Melatonin Treatment Improves Renal Fibrosis via miR-4516/SIAH3/PINK1 Axis

Dysregulation in mitophagy, in addition to contributing to imbalance in the mitochondrial dynamic, has been implicated in the development of renal fibrosis and progression of chronic kidney disease (CKD). However, the current understanding of the precise mechanisms behind the pathogenic loss of mitophagy remains unclear for developing cures for CKD. We found that miR-4516 is downregulated and its target SIAH3, an E3 ubiquitin protein ligase that reduces PINK1 accumulation to damaged mitochondria, is upregulated in the renal cortex of CKD mice. Here, we demonstrated that melatonin injection induces miR-4516 expression and suppresses SIAH3, and promotes PINK1/Parkin-mediated mitophagy. Furthermore, we demonstrated that melatonin injection attenuates the pathological features of CKD by improving mitochondrial homeostasis. Our data supports that mitochondrial autophagy regulation by activating miR-4516/SIAH3/PINK1 mitophagy signaling axis can be a viable new strategy for treating CKD.

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Melatonin Suppresses Renal Cortical Fibrosis by Inhibiting Cytoskeleton Reorganization and Mitochondrial Dysfunction through Regulation of miR-4516

International Journal of Molecular Sciences ◽

10.3390/ijms21155323 ◽

2020 ◽

Vol 21 (15) ◽

pp. 5323

Author(s):

Yeo Min Yoon ◽

Gyeongyun Go ◽

Chul Won Yun ◽

Ji Ho Lim ◽

Jun Hee Lee ◽

...

Keyword(s):

Mitochondrial Dysfunction ◽

Mitochondrial Function ◽

Renal Fibrosis ◽

Renal Cortex ◽

Th1 Cells ◽

Melatonin Treatment ◽

Cytoskeleton Reorganization ◽

Ros Formation ◽

Promising Treatment ◽

Novel Strategy

Renal fibrosis, a major risk factor for kidney failure, can lead to chronic kidney disease (CKD) and is caused by cytoskeleton reorganization and mitochondrial dysfunction. In this study, we investigated the potential of melatonin treatment to reduce renal fibrosis by recovering the cytoskeleton reorganization and mitochondrial dysfunction. We found that miR-4516 expression was downregulated in the renal cortex of CKD mice and P-cresol-treated TH1 cells. Decreased miR-4516 expression stimulated cytoskeleton reorganization and mitochondrial dysfunction, and induced renal fibrosis. Melatonin treatment suppressed fibrosis by inhibiting cytoskeleton reorganization and restoring mitochondrial function via increased miR-4516 expression. More specifically, melatonin treatment increased miR-4516 expression while decreasing ITGA9 expression, thereby inhibiting cytoskeleton reorganization. In addition, increased expression of miR-4516 by melatonin treatment reduced ROS formation and restored mitochondrial function. These findings suggest that melatonin may be a promising treatment for patients with CKD having renal fibrosis. Moreover, regulation of miR-4516 expression may be a novel strategy for the treatment of renal fibrosis.

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A PINCH-1–Smurf1 signaling axis mediates mechano-regulation of BMPR2 and stem cell differentiation

The Journal of Cell Biology ◽

10.1083/jcb.201902022 ◽

2019 ◽

Vol 218 (11) ◽

pp. 3773-3794

Author(s):

Ling Guo ◽

Rong Wang ◽

Kuo Zhang ◽

Jifan Yuan ◽

Jiaxin Wang ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Differentiation ◽

Bmp Signaling ◽

Signaling Mechanism ◽

Ubiquitin Protein Ligase ◽

Signaling Mechanisms ◽

Morphogenetic Protein ◽

Signaling Axis ◽

Fate Decision

Mechano-environment plays multiple critical roles in the control of mesenchymal stem cell (MSC) fate decision, but the underlying signaling mechanisms remain undefined. We report here a signaling axis consisting of PINCH-1, SMAD specific E3 ubiquitin protein ligase 1 (Smurf1), and bone morphogenetic protein type 2 receptor (BMPR2) that links mechano-environment to MSC fate decision. PINCH-1 interacts with Smurf1, which inhibits the latter from interacting with BMPR2 and consequently suppresses BMPR2 degradation, resulting in augmented BMP signaling and MSC osteogenic differentiation (OD). Extracellular matrix (ECM) stiffening increases PINCH-1 level and consequently activates this signaling axis. Depletion of PINCH-1 blocks stiff ECM-induced BMP signaling and OD, whereas overexpression of PINCH-1 overrides signals from soft ECM and promotes OD. Finally, perturbation of either Smurf1 or BMPR2 expression is sufficient to block the effects of PINCH-1 on BMP signaling and MSC fate decision. Our findings delineate a key signaling mechanism through which mechano-environment controls BMPR2 level and MSC fate decision.

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Thermoregulatory and soporific effects of very low dose melatonin injection

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1999.276.2.e249 ◽

1999 ◽

Vol 276 (2) ◽

pp. E249-E254 ◽

Cited By ~ 1

Author(s):

Cameron J. van den Heuvel ◽

David J. Kennaway ◽

Drew Dawson

Keyword(s):

Young Adults ◽

Core Temperature ◽

Low Dose ◽

Elevated Plasma ◽

Melatonin Treatment ◽

Hand Temperature ◽

Subjective Sleepiness ◽

The Mean ◽

C 30 ◽

Melatonin Injection

The effect of a rapid increase in circulating melatonin on body temperatures and sleepiness was investigated in eight young adults at 1000. Melatonin administered intravenously at 10- and 30-μg doses, but not 3 μg, resulted in elevated plasma and saliva levels consistent with endogenous levels measured in adults at night. Melatonin at 10 and 30 μg significantly attenuated the daytime increase in rectal core temperature ( P < 0.05 for both). The mean maximum rectal core temperature differences between saline and melatonin treatment were 0.11 ± 0.03°C, 0.16 ± 0.04°C, and 0.18 ± 0.04°C after the 3-, 10-, and 30-μg melatonin doses, respectively. All three doses significantly increased hand temperature compared with saline ( P < 0.05) within 30 min. The mean maximum hand temperature differences were 0.72 ± 0.12°C (3 μg), 0.95 ± 0.15°C (10 μg), and 0.65 ± 0.11°C (30 μg). Foot temperature and subjective sleepiness measures did not change at any melatonin dose. The results suggest that daytime intravenous injection of melatonin to achieve normal nocturnal levels in young adults may produce significant thermoregulatory changes without soporific effects.

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Analysis of Clinical Characteristics, Radiological Predictors, Pathological Features and Perioperative Outcomes Associated with Perinephric Fat Adhesion Degree

10.21203/rs.2.21034/v4 ◽

2021 ◽

Author(s):

Junqiang Liu ◽

Hongwei Huang ◽

Yiheng Jiang ◽

Zheng Zhu ◽

Jing Chen ◽

...

Keyword(s):

Multivariate Analysis ◽

Immune Cells ◽

Clinical Characteristics ◽

Renal Cortex ◽

Perioperative Outcomes ◽

Pathological Features ◽

Fat Thickness ◽

The Impact ◽

Perinephric Fat ◽

Masson Staining

Abstract Background To assess the clinical characteristics, radiological predictors and pathological features of perinephric fat adhesion degree (PFAD) graded based on fixed criteria and to determine the impact of adherent perinephric fat (APF) on retroperitoneal laparoscopic partial nephrectomy (RLPN) outcomes. Methods 84 patients undergoing RLPN were included and graded into 4 groups based on PFAD. Univariate and multivariate analysis were performed for clinical characteristics and radiological predictors of PFAD. Perioperative data was compared between APF groups and non-APF groups. Masson staining determined collagen fibers. Immunohistochemistry detected CD45 immune cells and CD34 vessels. Results: 20, 28, 18 and 18 patients were graded as normal perinephric fat (NPF), mild adherent perinephric fat (MiPF), moderate adherent perinephric fat (MoPF) and severe adherent perinephric fat (SPF), respectively. Multivariate analysis revealed that gender (p < 0.001), age (p = 0.003) and hypertension (p = 0.006) were significant clinical risk factors of PFAD, while radiological predictors included perinephric stranding (p = 0.001), posterior perinephric fat thickness (p = 0.009) and perinephric fat density (p = 0.02). APF was associated with drain output (P = 0.012) and accompanied by immune cells gathering in renal cortex near thickened renal capsule with many vessels. Conclusions Clinical characteristics and radiological predictors can evaluate PFAD and may assist guide preoperative surgical option. Pathological features of APF reflect decapsulation and bleeding during kidney mobilization at RLPN.

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Wnt5a induces and maintains prostate cancer cells dormancy in bone

Journal of Experimental Medicine ◽

10.1084/jem.20180661 ◽

2018 ◽

Vol 216 (2) ◽

pp. 428-449 ◽

Cited By ~ 27

Author(s):

Dong Ren ◽

Yuhu Dai ◽

Qing Yang ◽

Xin Zhang ◽

Wei Guo ◽

...

Keyword(s):

Prostate Cancer ◽

Bone Metastasis ◽

Cancer Cells ◽

Orphan Receptor ◽

Free Survival ◽

Ubiquitin Protein Ligase ◽

Signaling Axis ◽

Canonical Wnt

In a substantial fraction of prostate cancer (PCa) patients, bone metastasis appears after years or even decades of latency. Canonical Wnt/β-catenin signaling has been proposed to be implicated in dormancy of cancer cells. However, how these tumor cells are kept dormant and recur under control of Wnt/β-catenin signaling derived from bone microenvironment remains unknown. Here, we report that Wnt5a from osteoblastic niche induces dormancy of PCa cells in a reversible manner in vitro and in vivo via inducing Siah E3 Ubiquitin Protein Ligase 2 (SIAH2) expression, which represses Wnt/β-catenin signaling. Furthermore, this effect of Wnt5a-induced dormancy of PCa cells depends on receptor tyrosine kinase-like orphan receptor 2 (ROR2), and a negative correlation of ROR2 expression with bone metastasis–free survival is observed in PCa patients. Therefore, these results demonstrate that Wnt5a/ROR2/SIAH2 signaling axis plays a crucial role in inducing and maintaining PCa cells dormancy in bone, suggesting a potential therapeutic utility of Wnt5a via inducing dormancy of PCa cells in bone.

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Analysis of Clinical Characteristics, Radiological Predictors, Pathological Features, and Perioperative Outcomes Associated with Perinephric Fat Adhesion Degree

Journal of Oncology ◽

10.1155/2021/9095469 ◽

2021 ◽

Vol 2021 ◽

pp. 1-9

Author(s):

Junqiang Liu ◽

Yiheng Jiang ◽

Hongwei Huang ◽

Zheng Zhu ◽

Jing Chen ◽

...

Keyword(s):

Immune Cells ◽

Clinical Characteristics ◽

Renal Cortex ◽

Multivariate Analyses ◽

Perioperative Outcomes ◽

Pathological Features ◽

Fat Thickness ◽

The Impact ◽

Perinephric Fat ◽

Masson Staining

Background. To assess the clinical characteristics, radiological predictors, and pathological features of perinephric fat adhesion degree (PFAD) graded based on fixed criteria and to determine the impact of adherent perinephric fat (APF) on retroperitoneal laparoscopic partial nephrectomy (RLPN) outcomes. Methods. 84 patients undergoing RLPN were included and graded into 4 groups based on PFAD. Univariate and multivariate analyses were performed for clinical characteristics and radiological predictors of PFAD. Perioperative data were compared between APF groups and non-APF groups. Masson staining determined collagen fibers. Immunohistochemistry detected CD45 immune cells and CD34 vessels. Results. 20, 28, 18, and 18 patients were graded as normal perinephric fat (NPF), mild adherent perinephric fat (MiPF), moderate adherent perinephric fat (MoPF), and severe adherent perinephric fat (SPF), respectively. Multivariate analysis revealed that gender ( p < 0.001), age ( p = 0.003), and hypertension ( p = 0.006) were significant clinical risk factors of PFAD, while radiological predictors included perinephric stranding ( p = 0.001), posterior perinephric fat thickness ( p = 0.009), and perinephric fat density ( p = 0.02). APF was associated with drain output ( p = 0.012) and accompanied by immune cells gathering in renal cortex near thickened renal capsule with many vessels. Conclusions. Clinical characteristics and radiological predictors can evaluate PFAD and may assist to guide preoperative surgical option. Pathological features of APF reflect decapsulation and bleeding during kidney mobilization at RLPN.

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Abstract P208: N-acetyl-seryl-aspartyl-lysyl-proline Prevents Renal Fibrosis in Dahl Salt-sensitive Rats by an Early Upregulation of miR Let-7b

Hypertension ◽

10.1161/hyp.68.suppl_1.p208 ◽

2016 ◽

Vol 68 (suppl_1) ◽

Author(s):

Morel E Worou ◽

Nitin Kumar ◽

Nour-Eddine Rhaleb ◽

Edward L Peterson ◽

Oscar A Carretero

Keyword(s):

Mrna Expression ◽

Renal Fibrosis ◽

Renal Damage ◽

Renal Cortex ◽

High Salt ◽

Negative Regulator ◽

Antifibrotic Effect ◽

Collagen Protein ◽

Low Salt ◽

Endogenous Regulators

We recently showed that N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), a natural tetrapeptide with antifibrotic properties prevented high salt-induced albuminuria and renal damage including fibrosis in Dahl Salt-Sensitive (SS) rats and their consomic SS13BN controls. However, the mechanism of this antifibrotic effect is unknown. MicroRNAs (miRNAs) have been shown to be important endogenous regulators of several physiological and pathophysiological conditions. The miRNA let-7 family has been suggested as a negative regulator of profibrotic processes in many diseases and its downregulation has been associated with renal fibrosis. Here, we hypothesized that in SS rats, the antifibrotic effect of Ac-SDKP on high salt-induced renal fibrosis is due to an upregulation of miRNA let-7b expression. Dahl SS and consomic SS13BN rats were fed either 0.23% NaCl (low salt, LS) or 4% NaCl (high salt, HS) diet and infused with vehicle (Veh) or Ac-SDKP (1.6 mg/kg/day) subcutaneously via osmotic minipump for 1 week. Animals were divided into the following groups: LS + Veh, HS + Veh and HS + Ac-SDKP. HS increased the systolic blood pressure (SBP) in SS rats, but not in SS13BN rats. Ac-SDKP did not affect SBP. In both strains, one week of HS diet increased albuminuria. Ac-SDKP prevented HS-induced albuminuria. In SS rats, HS-induced a significant downregulation of the renal cortex miR-let 7b expression measured by quantitative RT-PCR (HS + Veh 0.27±0.16 vs. LS + Veh 1.00±0.09; P=0.005), whereas a treatment with Ac-SDKP significantly upregulated the miR-let 7b expression (HS + Ac-SDKP 2.80±0.11; P=0.002). No miR-let 7b expression difference was observed in SS13BN rats. The overexpression of miR-let 7b by Ac-SDKP is associated with a significant decrease in collagen1 mRNA expression (HS + Veh 3.89±0.74 vs. HS + Ac-SDKP 1.25±0.13; P=0.005). One week on HS diet was not sufficient to cause measurable changes in renal collagen protein. In summary, Ac-SDKP prevented albuminuria and renal cortex collagen1 mRNA expression in SS rats fed HS diet for 1 week, and this was associated with an upregulation of miRNA let-7b expression. The antifibrotic effect of Ac-SDKP on HS-induced renal fibrosis in SS rats may be in part due to preceded upregulation of miRNA let-7b expression.

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Mitochondrial Dynamics and Liver Cancer

Cancers ◽

10.3390/cancers13112571 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2571

Author(s):

María Isabel Hernández-Alvarez ◽

Antonio Zorzano

Keyword(s):

Liver Cancer ◽

Liver Tumors ◽

Mitochondrial Dynamics ◽

Primary Liver Cancer ◽

Mitochondrial Morphology ◽

Mitochondrial Dynamic ◽

Mitochondrial Homeostasis ◽

Liver Cancers ◽

Rising Incidence ◽

Novel Therapeutic Strategies

Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer. Due to its rising incidence and limited therapeutic options, HCC has become a leading cause of cancer-related death worldwide, accounting for 85% of all deaths due to primary liver cancers. Standard therapy for advanced-stage HCC is based on anti-angiogenic drugs such as sorafenib and, more recently, lenvatinib and regorafenib as a second line of treatment. The identification of novel therapeutic strategies is urgently required. Mitochondrial dynamics describes a group of processes that includes the movement of mitochondria along the cytoskeleton, the regulation of mitochondrial morphology and distribution, and connectivity mediated by tethering and fusion/fission events. In recent years, mitochondrial dynamic processes have emerged as key processes in the maintenance of liver mitochondrial homeostasis. In addition, some data are accumulating on the role played by mitochondrial dynamics during cancer development, and specifically on how such dynamics act directly on tumor cells or indirectly on cells responsible for tumor aggression and defense. Here, we review the data that suggest mitochondrial dynamics to be involved in the development of liver tumors.

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Analysis of clinical characteristics, radiological predictors, pathological features and perioperative outcomes associated with perinephric fat adhesion degree

10.21203/rs.3.rs-58068/v1 ◽

2020 ◽

Author(s):

Junqiang Liu ◽

Hongwei Huang ◽

Tianyu Cao ◽

Dikuan Liu ◽

Zheng Zhu ◽

...

Keyword(s):

Multivariate Analysis ◽

Immune Cells ◽

Clinical Characteristics ◽

Renal Cortex ◽

Perioperative Outcomes ◽

Pathological Features ◽

Fat Thickness ◽

The Impact ◽

Perinephric Fat ◽

Masson Staining

Abstract Background To assess the clinical characteristics, radiological predictors and pathological features of perinephric fat adhesion degree (PFAD) graded based on fixed criteria and to determine the impact of adherent perinephric fat (APF) on retroperitoneal laparoscopic partial nephrectomy (RLPN) outcomes. Methods 84 patients undergoing RLPN were included and graded into 4 groups based on PFAD. Univariate and multivariate analysis were performed for clinical characteristics and radiological predictors of PFAD. Perioperative data was compared between APF groups and non-APF groups. Masson staining determined collagen fibers. Immunohistochemistry detected CD45 immune cells and CD34 vessels. Results 20, 28, 18 and 18 patients were graded as normal perinephric fat (NPF), mild adherent perinephric fat (MiPF), moderate adherent perinephric fat (MoPF) and severe adherent perinephric fat (SPF), respectively. Multivariate analysis revealed that gender (p < 0.001), age (p = 0.003) and hypertension (p = 0.006) were significant clinical risk factors of PFAD, while radiological predictors included perinephric stranding (p = 0.001), posterior perinephric fat thickness (p = 0.009) and perinephric fat density (p = 0.02). APF was associated with drain output (P = 0.012) and accompanied by immune cells gathering in renal cortex near thickened renal capsule with many vessels. Conclusions Clinical characteristics and radiological predictors can evaluate PFAD and may assist guide preoperative surgical option. Pathological features of APF reflect decapsulation and bleeding during kidney mobilization at RLPN.

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Melatonin/Nrf2/NLRP3 Connection in Mouse Heart Mitochondria during Aging

Antioxidants ◽

10.3390/antiox9121187 ◽

2020 ◽

Vol 9 (12) ◽

pp. 1187

Author(s):

Marisol Fernández-Ortiz ◽

Ramy K. A. Sayed ◽

José Fernández-Martínez ◽

Antonia Cionfrini ◽

Paula Aranda-Martínez ◽

...

Keyword(s):

Nlrp3 Inflammasome ◽

Molecular Mechanisms ◽

Mitochondrial Dynamics ◽

Antioxidant Response ◽

Mouse Heart ◽

Wild Type ◽

Melatonin Treatment ◽

Mitochondrial Dynamic ◽

Age Related ◽

The Impact

Aging is a major risk for cardiovascular diseases (CVD). Age-related disorders include oxidative stress, mitochondria dysfunction, and exacerbation of the NF-κB/NLRP3 innate immune response pathways. Some of the molecular mechanisms underlying these processes, however, remain unclear. This study tested the hypothesis that NLRP3 inflammasome plays a role in cardiac aging and melatonin is able to counteract its effects. With the aim of investigating the impact of NLRP3 inflammasome and the actions and target of melatonin in aged myocardium, we analyzed the expression of proteins implied in mitochondria dynamics, autophagy, apoptosis, Nrf2-dependent antioxidant response and mitochondria ultrastructure in heart of wild-type and NLRP3-knockout mice of 3, 12, and 24 months-old, with and without melatonin treatment. Our results showed that the absence of NLRP3 prevented age-related mitochondrial dynamic alterations in cardiac muscle with minimal effects in cardiac autophagy during aging. The deficiency of the inflammasome affected Bax/Bcl2 ratio, but not p53 or caspase 9. The Nrf2-antioxidant pathway was also unaffected by the absence of NLRP3. Furthermore, NLRP3-deficiency prevented the drop in autophagy and mice showed less mitochondrial damage than wild-type animals. Interestingly, melatonin treatment recovered mitochondrial dynamics altered by aging and had few effects on cardiac autophagy. Melatonin supplementation also had an anti-apoptotic action in addition to restoring Nrf2-antioxidant capacity and improving mitochondria ultrastructure altered by aging.

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