Mechanism of microRNA-218-5p in mitochondrial biogenesis of sepsis-induced acute kidney injury by the regulation of PGC-1α.

BACKGROUND: Sepsis-induced acute kidney injury (SI-AKI) is a kind of kidney dysfunction, which brings a lot of suffering. This study aimed to figure out the role of the miR-218-5p/PGC-1α axis in SI-AKI. METHODS: AKI mouse model was established through cecal ligation and puncture. PGC-1α expression was activated using an activator ZLN005 before the serum and tissue samples were collected. Next, pathological structure and apoptosis of kidney tissues were observed. Levels of blood urea nitrogen, serum creatinine and indicators of inflammation and oxidative stress were assessed. Moreover, reactive oxygen species and mitochondrial membrane potential levels, adenosine 5'-triphosphate content and mitochondrial ultrastructure of kidney tissues were observed. HK2 cells were treated by lipopolysaccharide (LPS) to mimic sepsis in vitro, followed by evaluation of cell survival and apoptosis, inflammation and oxidative stress. Subsequently, the binding relation between PGC-1α and miR-218-5p was predicted and validated. Then expression of PGC-1α and miR-218-5p was detected. PGC-1α and miR-218-5p expression were intervened to detect their influences in mitochondrial biogenesis. At last, miR-218-5p was overexpressed in ZLN005 (PGC-1α activating agent) pretreated SI-AKI mice to validate the mechanism. RESULTS: PGC-1α is poorly expressed in SI-AKI, but overexpression of PGC-1α using ZLN005 alleviated SI-AKI injury and promoted mitochondrial biogenesis in AKI mice, and relieved LPS-induced cell injury. PGC-1α is a target of miR-218-5p. Downregulation of miR-218-5p expression in HK2 cells attenuated mitochondrial biogenesis disorder. Inhibition of PGC-1α annulled the role of miR-218-5p silencing in cells. In vivo, miR-218-5p overexpression partly reversed the protective role of ZLN005 in SI-AKI mice. CONCLUSION: miR-218-5p targeted PGC-1α to disrupt mitochondrial biogenesis, thereby exacerbating SI-AKI.

Case report: Temozolomide induced hypermutation indicates an unfavorable response to immunotherapy in patient with gliomas.

Background: Temozolomide (TMZ) is a key component in the treatment of gliomas. Hypermutation induced by TMZ can be encountered in routine clinical practice, and its significance is progressively gaining recognition. However, the relationship between TMZ-induced hypermutation and the immunologic response remains controversial. Case presentation: We present the case of a 38-year-old male patient who underwent five surgeries for glioma. Initially diagnosed with IDH-mutant astrocytoma (WHO grade 2) during the first two surgeries, the disease progressed to grade 4 in subsequent interventions. Prior to the fourth surgery, the patient received 3 cycles of standard TMZ chemotherapy and 9 cycles of dose-dense TMZ regimens. Genomic and immunologic analyses of the tumor tissue obtained during the fourth surgery revealed a relatively favorable immune microenvironment, as indicated by an immunophenoscore of 5, suggesting potential benefits from immunotherapy. Consequently, the patient underwent low-dose irradiation combined with immunoadjuvant treatment. After completing 4 cycles of immunotherapy, the tumor significantly shrank, resulting in a partial response. However, after a 6-month duration of response, the patient experienced disease progression. Subsequent analysis of the tumor tissue obtained during the fifth surgery revealed the occurrence of hypermutation, with mutation signature analysis attributing TMZ treatment as the primary cause. Unfortunately, the patient succumbed shortly thereafter, with a survival period of 126 months. Conclusion: Patients subjected to a prolonged regimen of TMZ treatment may exhibit heightened vulnerability to hypermutation. This hypermutation induced by TMZ holds the potential to function as an indicator associated with unfavorable response to immunotherapy in gliomas.

Upregulated microRNA-450b-5p represses the development of acute liver failure via modulation of liver function, inflammatory response, and hepatocyte apoptosis.

OBJECTIVE: It has been evidenced that microRNAs (miRs) exert crucial effects on acute liver failure (ALF), while the detailed function of miR-450b-5p in ALF progression remained obscure. The purpose of this research was to unravel the regulatory mechanism of miR-450b-5p in ALF via modulating Mouse Double Minute 2 protein (MDM2). METHODS: ALF was induced in mice by intraperitoneal injection of d-galactosamine ( d-GalN) and lipopolysaccharide (LPS). Adenoviruses containing overexpressed miR-450b-5p, MDM2 shRNA, and overexpressed MDM2 sequences were utilized to manipulate miR-450b-5p and MDM2 expression in the liver before the mice were treated with d-GalN/LPS-induced ALF. Subsequently, miR-450b-5p and MDM2 expression levels in liver tissues of ALF mice were examined. Serum biochemical parameters of liver function were tested, serum inflammatory factors were assessed, and the histopathological changes and hepatocyte apoptosis in liver tissues were observed. The relation between miR-450b-5p and MDM2 was verified. RESULTS: In ALF mice, miR-450b-5p was low-expressed while MDM2 was high-expressed. The upregulation of miR-450b-5p or downregulation of MDM2 could alleviate liver function, mitigate the serum inflammatory response and pathological changes in liver tissues, as well as inhibit the apoptosis of hepatocytes. MiR-450b-5p targeted MDM2. MDM2 overexpression reversed the repressive effects of elevated miR-450b-5p on ALF. CONCLUSION: The upregulated miR-450b-5p blocks the progression of ALF via targeting MDM2. This study contributes to affording novel therapeutic targets for ALF treatment.

Neonatal hemolytic disease due to anti-Diegoa antibody: a case report.

BACKGROUND: The Diegoa antigen commonly occurs in certain Asian and South American Indian populations. In general, hemolysis caused by anti-Diegoa antigen is not severe, and exchange transfusion is rarely needed. Here, we report a neonate with moderate hemolytic disease caused by anti-Diegoa antigen in the Baoji area of China. CASE PRESENTATION: A 39-week gestation male newborn of Han nationality was delivered by second cesarean section because of scarred uterus. The newborn's birth weight was 3700 g with an Apgar score of 9. Four hours after delivery, transcutaneous bilirubin test revealed a level of 17 mg/dl. After 23 hours, the neonate developed anemia and hyperbilirubinemia. Bacterium, virus and other pathogens, as well as tests for arcuate and glucose-6-phosphate dehydrogenase, were all negative. Direct antiglobulin test of the neonate was positive. Diegoa antigens of the baby and his father were positive, while his mother was negative. The newborn was successfully cured with phototherapy and one-dose intravenous injection of human albumin. CONCLUSIONS: It is important to consider and test for the anti-Diegoa antibody in cases of hemolytic disease of the newborn of the Han ethnicities of China.

Clinical Efficacy of Huangkui Capsule plus Methylprednisolone in the Treatment of Nephropathy and the Effect on Urinary Protein and Serum Inflammatory Factors in Patients.

Objective: The study aimed to assess the clinical efficacy of Huangkui capsule plus methylprednisolone in the treatment of nephropathy and the effect on urinary protein and serum inflammatory factors in patients. Methods: Between June 2017 and July 2020, 90 patients with nephropathy admitted to our hospital were recruited after assessment of eligibility and assigned via the random number table method (1 : 1) to receive either methylprednisolone tablets (observation group) or methylprednisolone tablets plus Huangkui capsules (experimental group). All eligible patients were also given dipyridamole and valsartan. Outcome measures included clinical efficacy, urine protein, hematuria, serum inflammatory factor levels, and adverse reactions. Results: A higher clinical efficacy was observed in the experimental group versus the observation group (P < 0.05). Huangkui capsules resulted in significantly lower levels of urine protein and hematuria in the experimental group versus the observation group after treatment (P < 0.05). The serum tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and monocyte chemoattractant protein-1 (MCP-1) levels in the experimental group were significantly lower than those in the observation group after treatment (P < 0.05). Huangkui capsules plus methylprednisolone were associated with a lower incidence of adverse events versus methylprednisolone (P < 0.05). Conclusion: The clinical efficacy of Huangkui capsule plus methylprednisolone in the treatment of patients with nephropathy is remarkable. It can effectively mitigate the inflammatory responses and enhance renal function, with reliable clinical safety, so it is worthy of clinical application.

Machine Learning for the Prediction of Lymph Nodes Micrometastasis in Patients with Non-Small Cell Lung Cancer: A Comparative Analysis of Two Practical Prediction Models for Gross Target Volume Delineation.

PURPOSE: The lymph node gross target volume (GTV) delineation in patients with non-small cell lung cancer (NSCLC) is crucial for prognosis. This study aimed to develop a predictive model that can be used to differentiate between lymph nodes micrometastasis (LNM) and non-lymph nodes micrometastasis (non-LNM). PATIENTS AND METHODS: A retrospective study involving 1524 patients diagnosed with NSCLC was collected in the First Hospital of Wuhan between January 1, 2017, and April 1, 2020. Duplicated and useless variables were excluded, and 16 candidate variables were selected for further analysis. The random forest (RF) algorithm and generalized linear (GL) algorithm were used to screen out the variables that greatly affected the LNM prediction, respectively. The area under the curve (AUC) was compared between the RF model and GL model. RESULTS: The RF model revealed that the variables, including pathology, degree of differentiation, maximum short diameter of lymph node, tumor diameter, pulmonary membrane invasion, clustered lymph nodes, and T stage, were more significant for LNM prediction. Multifactorial logistic regression analysis for the GL model indicated that vascular invasion, tumor diameter, degree of differentiation, pulmonary membrane invasion, and maximum standard uptake value (SUVmax) were positively associated with LNM. The AUC for the RF model and GL model was 0.83 (95% CI: 0.75 to 0.90) and 0.64 (95% CI: 0.60 to 0.70), respectively. CONCLUSION: We successfully established an accurate and optimized RF model that could be used to predict LNM in patients with NSCLC. This model can be used to evaluate the risk of an individual patient experiencing LNM and therefore facilitate the choice of treatment.

[Relationship between pulmonary vascular dysfunction and prognosis of patients with acute lung injury].

OBJECTIVE: To investigate the effect of pulmonary vascular dysfunction in the prognosis of patients with acute lung injury (ALI). METHODS: Patients with ALI who underwent pulmonary artery catheterization in the department of critical care medicine of Wuhan NO.1 Hospital from June 2017 to June 2019 were enrolled. The general information, clinical and hemodynamic indexes [central venous pressure (CVP), pulmonary artery wedge pressure (PAWP), pulmonary artery systolic pressure (sPAP), pulmonary artery diastolic pressure (dPAP), mean pulmonary artery pressure (mPAP), cardiac index (CI)], acute physiology and chronic health evaluation II (APACHE II) score, arterial blood gas parameters [pH, partial pressure of oxygen (PO2), partial pressure of carbon dioxide (PCO2), oxygenation index (PaO2/FiO2)], whether there was shock or not; ventilator parameters [platform pressure (Plat), positive end-expiratory pressure (PEEP)], etc. were recorded. Pulmonary artery oxygen saturation, pulmonary vascular function indexes [transpulmonary potential gradient (TPG) and pulmonary vascular resistance index (PVRi)] were calculated. The relationship between TPG, PVRi and mechanical ventilation time, the length of intensive care unit (ICU) stay, cardiovascular days and 60-day mortality were analyzed in patients with different prognosis of 60-day and whether the TPG increased (≥ 12 mmHg was defined as elevated TPG, 1 mmHg = 0.133 kPa). RESULTS: A total of 65 patients were included in the study, including 30 males and 35 females; aged (48.9±15.2) years old. Forty-eight cases survived in 60-days, 17 died, and the 60-day mortality was 26.2%. At the baseline, there were no significant differences in cardiopulmonary function measurements, such as CVP, sPAP, dPAP, PAWP, CI, etc. between the two groups of patients with different prognosis. The APACHE II score, shock ratio, TPG and PVRi of the death group were significant higher than those of the survival group [APACHE II: 34±9 vs. 28±11, shock: 52.9% vs. 25.0%, TPG (mmHg): 16.2±1.9 vs. 14.6±2.1, PVRi (kPa×s×L-1): 31.8±4.2 vs. 29.7±3.5, all P < 0.05]. The 60-day mortality of 47 patients with TPG ≥ 12 mmHg was significantly higher than that of 18 patients with TPG < 12 mmHg (34.0% vs. 5.6%), and the mechanical ventilation time and the length of ICU stay were also significantly longer (days: 17±9 vs. 11±8, 16±5 vs. 12±5), and the cardiovascular days also increased significantly (days: 23±7 vs. 18±6), and the differences were statistically significant (all P < 0.05). Pearson correlation analysis showed that PVRi was significantly correlated with mechanical ventilation time, the length of ICU stay and cardiovascular days (r1 = 0.317, P1 = 0.030; r2 = 0.277, P2 = 0.005; r3 = 0.285, P3 = 0.002). In the individual multivariate Logistic regression model, the highest PVRi was an independent risk factor for the 60-day mortality [odds ratio (OR) = 30.5, 95% confidence interval was 20.4-43.1, P = 0.023]. CONCLUSIONS: Pulmonary vascular dysfunction is common in ALI patients and is independently associated with adverse outcomes.

MicroRNA-7 Exerts Antiangiogenic Effect on Colorectal Cancer via ERK Signaling.

BACKGROUND: Recent studies have suggested that microRNA-7 (miR-7) family members may play important roles in human cancer by regulating cell proliferation, apoptosis, migration, and invasion. Therefore, the present study aimed to investigate the clinical significance and biological function of miR-7 in colorectal cancer (CRC). METHODS: Initially, cancer and adjacent tissues were collected from 76 patients with CRC. Then, microvascular density was detected using the Weidner counting method. The functional role of miR-7 in CRC was determined using ectopic expression, knockdown, and reporter assay experiments. The vasculogenic mimicry density was determined. Expression of miR-7, epidermal growth factor receptor (EGFR), extracellular signal-regulated kinase (ERK1/2), vascular endothelial growth factor, and thrombospondin-1 was determined. 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assays, scratch tests, and Transwell assays were conducted to examine cell proliferation, migration, and invasion, respectively. Finally, flow cytometry was applied to evaluate cell apoptosis. RESULTS: CRC tissues showed increased microvascular density and EGFR expression, activated ERK signaling, and miR-7 downregulation. EGFR was a target gene of miR-7. miR-7 overexpression and EGFR silencing decreased vasculogenic mimicry density, cell migration, and cell invasion, but increased cell apoptosis. In addition, miR-7 overexpression and EGFR silencing upregulated thrombospondin-1 and downregulated EGFR, ERK1/2, and vascular endothelial growth factor. Furthermore, we observed that the effect of miR-7 inhibition was abolished after EGFR silencing. CONCLUSIONS: Overexpressed miR-7 suppresses angiogenesis of CRC cells through ERK signaling by downregulating EGFR. It may identify new targets for CRC treatment.

[Assessment of pulpotomy in cariously exposed permanent teeth].

PURPOSE: To observe the clinical effect of pulpotomy for cariously exposed permanent teeth with closed apices and provide guidance for clinical application. METHODS: Sixty-two cariously exposed permanent teeth with closed apices and vital pulps were included. Preoperative pulpal and periapical diagnosis was established. The teeth were divided into two groups, the experimental group was treated with pulpotomy(32 cases), and the control group was treated with one-visit root canal therapy (one-visit RCT) (30 cases). Clinical and radiographic evaluation was completed at 1 month, 3 months, 6 months, 12 months postoperatively. Statistical analysis was performed using SPSS 18.0 software package. RESULTS: After 1 year, the success rate of pulpotomy was 93.75%, and the success rate of root canal therapy was 93.10%. There was no significant difference between pulpotomy and root canal therapy(P=0.665). CONCLUSIONS: The advantages of pulpotomy are less invasive and less tooth destruction. It is a successful treatment option for cariously exposed pulps in mature permanent teeth.

Hydrogen sulfide prolongs postharvest shelf life of strawberry and plays an antioxidative role in fruits.

Accumulating evidence shows that hydrogen sulfide (H(2)S) plays various physiological roles in plants, such as seed germination, root organogenesis, abiotic stress tolerance, and senescence of cut flowers. However, whether H(2)S participates in the regulation of ripening and senescence in postharvest fruits remains unknown. In the present study, the effect of H(2)S on postharvest shelf life and antioxidant metabolism in strawberry fruits was investigated. Fumigation with H(2)S gas released from the H(2)S donor NaHS prolonged postharvest shelf life of strawberry fruits in a dose-dependent manner. Strawberry fruits fumigated with various concentrations of H(2)S sustained significantly lower rot index, higher fruit firmness, and kept lower respiration intensity and polygalacturonase activities than controls. Further investigation showed that H(2)S treatment maintained higher activities of catalase, guaiacol peroxidase, ascorbate peroxidase, and glutathione reductase and lower activities of lipoxygenase relative to untreated controls. H(2)S also reduced malondialdehyde, hydrogen peroxide, and superoxide anion to levels below control fruits during storage. Moreover, H(2)S treatment maintained higher contents of reducing sugars, soluble proteins, free amino acid, and endogenous H(2)S in fruits. We interpret these data as indicating that H(2)S plays an antioxidative role in prolonging postharvest shelf life of strawberry fruits.