Knowledge mapping of research on the mitochondrial unfolded protein response: a bibliometric and visual analysis.

Background: The mitochondrial unfolded protein response (UPRmt) is a mitochondria stress response, which exerts a crucial role in maintaining mitochondrial proteostasis during stress. However, there is no bibliometric analyses systematically studied this field which could comprehensively review research trends, evaluate publication performances and provide future perspectives. Methods: Articles investigating UPRmt published between 1994 and 2021 were downloaded from the Core Collection of the Web of Science (WOS). CiteSpace and VOSviewer bibliometric software were applied for bibliometric and visual analyses. Results: A total of 2,073 papers researching UPRmt were retrieved. According to the published number of papers, the field of UPRmt research has gone through its infancy (after 2000) and rapid growth (after 2021) phases. The United States and China contributed the most to UPRmt research. Regarding the distribution of institutions, Harvard University was the most influential institution. The most prolific authors are Johan Auwerx and CM Haynes. PLoS One is the most extensive journal in the field of UPRmt research, while the Cell Death and Differentiation journal had the greatest impact among the most-authored journals. Moreover, biochemistry/molecular biology, and cell biology are the largest subject areas. UPRmt research is mainly categorized as UPRmt, transcription, endoplasmic reticulum (ER) stress, lipotoxicity, mitophagy, inflammation, skeletal muscle, hypoxia, apoptosis, mitochondrial dysfunction, neurodegeneration, mitochondrial permeability transition, and integrated stress response. Conclusions: At present, research on UPRmt is booming. Further strengthening the cooperation and exchanges between countries, institutions, and authors in the future will surely promote the development of this field.

Propofol Inhibits Ferroptotic Cell Death Through the Nrf2/Gpx4 Signaling Pathway in the Mouse Model of Cerebral Ischemia-Reperfusion Injury.

Ferroptosis is characterized by excessive accumulation of iron and lipid peroxides, which are involved in ischemia, reperfusion-induced organ injury, and stroke. Propofol, an anesthetic agent, has neuroprotective effects due to its potent antioxidant, anti-ischemic, and anti-inflammatory properties. However, the relationship between propofol and ferroptosis is still unclear. In the current study, we elucidated the role of ferroptosis in the neuroprotective effect of propofol in mouse brains subjected to cerebral ischemia reperfusion injury (CIRI). Ferroptosis was confirmed by Western blotting assays, transmission electron microscopy, and glutathione assays. Propofol regulated Nrf2/Gpx4 signaling, enhanced antioxidant potential, inhibited the accumulation of lipid peroxides in CIRI-affected neurons, and significantly reversed CIRI-induced ferroptosis. Additionally, Gpx4 inhibitor RSL3 and Nrf2 inhibitor ML385 attenuated the effects of propofol on antioxidant capacity, lipid peroxidation, and ferroptosis in CIRI-affected neurons. Our data support a protective role of propofol against ferroptosis as a cause of cell death in mice with CIRI. Propofol protected against CIRI-induced ferroptosis partly by regulating the Nrf2/Gpx4 signaling pathway. These findings may contribute to the development of future therapies targeting ferroptosis induced by CIRI.

Network and Pathway-Based Integrated Analysis Identified a Novel "rs28457673-miR-15/16/195/424/497 Family-IGF1R-MAPK Signaling Pathway" Axis Associated With Post-stroke Depression.

Single-nucleotide polymorphisms (SNPs) of microRNA (miRNA) (miRSNP) are SNPs located on miRNA genes or miRNA target sites, which have been supposed to be involved in the development of central nervous system diseases by interfering with miRNA-mediated regulatory functions. However, the association of miRSNP with post-stroke depression (PSD) has not been well-investigated. In this study, we collected 54 PSD risk genes via manual literature-mining and integrated PSD-related risk pathways based on multiple public databases. Furthermore, we systematically screened candidate functional miRSNPs for PSD and integrated a miRSNP-based PSD-associated pathway network, which included 99 miRNAs that target 12 PSD risk pathways. We also reviewed the association between three risk pathways and PSD pathogenetic mechanism thoroughly. Combining literature mining and network analysis, our results proposed an underlying mechanism of "miRSNP → miRNA → risk gene → pathway" axis effects on PSD pathogenesis, especially for rs28457673 (miR-15/16/195/424/497 family) → IGF1R → hsa04010 (MAPK signaling pathway). Our studies revealed a functional role in genetic modifier at the system level in the pathogenesis of PSD, which might provide further information for the miRSNP studies in PSD.

Cough Suppression during Flexible Bronchoscopy Using Transcutaneous Electric Acupoint Stimulation: A Randomized Controlled Study.

Background and Objective. Transcutaneous electric acupoint stimulation (TEAS) is recommended for its sedative and analgesic effects. We sought to evaluate the effect of TEAS on cough suppression during flexible bronchoscopy (FB) and explore the underlying mechanism. Methods. In this single-center, randomized, single-blind, parallel-controlled study, we randomized 100 patients scheduled for FB into two equal groups treated with or without TEAS (TEAS group and control group). Patients in the TEAS group received 30 min of stimulation at the Hegu (LI4), Neiguan (PC6), and Lieque (LU7) points before FB. The control group underwent the same procedure, but without stimulation. The primary outcome was the intraoperative cough score determined by the bronchoscopist. The secondary outcomes were patient-reported discomfort scores and other procedural parameters. Results. Compared with the controls, patients who received TEAS preconditioning had lower cough scores (P=0.0027) and requirement of lidocaine and fentanyl (P < 0.05) and significantly higher postprocedural plasma ß-endorphin levels (P=0.0367). There were no intergroup differences in discomfort scores, midazolam dosage, rate of premature termination, oxygen requirement, sedation level, airway assistance, oxygen saturation, lowest oxygen saturation level, heart rate, plasma substance-P levels, and rate of complications after 24 h. The total procedure duration, time for passage of the bronchoscope through the vocal cords, and systolic and diastolic blood pressure levels were less in the TEAS group than in the control group (P=0.033, 0.039 and <0.05, respectively). Conclusion. The combination of midazolam and TEAS was superior to midazolam alone for cough suppression during FB, probably due to increased plasma ß-endorphin levels. This trial is registered with ChiCTR1800016612 at chictr.org.cn/index.aspx.

Combination of propofol and dezocine to improve safety and efficacy of anesthesia for gastroscopy and colonoscopy in adults: A randomized, double-blind, controlled trial.

BACKGROUND: Gastroscopy and colonoscopy are important and common endoscopic methods for the diagnosis and treatment of gastrointestinal and colorectal diseases. However, endoscopy is usually associated with adverse reactions such as nervousness, nausea, vomiting, choking cough, and pain. Severe discomfort, such as vomiting, coughing, or body movement, may lead to aggravation of a pre-existing condition or even interruption of examination or treatment, especially in some critically ill patients with physiological dysfunction (e.g., cardiovascular or respiratory disease). The optimal methods for inducing analgesia and sedation in endoscopy are areas of ongoing debate; nevertheless, determining an appropriate regimen of sedation and analgesia is important. AIM: To evaluate the effects of propofol combined with dezocine, sufentanil, or fentanyl in painless gastroscopy and colonoscopy. METHODS: Four hundred patients were randomly assigned to one of four groups for anesthesia: intravenous dezocine, sufentanil, fentanyl, or saline. Propofol was administered intravenously for induction and maintenance of anesthesia. RESULTS: The dosage of propofol in the dezocine group was significantly lower than those in other groups (P < 0.01). Bispectral index and Steward score (0-6 points, an unresponsive, immobile patient whose airway requires maintenance to a fully recovered patient) after eye opening in the dezocine group were significantly higher than those in other groups (P < 0.01). Awakening time and postoperative pain score (0-10 points, no pain to unbearable pain) in the dezocine group were significantly lower than those in other groups (P < 0.01). Mean arterial pressure and pulse oxygen saturation in the dezocine group were significantly more stable at various time points (before dosing, disappearance of eyelash reflex, and wakeup) than those in other groups (P < 0.01). The rates of hypopnea, jaw thrust, body movements, and usage of vasoactive drugs in the dezocine group were significantly lower than those in other groups (P < 0.01). Additionally, the rates of reflex coughing, nausea, and vomiting were not statistically different between the four groups (P > 0.05). CONCLUSION: The combination of propofol and dezocine can decrease propofol dosage, reduce the risk for the development of inhibitory effects on the respiratory and cardiovascular systems, increase analgesic effect, decrease body movement, shorten awakening time, and improve awakening quality.

Exogenous ghrelin ameliorates acute lung injury by modulating the nuclear factor κB inhibitor kinase/nuclear factor κB inhibitor/nuclear factor κB pathway after hemorrhagic shock.

Previous studies have shown that ghrelin, a peptide produced in the stomach, attenuates acute lung injury (ALI) in various animal models, and that some of these effects are associated with inhibition of the nuclear factor κB signaling pathway. This study investigated whether ghrelin exerts beneficial effects on hemorrhagic shock (HS)-induced ALI by modulating nuclear factor κB inhibitor kinase/nuclear factor κB inhibitor/nuclear factor κB (IKK/IκBα/NF-κB) pathway activity. HS was induced in male SD rats by withdrawing blood to a mean arterial pressure (MAP) of 40 mm Hg for 1 h; rats then received ghrelin (10 nmol/kg) or vehicle intravenously and were resuscitated with the shed blood and an equal volume of Ringer lactate solution followed by observation for 2 h. After resuscitation, samples were collected and analyzed for lung histopathology, wet to dry weight ratio (W/D), bronchoalveolar lavage fluid (BALF) protein, neutrophil infiltration, plasma inflammatory cytokines (TNF-α and IL-6), and cytoplasmic phosphorylated IKKß, IκBα, phosphorylated IκBα and nuclear NF-κB expression. Compared to those in the two sham groups, lung injury, W/D, BALF protein, neutrophil infiltration, plasma TNF-α and IL-6 levels, and IKK/IκBα/NF-κB pathway activation were significantly increased in HS rats. After ghrelin administration, all parameters analyzed were decreased compared to those without ghrelin in HS rats. Moreover, ghrelin alleviated the decreased MAP after resuscitation compared to that in HS rats. Exogenous ghrelin attenuates the inflammatory response and acute lung injury after HS. These beneficial effects appear to be mediated through inhibition of IKK/IκBα/NF-κB signaling.

ALDH2 Protects Against Ischemic Stroke in Rats by Facilitating 4-HNE Clearance and AQP4 Down-Regulation.

Aldehyde dehydrogenase 2 (ALDH2) is a new therapeutic target in the central nervous system. However, the association between ALDH2 and brain edema following ischemic stroke (IS) remains unclear. The present study was investigated to whether active ALDH2 can attenuate brain edema by using a rat model of IS, with the aim of clarifying the underlying mechanisms involved. Rats were administered the ALDH2 agonist Alda-1, vehicle or the ALDH2 inhibitor cyanamide (CYA) 15 min prior to a 1.5 h middle cerebral artery occlusion (MCAO) surgery. The effects of ALDH2 were subsequently investigated 24 h after reperfusion by evaluating neurological function, infarct sizes, brain edema volumes, 4-hydroxy-2-nonenal (4-HNE) levels, and aquaporin 4 (AQP4) protein expression. The results demonstrated that increasing ALDH2 activity significantly improved neurological deficits, reduced infarct sizes, and attenuated brain edema after MCAO. Alda-1 administration led to decreased 4-HNE levels and inhibited AQP4 protein expression in the peri-infarct section of the brain. Whereas, CYA administration increased 4-HNE levels, AQP4 expression, and simultaneously aggravated brain edema following MCAO. In conclusion, increasing ALDH2 activity can improve brain edema, infarct volumes, and reduce neurological impairment in a rat IS model. The therapeutic benefits of ALDH2 are related to 4-HNE clearance and AQP4 down-regulation.

Marital status and survival in patients with renal cell carcinoma.

Previous studies have shown that marital status is an independent prognostic factor for survival in several types of cancer. In this study, we investigated the effects of marital status on survival outcomes among renal cell carcinoma (RCC) patients.We identified patients diagnosed with RCC between 1973 and 2013 from the Surveillance, Epidemiology and End Results (SEER) database. Kaplan-Meier analysis and Cox regression were used to identify the effects of marital status on overall survival (OS) and cancer-specific survival (CSS).We enrolled 97,662 eligible RCC patients, including 64,884 married patients, and 32,778 unmarried (9831 divorced/separated, 9692 widowed, and 13,255 single) patients at diagnosis. The 5-year OS and CSS rates of the married, separated/divorced, widowed, and single patients were 73.7%, 69.5%, 58.3%, and 73.2% (OS), and 82.2%, 80.7%, 75.7%, and 83.3% (CSS), respectively. Multivariate Cox regression showed that, compared with married patients, widowed individuals showed poorer OS (hazard ratio, 1.419; 95% confidence interval, 1.370-1.469) and CSS (hazard ratio, 1.210; 95% confidence interval, 1.144-1.279). Stratified analyses and multivariate Cox regression showed that, in the insured and uninsured groups, married patients had better survival outcomes while widowed patients suffered worse OS outcomes; however, this trend was not significant for CSS.In RCC patients, married patients had better survival outcomes while widowed patients tended to suffer worse survival outcomes in terms of both OS and CSS.

The effects of propofol on mitochondrial dysfunction following focal cerebral ischemia-reperfusion in rats.

Propofol has been shown to attenuate brain injury in experimental ischemia models, but few studies have focused on the direct effect of propofol on mitochondrial dysfunction. In this study, we observed the effects of propofol on multiple aspects of mitochondrial dysfunction by studying the mitochondria isolated from rat brains subjected to focal cerebral ischemia-reperfusion. The mitochondria of the cortical tissue were isolated by the Percoll density gradient centrifugation. The isolated mitochondria were fixed and examined with electron microscopy. The calcium-induced mitochondrial swelling was quantified by measuring the decrease in light transmission at 540 nm with a spectrometer. Fluorescent probes were used to selectively stain mitochondria. Flow cytometry was used to measure the membrane potential and the production of reactive oxidative species. Propofol improved the signs of injury in the cortical mitochondria that were exposed to reperfusion following 2 h of focal ischemia. Propofol prevented calcium-induced mitochondrial swelling in a concentration-dependent manner. It did not affect the reperfusion-induced reduction in mitochondrial membrane potential. However, it decreased the production of the mitochondrial reactive oxidative species, which are generated during reperfusion. These results demonstrate that propofol may protect against mitochondrial dysfunction by preventing the ultrastructural change to the mitochondria and the calcium-induced mitochondrial swelling. This protective effect may be mediated by inhibiting the mitochondrial membrane permeability transition and reducing the production of reactive oxidative species in mitochondria.

[Effects of dexmedetomidine combined with fentanyl in patients undergoing anesthesia induction by sevoflurane].

OBJECTIVE: To investigate the effects of dexmedetomidine combined with fentanyl in patients undergoing anesthesia induction by sevoflurane. METHOD: Eighty patients for elective endotracheal intubation under general anesthesia operations were randomly and double-blindly divided into Dex combined with fentanyl group (Group DF) and the fentanyl group (Group F) from April 2011 to September 2011 at the Fourth Affiliated Hospital of Harbin Medical University, and there were 40 cases in each group. The investigation was approved by all the patients and by the Ethics Committee of the hospital. In group DF, each patient was pumped in the 0.5 µg/kg Dex by vein before 10 minutes of anesthesia induction and group F were given the same amount of normal saline, and tidal volume method was used to induce anesthesia of sevoflurane. All the patients were given 2 µg/kg fentanyl and 0.1 mg/kg vecuronium by tracheal intubation and the MAP and HR and adverse reactions were observed before anesthesia induction (T(0)), before endotracheal intubation (T(1)), at the moment of tracheal intubation (T(2)), after 1 minutes of tracheal intubation (T(3)), after 3 minutes of tracheal intubation (T(4)) and after 5 minutes of tracheal intubation (T(5)). RESULT: The loss of eyelash reflex time of group DF is shorter (P < 0.05), adverse reaction is less (P < 0.05) and the number of adding atropine case is higher than that of group F (P < 0.05), the MAP of the two groups after induction of other moments are lower than that of T(0) (P < 0.05); MAP of group F at T(1) is lower than that of T(0), T(2), T(3) and group DF (P < 0.05); T(1) of group DF is lower than that of T(0) (P < 0.05), the HR after induction of group DF is lower than that of T(0) and F group (P < 0.05), and that of T(2) and T(4) are higher than that of T(1) (P < 0.05); HR of group F at T(1) is lower than that of T(2) and T(3) (P < 0.05). CONCLUSION: Dexmedetomidine in combination with fentanyl can inhibit stress response of tracheal intubation of sevoflurane induction efficiently and stabilize hemodynamics.

Angiotensin receptor blockade attenuates glomerulosclerosis progression by promoting VEGF expression and bone marrow-derived cells recruitment.

BACKGROUND: Previous studies have demonstrated that angiotensin Type I receptor blockade (ARB) reduces proteinuria, reverses glomerular injury and glomerulosclerosis in rat models of diabetic nephropathy and glomerulonephritis. However, the cellular and molecular mechanisms are unclear. To investigate the role of cells of the bone marrow (BM) in glomerular repair seen during ARB administration, we induced progressive glomerulosclerosis in enhanced green fluorescent protein BM chimeric rats by a single injection of anti-Thy 1.1 monoclonal antibody, followed by unilateral nephrectomy. METHODS: Cohorts of rats received valsartan or no treatment from Week 2 to Week 8 after induction of disease. Renal function, urinary protein excretion and histological changes were examined 8 weeks after anti-Thy-1.1 monoclonal antibody injection. RESULTS: Valsartan administration improved renal function, reduced severity of glomerulosclrosis and markedly reduced mortality. Valsartan administration promoted regeneration of the glomerular tuft, lowered proteinuria and resulted in enhanced vascular endothelial growth factor (VEGF) expression in the cortex and glomerular tuft. In addition, valsartan promoted increased recruitment of BM-derived cells (BMDCs) many of which expressed VEGF and likely contributed directly to glomerular repair. Nearly all BMDCs recruited to the glomerulus expressed the monocyte/macrophage marker CD68. CONCLUSIONS: In conclusion, the data shows that ARB by valsartan prevents glomerulosclerosis progression by enhancing glomerular capillary repair which is associated with the recruitment of VEGF producing 'reparative' monocytes and macrophages from the BM.