According to recent evidence, ferroptosis is a major cell death mechanism in the pathogenesis of kidney injury and fibrosis.Despite the renoprotective effects of classical ferroptosis inhibitors, therapeutic approaches targeting kidney ferroptosis remain limited. In this study, we assessed the renoprotective effects of melatonin and zileuton as a novel therapeutic strategy against ferroptosis-mediated kidney injury and fibrosis. First, we identified RSL3-induced ferroptosis in renal tubular epithelial HK-2 and HKC-8 cells. Lipid peroxidation and cell death induced by RSL3 were synergistically mitigated by the combination of melatonin and zileuton. Combination treatment significantly downregulated the expression of ferroptosis-associated proteins, 4-HNE and HO-1, and upregulated the expression of GPX4. The expression levels of p-AKT and p-mTOR also increased, in addition to that of NRF2 in renal tubular epithelial cells. When melatonin (20 mg/kg) and zileuton (20 mg/kg) were administered to a unilateral ureteral obstruction (UUO) mouse model, the combination significantly reduced tubular injury and fibrosis by decreasing the expression of profibrotic markers, such as α-SMA and fibronectin. More importantly, the combination ameliorated the increase in 4-HNE levels and decreased GPX4 expression in UUO mice. Overall, the combination of melatonin and zileuton was found to effectively ameliorate ferroptosis-related kidney injury by upregulating the AKT/mTOR/ NRF2 signaling pathway, suggesting a promising therapeutic strategy for protection against ferroptosis-mediated kidney injury and fibrosis.

Background: Neuroinflammation plays an important role in cognitive decline and memory impairment in neurodegenerative disorders. Previously, we demonstrated that Humulus japonicus (HJ) has anti-inflammatory effects in rodent models of Alzheimer’s disease and Parkinson’s disease. The present study aimed to examine the protective potential of HJ extracts against lipopolysaccharide (LPS)-induced cognitive impairment and scopolamine-induced amnesia in mouse models. Cognitive improvement of mice was investigated by novel object recognition test. For analyzing effects on neuroinflammation, immunohistochemistry and quantitative real-time polymerase chain reaction (qRTPCR) assays were performed. Results: We found that the oral administration of HJ significantly improved cognitive dysfunction induced by LPS in a novel object recognition test. The LPS-induced activation of microglia was notably decreased by HJ treatment in the cortex and hippocampus. HJ administration with LPS also significantly increased the mRNA expression of interleukin (IL)-10 and decreased the mRNA expression of IL-12 in the parietal cortex of mice. The increased expression of LPS-induced complement C1q B chain (C1bq) and triggering receptor expressed on myeloid cells 2 (Trem2) genes was significantly suppressed by HJ treatment. In addition, HJ administration significantly improved novel object recognition in a scopolamine-induced amnesia mouse model. Conclusions These findings revealed that HJ has a beneficial effect on cognitive impairment and neuroinflammation induced by systemic inflammation and on amnesia induced by scopolamine in mice.

Lesch-Nyhan disease (LND) is a rare X-linked recessive inherited purine metabolic disorder that accompanies neurodevelopmental problems. Neurofibromatosis type 1 (NF1) is a relatively common autosomal dominant inherited genetic disorder characterized by tumors in various systems. Some children with NF1 also accompanies neurodevelopmental problems.Here, we describe a 5-year-old boy with a maternally inherited pathogenic variant in NF-1 and hypoxanthine-guanine phosphoribosyltransferase (HPRT ). He was referred for severe neurodevelopmental impairment and hyperuricemia. His mother was diagnosed with NF1 and the patient was also suspected of having NF1 because of cafe au lait macules. He had dystonia, rigidity, cognitive deficit, and speech/language impairment. Serum and urine uric acid concentrations were elevated. He had more severe neurodevelopmental delay than patients with only NF1, so his clinical symptoms could not be fully understood by the disease alone. To find the cause of his neurologic symptoms and hyperuricemia, the patient and his mother underwent a whole-exome sequencing test. As a result, the pathogenic variant c.151C>T (p.Arg51Ter) in HPRT1 was identified as hemizygote in the patient and heterozygote in his mother. The pathogenic variant c.7682C>G (p.Ser2561Ter) in NF-1 was identified as heterozygotes in both of them. Although the clinical symptoms of both diseases were overlapping and complicated, genetic testing was helpful for accurate diagnosis and treatment. Therefore, we suggest to consider preemptive genetic evaluation if there are symptoms not sufficiently explained by known existing diseases. And it is considered valuable to review this rare case to understand the clinical course and possible synergic effects of these diseases.

10% of labeled tumor cells) of TNF receptor 1 (TNFR1), the protein product of TNFRSF1A gene, was correlated with sarcomatoid dedifferentiation and was an independent predictive factor of clinically unfavorable response and shorter survivals in separated TKI-treated ccRCC cohort.CONCLUSION: TNF-α signaling may play a role in TKI resistance, and TNFR1 expression may serve as a predictive biomarker for clinically unfavorable TKI responses in ccRCC.]]>
Biomarkers ; Carcinoma, Renal Cell ; Cohort Studies ; Dataset ; Drug Resistance ; Gene Expression ; Gene Expression Profiling ; Heterografts ; Humans ; Immunohistochemistry ; Protein-Tyrosine Kinases ; Receptors, Tumor Necrosis Factor ; Receptors, Tumor Necrosis Factor, Type I ; Tumor Necrosis Factor-alpha

BACKGROUND: Mechanism and predictive biomarkers for tyrosine kinase inhibitor (TKI) resistance of advanced clear cell renal cell carcinoma (ccRCC) have not been fully evaluated. METHODS: We performed gene expression profiling on samples from an acquired TKI resistance cohort that consisted of 10 cases of TKI-treated ccRCC patients with matched tumor tissues harvested at pre-treatment and TKI-resistant post-treatment periods. In addition, a public microarray dataset from patient-derived xenograft model for TKI-treated ccRCC (GSE76068) was retrieved. Commonly altered pathways between the datasets were investigated by Ingenuity Pathway Analysis using commonly regulated differently expressed genes (DEGs). The significance of candidate DEG on intrinsic TKI resistance was assessed through immunohistochemistry in a separate cohort of 101 TKI-treated ccRCC cases. RESULTS: TNFRSF1A gene expression and tumor necrosis factor (TNF)-α pathway were upregulated in ccRCCs with acquired TKI resistance in both microarray datasets. Also, high expression (> 10% of labeled tumor cells) of TNF receptor 1 (TNFR1), the protein product of TNFRSF1A gene, was correlated with sarcomatoid dedifferentiation and was an independent predictive factor of clinically unfavorable response and shorter survivals in separated TKI-treated ccRCC cohort. CONCLUSION TNF-α signaling may play a role in TKI resistance, and TNFR1 expression may serve as a predictive biomarker for clinically unfavorable TKI responses in ccRCC.

Background: The analgesic effect of perineural opioid in clinical practice are still controversial. This randomized controlled trial compared analgesic effect of ropivacaine with fentanyl or ropivacaine alone for continuous femoral nerve block following unilateral total knee arthroplasty. Methods: Fourty patients of ASA PS Ⅰ or Ⅱ receiving total knee arthroplasty with spinal anesthesia were enlisted and randomly allocated into two groups. Group R; bolus injection of 0.375% ropivacaine, 30 ml and an infusion of 0.2% ropivacaine at 8 ml/h (n = 20). Group RF; 0.375% ropivacaine, 29 ml added with 50 μg of fentanyl as a bolus and an infusion of 0.2% ropivacaine mixed with 1 μg/ml of fentanyl at 8 ml/h (n = 20). Local anesthetic infusion via a femoral nerve catheter was started at the end of operation and continued for 48 h. Intravenous patient-controlled analgesia with hydromorphone (0.15 mg/ml, 0-1-10) were used for adjuvant analgesics. Position of catheter tip and contrast distribution, visual analog scale of pain, hydromorphone consumption, side effects were recorded for 48 h after operation. Patient satisfaction for the pain control received were noted. Results: The pain visual analogue scale, incidences of side effects and satisfaction were not different between the two groups (P > 0.05), but the hydromorphone usage at 48 h after operation were lower in the Group RF than in the Group R (P = 0.047). Conclusions The analgesic effect of ropivacaine with fentanyl for continuous femoral nerve block after knee replacement arthroplasty was not superior to that of the ropivacaine alone.

Noninfectious aortitis, inflammatory abdominal periaortitis, and idiopathic retroperitoneal fibrosis are chronic inflammatory diseases with unclear causes. Recent studies have shown that some cases of aortitis are associated with immunoglobulin G4 (IgG4)-related systemic disease. Herein, we report a case of IgG4-related aortitis (IgG4-RA) that was diagnosed after surgery. Our patient was a 46-year-old man who had experienced abdominal pain for several weeks. Preoperative evaluations revealed an area of aortitis on the infrarenal aorta. He underwent surgery, and histological examination resulted in a diagnosis of IgG4-RA.
Abdominal Pain ; Aorta ; Aorta, Abdominal ; Aortitis ; Arteritis ; Diagnosis ; Humans ; Immunoglobulins ; Middle Aged ; Retroperitoneal Fibrosis

PURPOSE: The most common method of monitoring cardiac output (CO) is thermodilution using pulmonary artery catheter (PAC), but this method is associated with complications. Impedance cardiography (ICG) is a non-invasive CO monitoring technique. This study compared the accuracy and efficacy of ICG as a non-invasive cardiac function monitoring technique to those of thermodilution and arterial pressure contour. MATERIALS AND METHODS: Sixteen patients undergoing liver transplantation were included. Cardiac index (CI) was measured by thermodilution using PAC, arterial waveform analysis, and ICG simultaneously in each patient. Statistical analysis was performed using intraclass correlation coefficient (ICC) and Bland-Altman analysis to assess the degree of agreement. RESULTS: The difference by thermodilution and ICG was 1.13 L/min/m², and the limits of agreement were −0.93 and 3.20 L/min/m². The difference by thermodilution and arterial pressure contour was 0.62 L/min/m², and the limits of agreement were −1.43 and 2.67 L/min/m². The difference by arterial pressure contour and ICG was 0.50 L/min/m², and the limits of agreement were −1.32 and 2.32 L/min/m². All three percentage errors exceeded the 30% limit of acceptance. Substantial agreement was observed between CI of thermodilution with PAC and ICG at preanhepatic and anhepatic phases, as well as between CI of thermodilution and arterial waveform analysis at preanhepatic phase. Others showed moderate agreement. CONCLUSION: Although neither method was clinically equivalent to thermodilution, ICG showed more substantial correlation with thermodilution method than with arterial waveform analysis. As a non-invasive cardiac function monitor, ICG would likely require further studies in other settings.
Arterial Pressure ; Cardiac Output ; Cardiography, Impedance ; Catheters ; Electric Impedance ; Humans ; Liver Transplantation ; Methods ; Pulmonary Artery ; Thermodilution

Noninfectious aortitis, inflammatory abdominal periaortitis, and idiopathic retroperitoneal fibrosis are chronic inflammatory diseases with unclear causes. Recent studies have shown that some cases of aortitis are associated with immunoglobulin G4 (IgG4)-related systemic disease. Herein, we report a case of IgG4-related aortitis (IgG4-RA) that was diagnosed after surgery. Our patient was a 46-year-old man who had experienced abdominal pain for several weeks. Preoperative evaluations revealed an area of aortitis on the infrarenal aorta. He underwent surgery, and histological examination resulted in a diagnosis of IgG4-RA.

Gouty arthritis is a common crystal arthropathy, but gout tophus in the bipartite patella is a rare condition. This report presented a traumatic separation of bipartite patellar fragment caused by mild trauma in a patient with comorbid gout. When a patient with bipartite patella and underlying gouty arthritis complains of pain after trauma, clinical suspicion is needed about fragment separation of the bipartite patella.