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GJ 1148 is an M-dwarf star, which has two well-separated Saturn mass planets with an orbital period ratio of around 13 and eccentricities of around 0.375 at the current epoch. A plausible scenario for producing the orbital architecture of the GJ 1148 system is planet-planet scattering. To test this scenario, we perform scattering experiments, assuming the third planet of 0.1 MJ (Jupiter’s mass) in the initial GJ 1148 system with initial orbital separations set to 3.5, 4, and 4.5 mutual Hill radii Rm,H respectively and initial semi-major axis of the innermost planet ai,1 in the range of 0.10-0.50 AU. The majority of scattering results in planet-planet collisions, followed by planet ejections, and planet removals as its distance to the star are smaller than a critical value of 0.02 AU. Among them, only the post-ejection two-planet systems have similar properties to the GJ 1148 system, and when ai,1 is around 0.21 AU, the semi-major axis of the inner planet GJ 1148 b can be reproduced. We further perform simulations with ai,1 in a narrower range between 0.16 and 0.30 AU, and found one system with similar orbital properties to the GJ 1148 system. Therefore, the simulation results suggest that the GJ 1148 system may have lost a giant planet. The two-sample Kolmogorov–Smirnov (KS) test on simulations with and without GR apsidal precession shows that it does not affect the ejection outcomes. When setting the mass of the third planet to 0.227 MJ of GJ1148 c, the optimal ai,1 move to about 0.29 AU.

Cisplatin is extensively used to treat malignancies. However, its clinical use is always limited due to the serious side effects, especially the nephrotoxicity. Matrine (MAT), a tetracyclic quinolizine alkaloid found in sophora genus, exerts multiple pharmacological roles, including anti-oxidative stress, anti-inflammation and anti-apoptosis, but the role of MAT on acute kidney injury (AKI) has not been evaluated. Here, we found that MAT potently inhibited cell injury induced by cisplatin in HK2 cells in vitro, which was associated with the inhibition of oxidative injury and NF-κB-mediated inflammation. Moreover, MAT treatment could activate the SIRT3/OPA1 axis and subsequently suppress the mitochondrial fragmentation and improve mitochondrial function. More importantly, SIRT3 knockdown suppressed the deacetylation of OPA1, which blocked the protective role of MAT on cisplatin-induced cell injury. In vivo, MAT treatment alleviated renal dysfunction, histological damage and inflammation induced by cisplatin in mice. Furthermore, consistent with the founding in vitro, MAT also activated SIRT3-mediated deacetylation of OPA1 and alleviated mitochondrial dysfunction in AKI mice. Our study proved that MAT protected against cisplatin-induced AKI by synergic anti-oxidative stress and anti-inflammation actions via SIRT3/OPA1-mediated improvement of mitochondrial function, suggesting that MAT may be a novel and effective strategy for AKI.

Macrophages (Mφ) infiltration is a common characteristic of acute kidney injury (AKI). Exosomes-mediated cell communication between tubular epithelial cells (TECs) and Mφ has been suggested to be involved in AKI. Exosomes-derived from injured TECs could regulate Mφ polarization during AKI. However, little is known regarding how activated Mφ regulates kidney injury. To explore the role of activated Mφ in the AKI process, we revealed that Mφ-derived exosomes from AKI mice (Exos

Because of the key role of impaired mitochondria in the progression of acute kidney injury (AKI), it is striking that peroxisome proliferator γ coactivator 1-α (PGC-1α), a transcriptional coactivator of genes involved in mitochondrial biogenesis and autophagy, protects from kidney injury. However, the specific mechanism involved in PGC-1α-mediated autophagy remains elusive. In vivo, along with the severe kidney damage, the expression of PGC-1α was decreased in cisplatin-induced AKI mice. Conversely, PGC-1α activator (ZLN005) administration could alleviate kidney injury. Consistently, in vitro overexpression of PGC-1α or ZLN005 treatment inhibited cell apoptosis and mitochondrial dysfunction induced by cisplatin. Moreover, ZLN005 treatment increased the expression of LC3-II and co-localization between LC3 and mitochondria, suggesting that the mitophagy was activated. Furthermore, PGC-1α-mediated the activation of mitophagy was reliant on the increased expression of TFEB, and the protective effects were abrogated in TFEB-knockdown cells. These data suggest that the activation of PGC-1α could alleviate mitochondrial dysfunction and kidney injury in AKI mice via TFEB-mediated autophagy.

Aims: Cisplatin, an anticancer drug, always leads to nephrotoxicity by causing mitochondrial dysfunction. As a major mechanism for cellular self-degradation, autophagy has been proven to protect against cisplatin-induced acute kidney injury (AKI). Based on the activation of autophagy induced by trehalose, we aimed to investigate the nephroprotective effects of trehalose on cisplatin-induced AKI and its underlying mechanisms. Results: Due to the activation of autophagy, mitochondrial dysfunction (mitochondrial fragmentation, depolarization, reactive oxygen species (ROS), and reduced ATP generation) and apoptosis induced by cisplatin were markedly inhibited in trehalose-treated HK2 cells in vitro. Based on the transcriptional regulation role of transcription factor EB (TFEB) in autophagy and lysosome, we characterized trehalose-induced nuclear translocation of TFEB. Furthermore, consistent with trehalose treatment, overexpression of TFEB inhibited cell injury induced by cisplatin. However, the protective effects of trehalose were largely abrogated in tfeb-knockdown cells. In vivo, cisplatin injection resulted in severe kidney dysfunction and histological damage in mice. Trehalose administration activated TFEB-mediated autophagy, alleviated mitochondrial dysfunction and kidney injury in AKI mice. Innovation and conclusion: Our data suggest that trehalose treatment preserves mitochondria function via activation of TFEB-mediated autophagy and attenuates cisplatin-induced kidney injury.

Senescence of bone marrow-derived mesenchymal stem cells (BMSCs) has been widely reported to be closely correlated with aging-related diseases, including osteoporosis (OP). Moreover, the beneficial functions of BMSCs decline with age, limiting their therapeutic efficacy in OP. In the present study, using RNA sequencing (RNA-Seq), we found that leucine-rich repeat containing 17 (LRRc17) expression in BMSCs was highly positively correlated with age. Therefore, we investigated whether LRRc17 knockdown could rejuvenate aged MSCs and increase their therapeutic efficacy in OP. Consistent with the RNA-Seq results, the protein expression of LRRc17 in senescent BMSCs was significantly increased, whereas LRRc17 knockdown inhibited cell apoptosis and reduced the expression of age-related proteins and G2 and S phase quiescence. Furthermore, LRRc17 knockdown shifted BMSCs from adipogenic to osteogenic differentiation, indicating the critical role of LRRc17 in BMSC senescence and differentiation. Additionally, similar to rapamycin (RAPA) treatment, LRRc17 knockdown activated mitophagy via inhibition of the mTOR/PI3K pathway, which consequently reduced mitochondrial dysfunction and inhibited BMSC senescence. However, the effects of LRRc17 knockdown were significantly blocked by the autophagy inhibitor hydroxychloroquine (HCQ), demonstrating that LRRc17 knockdown prevented BMSC senescence by activating mitophagy. In vivo, compared with untransfected aged mouse-derived BMSCs (O-BMSCs), O-BMSCs transfected with sh-LRRc17 showed effective amelioration of ovariectomy (OVX)-induced bone loss. Collectively, these results indicated that LRRc17 knockdown rejuvenated senescent BMSCs and thus enhanced their therapeutic efficacy in OP by activating autophagy., Graphical abstract Image 1

Mesenchymal stem cells (MSCs) have fueled ample translation for treatment of immune-mediated diseases. Our previous study had demonstrated that MSCs could elicit macrophages (Mφ) into anti-inflammatory phenotypes, and alleviate kidney injury in diabetic nephropathy (DN) mice via improving mitochondrial function of Mφ, yet the specific mechanism was unclear. Recent evidence indicated that MSCs communicated with their microenvironment through exchanges of mitochondria. By a coculture system consisting of MSCs and Mφ, we showed that MSCs-derived mitochondria (MSCs-Mito) were transferred into Mφ, and the mitochondrial functions were improved, which contributed to M2 polarization. Furthermore, we found that MSCs-Mito transfer activated peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α)-mediated mitochondrial biogenesis. In addition, PGC-1α interacted with TFEB in high glucose-induced Mφ, leading to the elevated lysosome-autophagy, which was essential to removal of damaged mitochondria. As a result, in Mφ, the mitochondrial bioenergy and capacity to combat inflammatory response were enhanced. Whereas, the immune-regulatory activity of MSCs-Mito was significantly blocked in PGC-1α knockdown Mφ. More importantly, MSCs-Mito transfer could be observed in DN mice, and the adoptive transfer of MSCs-Mito educated Mφ (MφMito) inhibited the inflammatory response and alleviated kidney injury. However, the kidney-protective effects of MφMito were abolished when the MSCs-Mito was impaired with rotenone, and the similar results were also observed when MφMito were transfected with sipgc-1α before administration. Collectively, these findings suggested that MSCs elicited Mφ into anti-inflammatory phenotype and ameliorated kidney injury through mitochondrial transfer in DN mice, and the effects were relied on PGC-1α-mediated mitochondrial biogenesis and PGC-1α/TFEB-mediated lysosome-autophagy.

Background: Because the key role of impaired mitochondria in the progression of acute kidney injury (AKI), it is striking that peroxisome proliferator γ coactivator 1-α (PGC-1α), a transcriptional coactivator of genes involved in mitochondrial biogenesis and autophagy, protects kidney injury. However, the specific mechanism involved in PGC-1α-mediated autophagy remains elusive. Methods: In vivo Cisp-induced AKI mice were administrated with PGC-1α activator (ZLN005, Zln), and the kidneys were harvested to detect autophagy, mitochondrial function and kidney injury. In vitro the protective role of PGC-1α in Cisp-induced HK2 cells were analyzed via overexpression of PGC-1α or Zln treatment. Finally, the key of TFEB in PGC-1α-mediated autophagy was investigated by sitfeb. Findings: In vivo along with the severe kidney damage, the expression of PGC-1α was significantly decreased in AKI mice. Conversely, elevated expression of PGC-1α by Zln administration could alleviate kidney injury. Consistently, in vitro overexpression of PGC-1α or Zln treatment inhibited cell apoptosis and mitochondrial dysfunction. Moreover, Zln treatment increased the expression of LC3-II and co-localization between LC3 and mitochondria in HK2 cells, suggesting that the mitophagy was activated. Furthermore, we found that PGC-1α directly regulated the expression of TFEB, and the protective role of PGC-1α was rely on TFEB-mediated autophagy. Interpretation: These data suggest that the activation of PGC-1α could alleviate mitochondrial dysfunction and kidney injury in AKI mice via TFEB-mediated autophagy. Funding: This work was supported by grants from the National Natural Science Foundation of China (grant number: 81900666 and 81870609), 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University (ZYGD18014). Declaration of Interests: The authors declare no competing financial interests. Ethics Approval Statement: All animal experiments were approved and conducted in accordance with the guidelines of the Institutional Animal Care and Use Committee of Sichuan University.

Objectives Alzheimer's disease (AD) is one of the most prevalent brain diseases among the elderly, majority of which is caused by abnormal deposition of amyloid beta-peptide (Aβ). Galantamine, currently the first-line drug in treatment of AD, has been shown to diminish Aβ-induced neurotoxicity and exert favourable neuroprotective effects, but the detail mechanisms remain unclear. Materials and methods Effects of galantamine on Aβ-induced cytotoxicity were checked by MTT, clone formation and apoptosis assays. The protein variations and reactive oxygen species (ROS) production were measured by western blotting analysis and dichloro-dihydro-fluorescein diacetate assay, respectively. Results Galantamine reversed Aβ-induced cell growth inhibition and apoptosis in neuron cells PC12. Aβ activated the entire autophagy flux and accumulation of autophagosomes, and the inhibition of autophagy decreased the protein level of cleaved-caspase-3 and Aβ-induced cytotoxicity. Meanwhile, galantamine suppressed Aβ-mediated autophagy flux and accumulation of autophagosomes. Moreover, Aβ upregulated ROS accumulation, while ROS scavengers N-acetyl-l-cysteine impaired Aβ-mediated autophagy. Further investigation showed that galantamine downregulated NOX4 expression to inhibit Aβ-mediated ROS accumulation and autophagy. Conclusions Galantamine inhibits Aβ-induced cytostatic autophagy through decreasing ROS accumulation, providing new insights into deep understanding of AD progression and molecular basis of galantamine in neuroprotection.