecular Mechanisms and Risk Factors Related to the Pathogenesis of Peyronie’s Disease

Roflumilast improves resolution of sepsis‐induced acute kidney injury by retarding late phase renal interstitial immune cells infiltration and leakage in urinary sediments

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