Probiotics as an Adjunct Ameliorates Ovarian Toxicity in Endotoxemic Mice via Modulating TLR 4/MyD88/NF-κB Signalling Pathway: Insights from In Vivo and In Silico Study

Article

Gut microbiota plays a critical role in maintaining reproductive homeostasis, and mounting evidence highlights probiotic supplementation as a promising therapeutic candidate owing to its immunomodulatory potentials. Neurotensin (NTS), a tridecapeptide neuropeptide, has been shown to link with the regulation of inflammation and reproductive processes. This study aims to evaluate the possible simultaneous ameliorative effect of NTS receptor 1 agonist PD149163 co-administration with multi-strain probiotics in lipopolysaccharide/LPS induced ovarian dysfunction. Female Swiss albino mice (8 weeks old) were randomly assigned to seven groups: control, LPS (1 mg/kg bw), LPS + PD149163 (50 µg/kg bw), LPS + probiotics (0.6 gm/kg bw/day), LPS + PD149163 + probiotics, PD149163, and probiotics. After 32 days, plasma and ovarian samples were collected for biochemical and histological analyses. Additionally, an in-silico approach was employed to assess the potential interaction of probiotic-derived metabolites (butyrate and propionic acid) with the key proteins of TLR4/MyD88/NF-κB signalling pathway (TLR4/MD-2 complex, MyD88 and NF-κB). Co-administration of PD149163 with multi-strain probiotics attenuated inflammatory markers (NF-κB, TNF-α, IL-6), restored anti-oxidant enzyme activity (SOD, CAT), reduced lipid peroxidation (LPx), normalized hormonal levels (NTS, LH, FSH, E2) and improved ovarian histopathological features. Co-supplementation of probiotics with PD149163 as an adjunct therapy has shown superior efficacy in mitigating the ovarian dysfunction compared to employing single treatment approach. This ameliorative effect is presumably mediated by suppressing TLR4/MyD88/NF-κB signalling pathway, thereby dampening inflammatory cascade and alleviating ovarian dysfunction. Therefore, further investigations are warranted to unravel the underlying mechanisms of probiotic action on reproductive physiology, thereby providing therapeutic insights for the management of sepsis-related reproductive dysfunction.

2025-05-01·EUROPEAN JOURNAL OF PHARMACOLOGY

Efficacy of the neurotensin receptor 1 analog PD149163 in modulation of the kidney inflammation: Inhibition of the nuclear factor kappa β signaling pathway and oxidative stress in endotoxemic mice

Article

作者: Mohanty, Banalata ; Mishra, Swarnima ; Srivastava, Sonia

This study elucidated that the neurotensin receptor 1 agonist PD149163 ameliorated the kidney inflammation in endotoxemic mice inhibiting the nuclear factor kappa β (NF-kβ) pathway and reducing the oxidative stress in a dose-dependent manner. Swiss albino female mice (8 weeks; 25 ± 5 gms) were maintained in six groups (n = 6): Group 1/control, Group 2, Group 3 and Group 4 were exposed to lipopolysaccharide/LPS (1 mg/kg bw; i.p; 5 days) followed by PD149163 treatment with low dose/NTS₅₀ (50 μg/kg BW i.p. 28 days) and high dose/NTS₁₀₀ (100 μg/kg BW i.p. 28 days) to Group 3 and Group 4 respectively. Group 5 and Group 6 mice were only treated with the agonist, similar low and high doses respectively for the same duration. The results showed LPS-induced significant increase in the plasma levels of the NF-kβ, pro-inflammatory cytokines (TNF-α, IL-6) and a decrease in the anti-inflammatory cytokine IL-10. A significant increase in the pro-oxidant (LPx) and decrease of the anti-oxidants (SOD, CAT) in the kidney tissue was noted. Plasma NTS level was significantly decreased along with a significant increase of the corticosterone. The inflammation was reflected in the kidney histopathology. PD149163 significantly reduced inflammation by down-regulating NF-kβ, TNF-α, IL-6, CORT levels, oxidative stress and alleviated kidney injury. PD149163 enhanced the plasma level of NT. The role of PD149163 in the modulation of inflammation of kidney tissue by its anti-inflammatory and anti-oxidative effects is suggested. Further studies may better confirm the efficacy of the NTS analog for therapeutic intervention in inflammation-related diseases of the kidney.

2024-12-01·NEUROGASTROENTEROLOGY AND MOTILITY

The neurotensin receptor 1 agonist PD149163 alleviates visceral hypersensitivity and colonic hyperpermeability in rat irritable bowel syndrome model

Article

作者: Nozu, Tsukasa ; Takakusaki, Kaoru ; Ishioh, Masatomo ; Miyagishi, Saori ; Okumura, Toshikatsu

Abstract:

Background:

An impaired intestinal barrier with the activation of corticotropin‐releasing factor (CRF), Toll‐like receptor 4 (TLR4), and proinflammatory cytokine signaling, resulting in visceral hypersensitivity, is a crucial aspect of irritable bowel syndrome (IBS). The gut exhibits abundant expression of neurotensin; however, its role in the pathophysiology of IBS remains uncertain. This study aimed to clarify the effects of PD149163, a specific agonist for neurotensin receptor 1 (NTR1), on visceral sensation and gut barrier in rat IBS models.

Methods:

The visceral pain threshold in response to colonic balloon distention was electrophysiologically determined by monitoring abdominal muscle contractions, while colonic permeability was measured by quantifying absorbed Evans blue in colonic tissue in vivo in adult male Sprague–Dawley rats. We employed the rat IBS models, i.e., lipopolysaccharide (LPS)‐ and CRF‐induced visceral hypersensitivity and colonic hyperpermeability, and explored the effects of PD149163.

Key Results:

Intraperitoneal PD149163 (160, 240, 320 μg kg−1) prevented LPS (1 mg kg−1, subcutaneously)‐induced visceral hypersensitivity and colonic hyperpermeability dose‐dependently. It also prevented the gastrointestinal changes induced by CRF (50 μg kg−1, intraperitoneally). Peripheral atropine, bicuculline (a GABAA receptor antagonist), sulpiride (a dopamine D2 receptor antagonist), astressin2‐B (a CRF receptor subtype 2 [CRF2] antagonist), and intracisternal SB‐334867 (an orexin 1 receptor antagonist) reversed these effects of PD149163 in the LPS model.

Conclusions and Inferences:

PD149163 demonstrated an improvement in visceral hypersensitivity and colonic hyperpermeability in rat IBS models through the dopamine D2, GABAA, orexin, CRF2, and cholinergic pathways. Activation of NTR1 may modulate these gastrointestinal changes, helping to alleviate IBS symptoms.

100 项与 PD-149163 相关的药物交易

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