Klf5 down-regulation induces vascular senescence through eIF5a depletion and mitochondrial fission.

Although dysregulation of mitochondrial dynamics has been linked to cellular senescence, which contributes to advanced age-related disorders, it is unclear how Krüppel-like factor 5 (Klf5), an essential transcriptional factor of cardiovascular remodeling, mediates the link between mitochondrial dynamics and vascular smooth muscle cell (VSMC) senescence. Here, we show that Klf5 down-regulation in VSMCs is correlated with rupture of abdominal aortic aneurysm (AAA), an age-related vascular disease. Mice lacking Klf5 in VSMCs exacerbate vascular senescence and progression of angiotensin II (Ang II)-induced AAA by facilitating reactive oxygen species (ROS) formation. Klf5 knockdown enhances, while Klf5 overexpression suppresses mitochondrial fission. Mechanistically, Klf5 activates eukaryotic translation initiation factor 5a (eIF5a) transcription through binding to the promoter of eIF5a, which in turn preserves mitochondrial integrity by interacting with mitofusin 1 (Mfn1). Accordingly, decreased expression of eIF5a elicited by Klf5 down-regulation leads to mitochondrial fission and excessive ROS production. Inhibition of mitochondrial fission decreases ROS production and VSMC senescence. Our studies provide a potential therapeutic target for age-related vascular disorders.

Wounding characteristics and treatment principles of ground anti-armored vehicle ammunition against armored crew.

The wound mechanism, injury characteristics and treatment principles of anti-armored vehicle ammunition against armored crew in the past 20 years are summarized in this paper. Shock vibration, metal jet, depleted uranium aerosol and post armor breaking effect are the main factors for wounding armored crew. Their prominent characteristics are severe injury, high incidence of bone fracture, high rate of depleted uranium injury, and high incidence of multiple/combined injuries. During the treatment, attention must be paid on that the space of armored vehicle is limited, and the casualties should be moved outside of the cabin for comprehensive treatment. Especially, the management of depleted uranium injury and burn/inhalation injury are more important than other injuries for the armored wounds.

MicroRNA-34a induces apoptosis in the human glioma cell line, A172, through enhanced ROS production and NOX2 expression.

BACKGROUND: MicroRNA is a type of non-coding small RNA involved in regulating genes and signaling pathways through incomplete complementation with target genes. Recent research supports key roles of miRNA in the formation and development of human glioma. METHODS: The relative quantity of miR-34a was initially determined in human glioma A172 cells and glioma tissues. Next, we analyzed the impact of miR-34a on A172 cell viability with the MTT assay. The effects of miR-34a overexpression on apoptosis were confirmed with flow cytometry and Hoechst staining experiments. We further defined the target genes of miR-34a using immunofluorescence and Western blot. RESULTS: MiR-34a expression was significantly reduced in human glioma A172 cells and glioma tissue, compared with normal glial cells and tissue samples. Our MTT data suggest that up-regulation of miR-34a inhibits cell viability while suppression of miR-34a enhances cell viability. Flow cytometry and Hoechst staining results revealed increased rates of apoptosis in A172 human glioma cells overexpressing miR-34a. Using immunofluorescence and Western blot analyses, we identified NOX2 as a target of miR-34a in A172 cells. CONCLUSION: MiR-34a serves as a tumor suppressor in human glioma mainly by decreasing NOX2 expression.

Protein phosphorylation differs significantly among ontogenetic phases in Malus seedlings.

BACKGROUND: Although protein phosphorylation is an important post-translational modification affecting protein function and metabolism, dynamic changes in this process during ontogenesis remain unexplored in woody angiosperms. METHODS: Phosphorylated proteins from leaves of three apple seedlings at juvenile, adult vegetative and reproductive stages were extracted and subjected to alkaline phosphatase pre-treatment. After separating the proteins by two-dimensional gel electrophoresis and phosphoprotein-specific Pro-Q Diamond staining, differentially expressed phosphoproteins were identified by MALDI-TOF-TOF mass spectrometry. RESULTS: A total of 107 phosphorylated protein spots on nine gels (three ontogenetic phases × three seedlings) were identified by MALDI-TOF-TOF mass spectrometry. The 55 spots of ribulose-1, 5-bisphosphate carboxylase/oxygenase (Rubisco) large-chain fragments varied significantly in protein abundance and degree of phosphorylation among ontogenetic phases. Abundances of the 27 spots corresponding to Rubisco activase declined between juvenile and reproductive phases. More extensively, phosphorylated ß-tubulin chain spots with lower isoelectric points were most abundant during juvenile and adult vegetative phases. CONCLUSIONS: Protein phosphorylation varied significantly during vegetative phase change and floral transition in apple seedlings. Most of the observed changes were consistent among seedlings and between hybrid populations.

α-HBDH is a superior to LDH in predicting major adverse cardiovascular events in patients with acute aortic dissection.

Objective: Acute aortic dissection (AAD) with a high mortality and postoperative complications remains presently no effective indicators to conjunctly predict the short-term mortality and the prognosis. This study aimed to investigate the predictive role of α-HBDH on in-hospital mortality and postoperative Major adverse cardiovascular events (MACE) in patients with AAD. Methods: In this retrospective study, a total of 369 enrolled patients from 2015 to 2021 were divided into three groups (T1: low, T2: medium and T3: high) based on the tertiles of α-HBDH levels on admission. In terms of the preoperative, intraoperative and postoperative indicators among 3 groups, the relationship between α-HBDH and studying endpoints was determined by logistic regression models, along with the consolidation using Kaplan-Meier and restricted cubic spline (RCS) analysis for predicting the in-hospital death and MACE complications. Last, subgroup analysis further verified the predictive value of α-HBDH. Results: Logistic regression analysis showed that α-HBDH was independently associated with in-hospital mortality of patients with AAD [OR(95CI): 4.771(1.043-21.832), P = 0.044] and MACE [OR(95CI): 9.869(2.148-45.349), P = 0.003]. Moreover, Kaplan-Meier analysis also showed an increased α-HBDH levels associated with poor survival within 30 days (log rank test, P < 0.01), especially in acute Stanford A dissection. RCS presented that 204 U/L was the optimal cut-off value of α-HBDH for in-hospital mortality and postoperative MACE, which facilitated clinical stratification of patients with AAD. Subgroup analysis confirmed a stable correlation between α-HBDH level and hospital mortality and MACE (P > 0.05). Conclusions: α-HBDH is a predictor of the in-hospital mortality and postoperative MACE, guiding admission stratification of patients with AAD.

A new diagnostic technique for identifying Angiostrongylus spp. larvae in intermediate snail species by examining the buccal cavity.

BACKGROUND: Angiostrongyliasis is a zoonotic parasitic disease caused by the rat lungworm Angiostrongylus cantonensis. The intermediate hosts of A. cantonensis are gastropods, and snail species such as Pomacea canaliculata play a key role in the transmission of human angiostrongyliasis. Detecting A. cantonensis infection in snails is an important component of epidemiological surveillance and the control of angiostrongyliasis. METHODS: In this study, a new method for diagnosing A. cantonensis infection in gastropods was developed by recovering larvae from the buccal cavity of three snail species. The entire buccal cavity of a snail was extracted, and the tissue was pressed between two microscope slides to observe whether A. cantonensis larvae were present. Our new method was compared with traditional pathogenic detection methods of lung microscopy, tissue homogenization, and artificial digestion. We artificially infected 160 P. canaliculata, 160 Cipangopaludina chinensis, and 160 Bellamya aeruginosa snails with A. cantonensis. Then, the four different detection methods were used to diagnose infection in each snail species at 7, 14, 21, and 28 days post exposure. RESULTS: We found no significant difference in the percentages of infected P. canaliculata snails using the four methods to detect A. cantonensis larvae. The radula pressing method had a mean detection rate of 80%, while the lung microscopy (81.3%), tissue homogenization (83.8%), and artificial digestion (85%) methods had slightly greater detection rates. Similarly, the percentages of infected C. chinensis snails that were detected using the radula pressing (80%), tissue homogenization (82.1%), and artificial digestion (83.8%) methods were not significantly different. Finally, the percentages of infected B. aeruginosa snails that were detected using the radula pressing (81.3%), tissue homogenization (81.9%), and artificial digestion (81.4%) methods were not significantly different. These results showed that the radula pressing method had a similar detection rate to traditional lung microscopy, tissue homogenization, or artificial digestion methods. CONCLUSIONS: This study demonstrates a new method for the qualitative screening of gastropods that act as intermediate hosts of A. cantonensis (and other Angiostrongylus species), provides technical support for the control of human angiostrongyliasis, and furthers research on A. cantonensis.

Inositol-requiring protein 1α signaling pathway is activated in the temporal cortex of patients with mesial temporal lobe epilepsy.

Accumulating evidence suggests that repeated seizures could induce endoplasmic reticulum (ER) stress. Inositol-requiring protein 1α (IRE1α) is a vital pro-apoptotic molecule in ER stress, but it remains unclear whether the signaling pathway mediated by IRE1α is involved in human temporal lobe epilepsy. In this report, we investigated IRE1α-mediated ER stress pro-apoptotic signaling pathway in resected anterior temporal neocortex from 32 patients with intractable mesial temporal lobe epilepsy by immunofluorescence and western blot analysis. Our results indicate that chronic epilepsy induces ER stress, and IRE1α-mediated ER stress apoptotic signaling pathway is involved in brain damage after repeated seizures, which may provide a new therapeutic target to prevent brain damage caused by epilepsy.

Predictive value of admission CO2 combining power combined with serum sodium for the prognosis in acute Stanford type A aortic dissection patients.

Acute Stanford type A aortic dissection (ATAAD) with sudden onset and high mortality requiries a standard Bentall operation and a accurate prognosis in common, together with alteration of CO2 combining power (CO2CP) and serum sodium rase concern, hence, we evaluated the prognostic value of CO2CP combined with serum sodium in ATAAD patients. This retrospective study included 183 patients who underwent Bentall operation for ATAAD from 2015 to 2021 in the Fourth Hospital of Hebei Medical University, subsequently followed grouping by the levels of CO2CP and serum sodium. The study endpoint was 30-day all-cause mortality, and the prognostic value of CO2CP combined with serum sodium levels in ATAAD patients were evaluated with multivariate logistic regression method. The postoperative incidence of in-hospital death and adverse events in patients with ATAAD were 18% and 25.7%, respectively. Combination of CO2CP and serum sodium for predicting ATAAD death and adverse events presented a higher predictive value than each single indicator with ROC curve analysis (the AUC of CO2CP combined with serum sodium was 0.786, 95% CI 0.706-0.869, P < 0.001), along with CO2CP < 22.5 mmol/L + serum sodium > 138.5 mmol/L group had the worst prognostic. Multivariate regression analyse showed that CO2CP < 22.5 mmol/L combined with serum sodium > 138.5 mmol/L preferably predicted the prognosis of ATAAD (OR =6.073, 95% CI 2.557-14.425, P < 0.001). Consistently, the cumulative 30-day survival after surgery in ATAAD patients with the low CO2CP and high serum sodium simultaneously was the worst (log-rank P < 0.05). The combination of CO2CP and serum sodium increases the predictive value of prognosis, which is conducive to risk stratification of patients with ATAAD.

Sox10 escalates vascular inflammation by mediating vascular smooth muscle cell transdifferentiation and pyroptosis in neointimal hyperplasia.

Vascular smooth muscle cells (VSMCs) can transdifferentiate into macrophage-like cells in the context of sustained inflammatory injury, which drives vascular hyperplasia and atherosclerotic complications. Using single-cell RNA sequencing, we identify that macrophage-like VSMCs are the key cell population in mouse neointimal hyperplasia. Sex-determining region Y (SRY)-related HMG-box gene 10 (Sox10) upregulation is associated with macrophage-like VSMC accumulation and pyroptosis in vitro and in the neointimal hyperplasia of mice. Tumor necrosis factor α (TNF-α)-induced Sox10 lactylation in a phosphorylation-dependent manner by PI3K/AKT signaling drives transcriptional programs of VSMC transdifferentiation, contributing to pyroptosis. The regulator of G protein signaling 5 (RGS5) interacts with AKT and blocks PI3K/AKT signaling and Sox10 phosphorylation at S24. Sox10 silencing mitigates vascular inflammation and forestalls neointimal hyperplasia in RGS5 knockout mice. Collectively, this study shows that Sox10 is a regulator of vascular inflammation and a potential control point in inflammation-related vascular disease.

Serum levels of inflammation factors and cognitive performance in amnestic mild cognitive impairment: a Chinese clinical study.

Early diagnosis of Alzheimer's disease (AD) is important for initiating timely therapy to block or slow the rate of disease progression. This study was designed to investigate the potential of inflammation-related biomarkers in peripheral blood to accurately reflect AD onset and progression. Individuals (n=150) with amnestic mild cognitive impairment (aMCI) were divided into two subgroups (low- and high-risk) based on APOEε4 allele carrier status, and administered a battery of neuropsychological tests and tested for serum levels of IL-6, IL-10, TNF-α, and IFN-γ by using specific enzyme-linked immunosorbent assays. Results were compared with those from age-matched healthy controls (n=150). The levels of IL-6 were significantly higher in the aMCI group than in controls (P<0.01). When the aMCI group was stratified by APOEε4 status, significant differences were found between the low- and high-risk groups and controls in the levels of IL-6 and IFN-γ (P<0.01 and P=0.041, respectively). Moreover, the IL-6 level in the low-risk aMCI group was higher than that in the high-risk aMCI group (P=0.028). A weak but significant negative correlation was found between IL-6 and cognitive performance. Taken together, these findings indicate that IL-6, while not useful alone, has potential in combination with other biomarkers to support early diagnosis of aMCI due to its association with the progression of cognitive impairment.

Analysis on Early and Late Operation Results and Risk Factors of Elderly Acute Type-A Aortic Dissection.

OBJECTIVE: To explore the early and late operation results and risk factors of elderly acute type-A aortic dissection. METHODS: The regression analysis was conducted on the data of patients diagnosed with acute type-A aortic dissection in our hospital from January 2018 to January 2020, and a total of 98 patients aged over 70 years were included in the study. The patients were listed into the early operation group (a total of 51 patients operated within 3 days after admission) and the late operation group (a total of 47 patients operated within 10 days after admission) according to the time of operation. The operation results, postoperative complications and death were compared between the two groups, and the prognosis risk factors were analyzed through Logistic multi-factor regression. RESULTS: The operative time, aortic obstruction time and extracorporeal circulation time of the late operation group were all higher than those in the early operation group (p <0.05). The postoperative complications and mortality in the late operation group (12.77%) were higher than those in the early operation group (3.92%) (p < 0.05). The Logistic multi-factor regression showed that late operation (p=0.005, OR=4.213, 95% CI=1.567~11.201), postoperative acute renal insufficiency (p=0.028, OR=3.281, 95% CI=0.937~10.283), and postoperative pulmonary infection (p=0.033, OR=1.421, 95% CI=0.417~8.329) were risk factors affecting postoperative mortality (p <0.05). CONCLUSION: The early operation can effectively reduce the postoperative complications of elderly acute type-A aortic dissection, so early operation should be performed according to the conditions of patients and hospital.

Vascular Smooth Muscle FTO Promotes Aortic Dissecting Aneurysms via m6A Modification of Klf5.

Background: Aortic dissecting aneurysm (ADA) represents an aortic remodeling disease with a high mortality rate. Fat mass and obesity-associated protein (FTO) exerts RNA demethylation function to regulate gene expression related to stem cell differentiation, DNA damage repair, and tumorigenesis, but the role of FTO in ADA is still unclear. Methods: The expression and location of FTO in 43 ADA tissues and 11 normal tissues were determined by RT-qPCR, WB, immunohistochemistry, and immunofluorescence staining. Detecting proliferation and migration of VSMCs. M6A methylated RNA immuno-precipitation qRT-PCR and dual luciferase reporter assay were performed for determining m6A level and interaction between m6A modulation and Klf5 mRNA, respectively. Results: FTO are highly expressed in VSMCs. FTO was positively correlated with BMI, triglyceride, and D-dimer (all P < 0.05). Functionally, both AngII-induced FTO expression and over expression of FTO promote cell proliferation and migration, whereas knockdown of FTO inhibits these functions. Mechanically, we identified Krüppel-like factor 5 (Klf5) as a target of FTO mediating m6A modification. Overexpression of FTO reduced m6A modification on Klf5 mRNA and promoted Klf5 mRNA expression. Furthermore, the p-GSK3ß and Klf5 levels increased after FTO overexpression. Finally, knockdown of FTO suppresses the p-GSK3ß levels and Klf5 expression regardless of AngII treatment. Conclusions: Our study revealed that FTO expression significantly contributes to the phenotype conversion of VSMCs and the ADA by the demethylation function (m6A), thereby providing a novel therapeutic target.

Migraine: sex-influenced trait model?

Migraine is a periodic disorder with a worldwide prevalence of 5-19%. This study raises the hypothesis of a sex-influenced genetic model of migraine transmission. That migraine may be sex-influenced (autosomal dominant in females and autosomal recessive in males) is supported by such evidences as: (1) familial hemiplegic migraine, subtype from migraine with aura, being dominantly assigned to autosomal chromosome 19p, 1q, and 2q; (2) a male to female prevalence of 1:2-4; (3) primarily young age of onset; (4) provocation by pharmaceutical contraception; (5) induction by menstruation; (6) self-limitation after menopause; and (7) only female migraineurs in some migraine families. Female sex hormone in the migraineur may be the key factor, comparable to the male sex hormone: androgen, in the genetic baldness. Migraine appears caused by a multi-factor inheritance with higher rates among females than males, and influenced by environmental and cultural factors.

Potential polyphenol markers of phase change in apple (Malus domestica).

In order to identify potential biochemical markers that can be used as indicators for phase change, the dynamics of polyphenolic compounds across apple seedlings (Malus domestica, Jonathan x Golden Delicious) were analyzed in this study by high performance liquid chromatography. Precocious flowering was induced by foliar sprays of plant growth regulators. Qualitative changes in the concentration of polyphenols were observed at node nos. 50, 80 and 120. Spontaneous and induced flowering was found at node nos. 122 and 77. It was reasonable to conclude that node no. 77 represented the point of transition between the juvenile phase and the adult vegetative phase, which was marked by the presence of phloridzin in the buds. The disappearance of myricitrin in the bark and the absence of caffeic acid in the aboveground tissues were qualitative markers of the reproductive phase, which was reached at node no. 122.

AIDS dementia complex in China.

The AIDS dementia complex (ADC) is one of the most common neurological complications in patients with AIDS. However, little is known about the clinical features of ADC in China. We prospectively studied six patients with confirmed ADC out of a total of 36 AIDS patients treated from 1999 to 2003. All patients had short-term memory loss and poor concentration, with preserved alertness. Motor disability was identified in three patients. Of the six ADC patients, two had accompanying vacuolar myelopathy. All of the patients died, with a mean age at death of 41.8 years. The median survival of these ADC patients from the time of diagnosis was 4.7 months. In this context, we suggest that early diagnosis and highly active antiretroviral therapy treatment is an urgent priority in developing countries.

[Effects of Nurr1 down-regulation on the expression of tyrosine hydroxylase and neurite extension in dopaminergic cells.].

In the experiment, we designed and synthesized two siRNAs based on the sequence of nuclear receptor-related factor 1 (Nurr1) mRNA. They were separately subcloned into the plasmid of pSilenCircle (pSC) containing U6 promoter. The pSC-Nurr1 vectors (pSC-N1 and pSC-N2) specific to Nurr1 gene and the negative control vector of short-hairpin RNA (shRNA) eukaryotic expression vector were constructed. We cultured the dopaminergic cell line MN9D and the verified vectors were transfected with LipofectamineTM 2000 in vitro. The positive cell clones transfected with pSC were obtained after being screened with 500 mug/ml G418. After that, the silencing effects of Nurr1 and TH mRNA or protein were detected by real time RT-PCR and Western blot. The neurite extension of MN9D cells was observed and photographed by inverted microscope. The results showed that Nurr1 mRNA expression in MN9D cells was specifically down-regulated by the vectors of pSC-N1 and pSC-N2, and the silencing effects were 62.3% and 45.6%, respectively. The dopaminergic phenotype of TH mRNA was also suppressed significantly and the silencing effects were 76.3% and 62.6%, respectively. Meanwhile, the expressions of Nurr1 and TH proteins were also significantly suppressed, and the silencing effects of Nurr1 and TH protein were 57.4%, 72.0% and 79.1%, 70.1% respectively. The negative control and liposome groups had no effect on the two genes. In conclusion, Nurr1 shRNA expressing vectors can inhibit the expressions of Nurr1 and TH mRNA or protein in MN9D cells, and Nurr1 might play a role in neurite extension of MN9D cells. Nurr1 shRNA expressing vector may provide a novel applicable strategy for the study on the function of the genes associated with Parkinson disease and the development of dopaminergic neuron.

Effects of bilateral subthalamic nucleus stimulation on resting-state cerebral glucose metabolism in advanced Parkinson's disease.

BACKGROUND: The major neuropathological symptoms of Parkinson's disease (PD) consist of a loss of pigmented dopaminergic neurons in the substantia nigra and the presence of Lewy bodies. This study was to investigate the effects of bilateral subthalamic nucleus (STN) stimulation on resting-state cerebral glucose metabolism in advanced PD, and investigate the mechanism of deep brain stimulation (DBS). METHODS: Seven consecutive advanced PD patients (4 men and 3 women, mean age 64 +/- 4 years, mean H-Y disability rating 4.4 +/- 0.65) receiving bilateral STN DBS underwent 18F-fluorodeoxyglucose (18F-FDG)/positron-emission tomography (PET) examinations at rest both preoperatively and one month postoperatively, with STN stimulation still on. The unified PD rating scale was used to evaluate the clinical state under each condition. Statistical parametric mapping (SPM) was used to investigate the regional cerebral metabolic rates of glucose (rCMRGlu) during STN stimulation, and to compare these values to rCMRGlu preoperation. RESULTS: STN stimulation clearly improved clinical symptoms in all patients. A significant increase in rCMRGlu was found in the bilateral lentiform nucleus, brainstem (midbrain and pons), bilateral premotor area (BA6), parietal-occipital cortex, and anterior cingulated cortex, and a marked decrease in rCMRGlu was noted in the left limbic lobe and bilateral inferior frontal cortex (P < 0.05). CONCLUSION: Bilateral STN stimulation may activate the projection axon from the STN, improving clinical symptoms in advanced PD patients by improving both ascending and descending pathways from the basal ganglia and increasing the metabolism of higher-order motor control in the frontal cortex.

The expression of hepatoma-derived growth factor in primary central nervous system lymphoma and its correlation with angiogenesis, proliferation and clinical outcome.

Hepatoma-derived growth factor (HDGF), a potential predictive and prognostic marker in several human cancers, is the firstly reported member of the HDGF family of proteins containing a well-conserved N-terminal amino acid sequence. HDGF is implicated in tumorigenesis by direct angiogenic activity, and its expression is correlated with aggressive biological ability of cancer cells including proliferation and angiogenesis. So, we propose that HDGF may be a valuable factor in progression and prognosis for primary central nervous system lymphoma (PCNSL) through its angiogenic and proliferative activity. So, HDGF, CD31 and Ki67 expression in the specimens of 60 patients suffering from PCNSL was investigated by immunohistochemistry in this study. Their correlations with clinicopathologic features and prognosis were evaluated to determine whether HDGF, CD31 and Ki67 expression levels correlate with the prognosis of the 60 patients suffering from PCNSL. We found that all PCNSL specimens showed HDGF, CD31 and Ki67 expression with different expression levels. Statistical analysis showed that HDGF had a positive correlation with CD31, but not with Ki67. Patients with higher HDGF and CD31 expression level had poorer overall survival rates than those with lower expression levels of HDGF and CD31, while Ki67 expression level did not correlate with overall survival. Multivariate analysis revealed that postoperative adjuvant chemotherapy and high expression of HDGF was independent prognostic indicator of patient survival.