From Physiology to Pathology: The Role of Mitochondria in Acute Kidney Injuries and Chronic Kidney Diseases.

Background: Renal diseases remain an increasing public health issue affecting millions of people. The kidney is a highly energetic organ that is rich in mitochondria. Numerous studies have demonstrated the important role of mitochondria in maintaining normal kidney function and in the pathogenesis of various renal diseases, including acute kidney injuries (AKIs) and chronic kidney diseases (CKDs). Summary: Under physiological conditions, fine-tuning mitochondrial energy balance, mitochondrial dynamics (fission and fusion processes), mitophagy, and biogenesis maintain mitochondrial fitness. While under AKI and CKD conditions, disruption of mitochondrial energy metabolism leads to increased oxidative stress. In addition, mitochondrial dynamics shift to excessive mitochondrial fission, mitochondrial autophagy is impaired, and mitochondrial biogenesis is also compromised. These mitochondrial injuries regulate renal cellular functions either directly or indirectly. Mitochondria-targeted approaches, containing genetic (microRNAs) and pharmaceutical methods (mitochondria-targeting antioxidants, mitochondrial permeability pore inhibitors, mitochondrial fission inhibitors, and biogenesis activators), are emerging as important therapeutic strategies for AKIs and CKDs. Key Messages: Mitochondria play a critical role in the pathogenesis of AKIs and CKDs. This review provides an updated overview of mitochondrial homeostasis under physiological conditions and the involvement of mitochondrial dysfunction in renal diseases. Finally, we summarize the current status of mitochondria-targeted strategies in attenuating renal diseases.

The Potential Roles of CHI3L1 in Failed Autologous Arteriovenous Fistula in End-Stage Renal Disease.

Autologous arteriovenous fistula (AVF) is commonly placed for hemodialysis treatment. Recent studies show that increased baseline serum level of Chitinase-3-like protein 1 (CHI3L1) is independently associated with a higher risk of the early failure of forearm AVFs. However, the changes and mechanisms of CHI3LI in local vascular tissues of failed AVF have not be revealed. This study aims to conduct the expression and mechanism of CHI3L1 in vascular tissues from patients. Immunoreactivity of CHI3L1, matrix metalloproteinase 2 (MMP-2) and vascular endothelial growth factor-A (VEGF-A) were detected in vascular tissues collected from nine patients with AVF surgery. Due to the significant stenosis clinically, six of the nine patients received arteriovenous fistula reconstruction. The expression differences of CHI3L1 between the initial vascular tissues and failed AVF are significant (P < 0.05). Failed AVF due to stenosis shows intraluminal thrombus, collagen fiber rupture, fibrous connective tissue hyperplasia, tube wall thickening, neovascularization, scattered inflammatory cell infiltration in the tunica media as well as high CHI3L1 expression level, and the expression of MMP-2 (r = 0.9022, P = 0.0139) and VEGF-A (r = 0.8355, P = 0.0393) was positively correlated with CHI3L1. CHI3L1 expression in vascular tissues possibly plays an important role in AVF failure. MMP-2 and VEGF-A may participate in venous stenosis with CHI3L1.

PM2.5 promotes apoptosis of alveolar epithelial cells via targeting ROS/p38 signaling pathway and thus leads to emphysema in mice.

BACKGROUND: The aim of this study was to uncover the ability of PM2.5 exposure to induce apoptosis in alveolar epithelial cells by stimulating excessive production of reactive oxygen species (ROS), thus activating p38 to result in emphysema in mice. METHODS: Male BALB/c mice with 6-8-week-old were exposed to 200 TPM mg/L PM2.5 for 12 weeks. Lung tissues of mice were harvested after sacrifice. Hematoxylin and eosin staining was conducted for observing alveolar structure change. Protein levels of p-p38 and p38, as well as ROS level in mouse liver tissues were determined. A549 cells were exposed to different doses of PM2.5, followed by ROS detection, protein level detection of p-p38 and p38, and apoptosis determination. After transfection of si-p38, protein level of clv-caspase3 and apoptotic rate in PM2.5-exposed A549 cells were assessed. RESULTS: After 12-week exposure to PM2.5, enlarged alveolar space, elevated ROS level in lung tissues and activated p38 were observed in mice. In PM2.5-exposed A549 cells, ROS level, p-p38 expression and apoptotic rate were dose-dependently enhanced. The antioxidant NAC reversed the above changes in PM2.5-exposed A549 cells. Silence of p38 reversed the enhanced clv-claspase3 level and apoptotic rate in PM2.5-exposed A549 cells. CONCLUSIONS: PM2.5 exposure elevates ROS level in lung tissues, and activates p38, thus leading to apoptosis of alveolar epithelial cells. PM2.5 finally results in the development of emphysema in mice.

A novel 3-phenylglutaric acid derivative (84-B10) alleviates cisplatin-induced acute kidney injury by inhibiting mitochondrial oxidative stress-mediated ferroptosis.

Cisplatin is one of the most effective chemotherapy drugs and is widely used for cancer treatment. However, its clinical use is limited by nephrotoxicity. Emerging findings suggested that both ferroptosis and mitochondrial dysfunction mediate cisplatin-induced nephrotoxicity. In the current study, a novel 3-phenylglutaric acid derivative 5-[[2-(4-methoxyphenoxy)-5-(trifluoromethyl)phenyl]amino]-5-oxo-3-phenylpentanoic acid (referred to as 84-B10) was found to play a protective role in cisplatin-induced acute kidney injury with no tumor promoting effects. A genome-wide transcriptome analysis indicated that the protective effect of 84-B10 might be dependent on antagonizing ferroptosis. In accordance, lipid peroxide accumulation and downregulation of key ferroptosis suppressors were reversed using 84-B10 treatment both in vivo and in vitro. In addition, 84-B10 inhibited cisplatin-induced mitochondrial damage and mitochondrial reactive oxygen species (mtROS) production and restored superoxide dismutases (SODs). Furthermore, 84-B10 showed similar therapeutic effects to MnTBAP (a cell-permeable SOD mimetic) in eliminating mtROS, restoring mitochondrial homeostasis, and inhibiting ferroptosis under cisplatin challenge. Comparable effects of 84-B10 and liproxstatin-1 in ameliorating cisplatin-induced ferroptosis were observed. However, liproxstatin-1 failed to prevent mitochondrial dysfunction. These data indicated that mtROS might act upstream of cisplatin-induced tubular ferroptosis. Taken together, the novel 3-phenylglutaric acid derivative 84-B10 showed therapeutic potential against cisplatin-induced nephrotoxicity possibly by restoring mitochondria homeostasis and inhibiting mtROS-induced ferroptosis, which suggests the potential use of 84-B10 in preventing and treating cisplatin-nephrotoxicity.

Clinical Potential of Hypoxia Inducible Factors Prolyl Hydroxylase Inhibitors in Treating Nonanemic Diseases.

Hypoxia inducible factors (HIFs) and their regulatory hydroxylases the prolyl hydroxylase domain enzymes (PHDs) are the key mediators of the cellular response to hypoxia. HIFs are normally hydroxylated by PHDs and degraded, while under hypoxia, PHDs are suppressed, allowing HIF-α to accumulate and transactivate multiple target genes, including erythropoiesis, and genes participate in angiogenesis, iron metabolism, glycolysis, glucose transport, cell proliferation, survival, and so on. Aiming at stimulating HIFs, a group of small molecules antagonizing HIF-PHDs have been developed. Of these HIF-PHDs inhibitors (HIF-PHIs), roxadustat (FG-4592), daprodustat (GSK-1278863), vadadustat (AKB-6548), molidustat (BAY 85-3934) and enarodustat (JTZ-951) are approved for clinical usage or have progressed into clinical trials for chronic kidney disease (CKD) anemia treatment, based on their activation effect on erythropoiesis and iron metabolism. Since HIFs are involved in many physiological and pathological conditions, efforts have been made to extend the potential usage of HIF-PHIs beyond anemia. This paper reviewed the progress of preclinical and clinical research on clinically available HIF-PHIs in pathological conditions other than CKD anemia.

The phosphatase of regenerating liver-3 protein (PRL-3) promotes glioma cell invasiveness by interacting with ß3 -tubulin.

PRL-3 is a tyrosine phosphatase linked with tumor metastasis. It is detected high expression in different kinds of cancers, including colorectal, gastric, ovarian, and liver cancer. Its high expression is positively correlated with the progression of tumors and negatively with survivals of patients. However, the detailed mechanism underlying PRL-3 in tumor metastasis still remains unclear. In the present study, we found that PRL-3 is able to bind to ß3-tubulin in pull-down and co-immunoprecipitation assays. Furthermore, overexpression of PRL-3 dephosphorylated ß3-tubulin, a component of cytoskeleton, which plays critical role in cell shape formation and migration. Using cell wound healing and matrigel invasion assays, we found that PRL-3 could promote the migration and invasion of glioma cells. Taken together, our study revealed that PRL-3 may be involved in migration and invasion of glioma by dephosphorylating ß3-tubulin. It is tempting to speculate that dephosphorylation of ß3-tubulin by PRL-3 results in assembly of the cytoskeleton and facilitates cell migration and/or tumor metastasis.

Radiofrequency thermocoagulation combined with doxorubicin injection for treatment of trigeminal neuralgia mandibular branch.

OBJECTIVES: This study aimed to evaluate the clinical application value of 3D printed template-guided radiofrequency thermocoagulation combined with doxorubicin injection for the treatment of trigeminal neuralgia mandibular branch. METHODS: A total of 50 patients with primary trigeminal neuralgia mandibular branch in the hospital from January 2019 to September 2020 were randomly divided into two groups: 3D printed template-guided radiofrequency thermocoagulation combined with doxorubicin injection was used as the research group (n=25), and 3D printed template guided radiofrequency thermocoagulation was used as the control group (n=25). Comparative analysis of visual analogue score (VAS) was conducted before and immediately after surgery and at 1, 3, 6, and 12 months after surgery. The Brisman efficacy evaluation criteria for trigeminal neuralgia was used to evaluate the therapeutic effect of each postoperative follow-up period, and postoperative complications were observed. RESULTS: The VAS immediately after surgery and at 1, 3, 6, and 12 months after surgery in the two groups was significantly lower than that before surgery, with statistical significance (P<0.05). According to Brisman efficacy evaluation criteria for trigeminal neuralgia, no significant difference was found in the efficacy between the two groups at 1 and 3 months after surgery (P>0.05). At 6 and 12 months postoperatively, the effectiveness of the research group was higher than that of the control group, and the differences were statistically significant (P<0.05). In the research group, no recurrence occurred during the follow-up period, whereas in the control group, one, two, and four recurrences occurred 3, 6, and 12 months after surgery, respectively. No obvious complications were found in both groups. CONCLUSIONS: 3D printed template-guided radiofrequency thermocoagulation combined with doxorubicin injection for the treatment of trigeminal neuralgia mandibular branch could enhance the long-term curative effect and reduce the recurrence rate, thus worthy of clinical promotion and application.

[Evaluation of the symmetry in nasolabial area of unilateral complete cleft lip with the method of rotation descent step by step].

PURPOSE: To evaluate the symmetry and stability of nasolabial area of unilateral complete cleft lip (UCCL) after primary repair with the method of rotation descent step by step. METHODS: Thirty patients with UCCL who were operated on were photographed before, 1 week after and 1 year after surgery, the distances from alare point (al), sub alare point (sba), christa phlitri point (cph) and chelion point (ch) to the facial vertical midline (VML) were measured and compared with the opposite side by paired t test. Statistical analysis was performed with SPSS 19.0 software package. RESULTS: There were significant differences in al, sba and cph between the cleft side and non-cleft side before(P<0.05) and 1 week after surgery; significant differences were found in al, sba and ch between the affected and unaffected side (P<0.05); but 1 year after surgery, there was no significant difference between the two sides except sba. After surgery, all the distances from VML were less than those before surgery. There was no significant difference in symmetry rate between 1 week and 1 year after surgery for all the points except sba. CONCLUSIONS: The results indicated that the method of rotation descent step by step is very helpful in reconstruction of lip symmetry, but primary repair can not achieve full recovery of nasal symmetry.

[Establishment of human B lymphocyte strain overexpressing Epstein-Barr virus latent membrane protein 1 (LMP1)].

Objective To establish a human B lymphoma cell line which can stably express Epstein-Barr virus latent membrane protein 1 (LMP1). Methods The LMP1 coding gene with EcoRI and BamHI restriction sites was amplified, cloned into pcDNA3.1-EF1a-mcs-3FLAG-CMV-EGFP plasmid, and positive monoclonal competent cells were picked for PCR and sequencing. The recombinant plasmid was transfected into Ramos cells by electroporation, and the cell line stably expressing LMP1 was picked by G418. The expression of LMP1 in Ramos cells was detected by PCR, Western blot analysis and green fluorescent protein Tag. Results PCR and sequencing confirmed that the LMP1 recombinant plasmid was successfully constructed and a stably transfected Ramos cell line was established. Western blot analysis confirmed that LMP1 protein was successfully expressed in this cell line. Conclusion The Ramos cells stably expressing LMP1 have been successfully established.

[3D printing navigation template-guided percutaneous radiofrequency thermocoagulation for V2 trigeminal neuralgia treatment].

OBJECTIVE: This paper aimed to evaluate the effectiveness of the 3D printing puncture navigation template-guided percutaneous radiofrequency thermocoagulation for V2 trigeminal neuralgia treatment. METHODS: A total of 52 patients with V2 trigeminal neuralgia were treated with radiofrequency thermocoagulation. A total of 32 patients were treated under the guidance of the 3D printing puncture navigation template (guide plate group), while 20 patients underwent puncture via pterygopalatine fossa routinely (routine treatment group). The puncture time, operation time, puncture success rate, and immediate postoperative pain were recorded. The degree of immediate postoperative pain was indicated by visual analogue scale (VAS). Barrow Neurological Institute (BNI) classification criteria were used to evaluate the efficacy, and the postoperative complications were observed. All patients were followed up for 1 year. RESULTS: The two groups showed significant decrease in VAS after the operation (P<0.05). The puncture and operation times of the guide plate group were significantly lower than those of the routine treatment group (P<0.05). The difference in terms of the clinical effects and recurrence rate between the two groups was insignificant (P>0.05). CONCLUSIONS: 3D printing puncture navigation template-guided radiofrequency thermocoagulation may increase the operation success rate and reduce complication incidence. Therefore, this technique possesses clinical promotional value.