Magnoflorine Ameliorates Inflammation and Fibrosis in Rats With Diabetic Nephropathy by Mediating the Stability of Lysine-Specific Demethylase 3A

Chang, Liang; Wang, Qi; Ju, Jiannan; Li, Yue; Cai, Qiao; Hao, Lirong; Zhou, Yang

doi:10.3389/fphys.2020.580406

Cited by 22 publications

(23 citation statements)

References 37 publications

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“…Collectively, KDM3A may act as a mediator between TGF-β1 and Smad3, and jointly mediate the pathological process of myocardial brosis. Supporting these ndings, KDM3A was robustly delayed renal brosis degree via elevate Smad2/3 phosphorylation [33] . Accumulating evidence indicates that Smad3 is a key intracellular regulatory protein in the TGF-β superfamily signal cascade [17] .…”

Section: Discussionsupporting

confidence: 59%

KDM3A is a Positive Regulator of Cardiac Fibroblasts Conversion that Increases Smad3 Phosphorylation Following TGFβ1 Stimulation

Liu¹,

Zhou²,

Zhang³

et al. 2021

Preprint

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The epigenetic molecule KDM3A has been shown to be involved in improving cardiovascular diseases, but its effect on cardiac fibroblasts (CFs) remains unclear. Thus, we designed the gain- and loss-of-function experiments to investigate the biological functions of KDM3A in cardiac fibroblasts (CFs). Moreover, we added a SIS3-HCL (a specific inhibitor of p-Smad3) to explore the underlying mechanism. The cells viability and migration were verified by CCK-8 and cell migration experiments, respectively, and the degree of fibrosis was measured by Western blot analysis. Our data reveal that KDM3A enhance the proliferation and migration of cardiac fibroblasts, meanwhile, increasing the fibroblast-to-myofibroblast transition, while enabling Smad3 phosphorylation response to TGFβ1 stimuli. However, these results could be abolished by SIS3-HCL, an inhibitor of the p-Smad3. Furthermore, KDM3A inhibition obviously protect cardiac fibroblasts conversion against TGFβ1 stimuli. These results identify that KDM3A may be a novel regulator of the cardiac fibroblasts conversion, through its ability to modulate phosphorylation of Smad3 following TGFβ1 stimuli.

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Section: Discussionsupporting

confidence: 59%

KDM3A is a Positive Regulator of Cardiac Fibroblasts Conversion that Increases Smad3 Phosphorylation Following TGFβ1 Stimulation

Liu¹,

Zhou²,

Zhang³

et al. 2021

Preprint

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“…Hyperglycemia can induce α-sma and collagen IV production in mesangial cells and ubiquitination seems involved in this process. In particular, ubiquitination and degradation of lysine-specific demethylase 3A and the downstream modulation of the TGF-β1/Smad2/Smad3 signaling induced by the plant extract magnoflorine attenuates DN and suppresses inflammatory responses and fibrosis in mesangial cells both in vitro and in vivo [ 27 ]. Mesangial collagen synthesis in DN is also modulated by the E3 ubiquitin ligase, TRIM13, by promoting ubiquitination and degradation of C/EBP homologous protein [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Lysine 63 Ubiquitination Prevents the Progression of Renal Fibrosis in Diabetic DBA/2J Mice

Pontrelli

Conserva

Menghini

et al. 2021

IJMS

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Diabetic nephropathy (DN) is the most frequent cause of end-stage renal disease. Tubulointerstitial accumulation of lysine 63 (K63)-ubiquitinated (Ub) proteins is involved in the progression of DN fibrosis and correlates with urinary miR-27b-3p downregulation. We explored the renoprotective effect of an inhibitor of K63-Ub (NSC697923), alone or in combination with the ACE-inhibitor ramipril, in vitro and in vivo. Proximal tubular epithelial cells and diabetic DBA/2J mice were treated with NSC697923 and/or ramipril. K63-Ub protein accumulation along with α-SMA, collagen I and III, FSP-1, vimentin, p16INK4A expression, SA-α Gal staining, Sirius Red, and PAS staining were measured. Finally, we measured the urinary albumin to creatinine ratio (uACR), and urinary miR-27b-3p expression in mice. NSC697923, both alone and in association with ramipril, in vitro and in vivo inhibited hyperglycemia-induced epithelial to mesenchymal transition by significantly reducing K63-Ub proteins, α-SMA, collagen I, vimentin, FSP-1 expression, and collagen III along with tubulointerstitial and glomerular fibrosis. Treated mice also showed recovery of urinary miR-27b-3p and restored expression of p16INK4A. Moreover, NSC697923 in combination with ramipril demonstrated a trend in the reduction of uACR. In conclusion, we suggest that selective inhibition of K63-Ub, when combined with the conventional treatment with ACE inhibitors, might represent a novel treatment strategy to prevent the progression of fibrosis and proteinuria in diabetic nephropathy and we propose miR-27b-3p as a biomarker of treatment efficacy.

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“…* indicates p < 0.05, ** p < 0.01, and *** p < 0.001, respectively. with diabetic nephropathy via regulating the stability of LSD3A (Chang et al, 2020). MGN inhibited the proliferation of breast cancer, gastric cancer, and rhabdomyosarcoma cells in a dose-dependent manner as well as induced cell apoptosis and blocked cell cycle (Okon et al, 2020a(Okon et al, , 2020bSun et al, 2020c].…”

Section: Statisticsmentioning

confidence: 99%

“…Magnoflorine (MGN), also named as thalictrine, occurs naturally in the root of buttercup plant, and can be produced by chemical synthesis as well. It has neuropsychopharmacological, antianxiety, immunomodulatory, anti-inflammatory, antioxidant, and antifungal activities (Chang et al, 2020;Okon et al, 2020aOkon et al, , 2020b. MGN ameliorates inflammation and fibrosis in rats Xu J et al fetal bovine serum (FBS) and incubated at 37°C in a 5% CO 2 incubator.…”

Section: Introductionmentioning

confidence: 99%

Magnoflorine promotes Huh-7 cell apoptosis and autophagy by regulating PI3K/Akt/mTOR pathway

Liu

et al. 2022

qas

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Hepatoma is a malignant tumor with high rates of heterogeneity, metastasis, and mortality. Currently, there is no effective treatment available for hepatoma. In order to treat advanced hepatoma in a better manner, new and more effective therapeutic targets still need to be developed. Magnoflorine (MGN) is a quaternary ammonium alkaloid with a variety of therapeutic properties. MGN inhibited the proliferation of lung cancer, breast cancer, glioma, and rhabdomyosarcoma cells, induced apoptosis, and blocked cell cycle. However, its possible effects on the pro-gression of hepatoma are still indefinite. In this study, the effects of MGN on the progression of hepatoma in vitro and the underlying mechanisms were determined. MGN suppressed the proliferation, induced the autophagy, and stimulated the apoptosis of human hepatoma Huh-7 cells. Mechanically, MGN could regulate PI3K/AKT/mTOR pathway, which therefore affects the progression of hepatoma in vitro. Taken together, MGN affected Huh-7 cell proliferation, autophagy, and apoptosis, and might act as a promising therapeutic drug for treating hepatoma.

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Magnoflorine Ameliorates Inflammation and Fibrosis in Rats With Diabetic Nephropathy by Mediating the Stability of Lysine-Specific Demethylase 3A

Cited by 22 publications

References 37 publications

KDM3A is a Positive Regulator of Cardiac Fibroblasts Conversion that Increases Smad3 Phosphorylation Following TGFβ1 Stimulation

KDM3A is a Positive Regulator of Cardiac Fibroblasts Conversion that Increases Smad3 Phosphorylation Following TGFβ1 Stimulation

Inhibition of Lysine 63 Ubiquitination Prevents the Progression of Renal Fibrosis in Diabetic DBA/2J Mice

Magnoflorine promotes Huh-7 cell apoptosis and autophagy by regulating PI3K/Akt/mTOR pathway

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