Study on the Influencing Factors of Short-Term Recovery of Neurological Symptoms after Carotid Body Tumor Resection.

OBJECTIVE: To compare the differences in the short-term recovery from neurological symptoms (SRN) (≤ 6 months) and clinical characteristics of patients with different Shamblin classifications carotid body tumor (CBT) resection and to analyze the risk factors affecting SRN after surgery. METHODS: Patients who underwent CBT resection between June 2018 and September 2022 were recruited. Perioperative factors and indicators of the nature of the tumor were recorded. The risk factors affecting SRN after CBT resection were analyzed using logistic regression analysis. RESULTS: Eighty-five patients (43.86 ± 12.7 years, 46 females) were included, 40 (47.06%) of whom exhibited SRN. Univariate logistic regression showed that preoperative symptoms, surgical side, bilateral posterior communicating artery (PcoA) opening, some indicators of tumor size, operative/anesthesia time, and Shamblin III classification were correlated with postoperative neurological prognosis (all p < 0.05). After adjusting for confounders, preoperative symptoms (OR, 5.072; 95% CI 1.027-25.052; p = 0.046), surgical side (OR, 0.025; 95% CI 0.003-0234; p = 0.001), bilateral PcoA opening (OR, 22.671; 95% CI 2.549-201.666; p = 0.005), distance from the tip of the C2 dens to the superior aspect (dens-CBT) (OR, 0.918; 95% CI 0.858-0.982; p = 0.013) and Shamblin III classification (OR, 28.488; 95% CI 1.986-408.580; p = 0.014) were correlated with postoperative neurological symptom recovery. CONCLUSION: Preoperative symptoms, surgical side (right), bilateral PcoA opening, a short dens-CBT and Shamblin III classification are risk factors affecting SRN after CBT resection. Early resection is recommended for small-volume CBTs without neurovascular compression or invasion to obtain SRN.

Revisiting Fur Regulon Leads to a Comprehensive Understanding of Iron and Fur Regulation.

Iron is an essential element because it functions as a cofactor of many enzymes, but excess iron causes cell damage. Iron hemostasis in Escherichia coli was transcriptionally maintained by the ferric uptake regulator (Fur). Despite having been studied extensively, the comprehensive physiological roles and mechanisms of Fur-coordinated iron metabolism still remain obscure. In this work, by integrating a high-resolution transcriptomic study of the Fur wild-type and knockout Escherichia coli K-12 strains in the presence or absence of iron with high-throughput ChIP-seq assay and physiological studies, we revisited the regulatory roles of iron and Fur systematically and discovered several intriguing features of Fur regulation. The size of the Fur regulon was expanded greatly, and significant discrepancies were observed to exist between the regulations of Fur on the genes under its direct repression and activation. Fur showed stronger binding strength to the genes under its repression, and genes that were repressed by Fur were more sensitive to Fur and iron regulation as compared to the genes that were activated by Fur. Finally, we found that Fur linked iron metabolism to many essential processes, and the systemic regulations of Fur on carbon metabolism, respiration, and motility were further validated or discussed. These results highlight how Fur and Fur-controlled iron metabolism affect many cellular processes in a systematic way.

Hypoxic Signaling Pathways in Carotid Body Tumors.

Carotid body tumors (CBTs) are rare tumors with a 1-2 incidence per 100,000 individuals. CBTs may initially present without apparent symptoms, and symptoms begin to arise since tumors grow bigger to compress surrounding tissue, such as recurrent laryngeal nerve and esophagus. Also, the etiology of CBTs remains unclear since it is more likely to occur in those who live in high-altitude areas or suffer from chronic hypoxic diseases such as COPD. SDH mutations and familial inheritance have been reported to be related to CBTs. SDH complexes play crucial roles in aerobic respiration, and SDH mutations in CBTs have been reported to be associated with hypoxia. Hypoxic signaling pathways, specifically hypoxic markers, have attracted more research attention in tumor exploration. However, the existing literature on these signaling and markers lacks a systematic review. Also, therapeutic approaches in CBTs based on hypoxic signaling are rarely used in clinics. In this review, we concluded the role of hypoxic signaling and markers and their potential implications in the initiation and progression of CBTs. Our findings underscore the involvement of the SDH family, the HIF family, VEGFs, and inflammatory cytokines (ICs) in tumorigenesis and treatment. Of particular interest is the role played by SDHx, which has recently been linked to oxygen sensing through mutations leading to hereditary CBTs. Among the SDH family, SDHB and SDHD exhibit remarkable characteristics associated with metastasis and multiple tumors. Besides SDH mutations in CBTs, the HIF family also plays crucial roles in CBTs via hypoxic signaling pathways. The HIF family regulates angiogenesis during mammalian development and tumor growth by gene expression in CBTs. HIF1α could induce the transcription of pyruvate dehydrogenase kinase 1 (PDK1) to inhibit pyruvate dehydrogenase kinase (PDH) by inhibiting the TCA cycle. Then, carotid body cells begin to hyperplasia and hypertrophy. At the same time, EPAS1 mutation, an activating mutation, could decrease the degradation of HIF2α and result in Pacak-Zhuang syndrome, which could result in paraganglioma. HIFs can also activate VEGF expression, and VEGFs act on Flk-1 to control the hyperplasia of type I cells and promote neovascularization. ICs also play a pivotal signaling role within the CB, as their expression is induced under hypoxic conditions to stimulate CB hyperplasia, ultimately leading to CBTs detecting hypoxic areas in tumors, and improving the hypoxic condition could enhance photon radiotherapy efficacy. Moreover, this review offers valuable insights for future research directions on understanding the relationship between hypoxic signaling pathways and CBTs.

Intraperitoneal Injection of Human Ferritin Heavy Chain Attenuates the Atherosclerotic Process in APOE-Knockout Mice.

Background: Iron overload can accelerate the accumulation of lipid oxides and contribute to the progression of atherosclerosis. Ferritin heavy chain (FT-H) exhibits oxidase activity, which inhibits the toxicity of ferrous ions and reduces oxidative damage. We investigated the effect of the intraperitoneal injection of FT-H on the progression of atherosclerosis in APOE-knockout mice (Apo-E(-/-) mice). Methods: All mice were fed on a high-fat diet. After 10 weeks, the mice were divided into an injection group (n = 4) and a control group (n = 4). The injection group was injected intraperitoneally with FT-H (50 mg/kg, once a week), and the control group was treated with PBS buffer (at an equal volume to the injection group, once a week). After 10 weeks of intervention, MRI of the aortas was performed. Then, the animals were sacrificed, and tissues were taken. Hematoxylin-eosin (HE) staining was used for histomorphometry, Masson staining was used to quantify the collagen content in the arteries, Prussian blue staining was used to visualize iron deposition in the arteries, and MRI was used to analyze the structure of the aorta in vivo. Immunohistochemistry was performed to detect the expression of MCP-1, MMP-2, MMP-9, FT-H, FT-L, TfR1, NRF-2 and GPX-4. Results: The serological results showed that the injection group had lower levels of glucose (Glu), triacylglycerol (TG), cholesterol (CHO), low-density lipoprotein-C (LDL-C) and malondialdehyde (MDA) (p = 0.0058, p = 0.0098, p = 0.0019, p = 0.0368 and p = 0.0025, respectively), and their serum ferritin (SF) and superoxide dismutase (SOD) levels were higher (p = 0.0004 and p < 0.0001). The Masson staining and MRI results showed that the injection group had less collagen deposition (p = 0.0226), a larger arterial lumen area and arterial volume (p = 0.0006 and p = 0.0005), thinner arterial wall thickness (p = 0.0013) and a more stable arterial plaque structure (p < 0.0001). The immunohistochemical results showed reduced expression of FT-H, FT-L, TfR1, MMP-2, MMP-9, MCP-1 and NRF-2 in the injection group (p = 0.0054, p = 0.0242, p = 0.0221, p = 0.0477, p = 0.0131, p = 0.0435 and p = 0.0179). Prussian blue staining showed that the area of iron-positive areas in the aortic plaques of the control group was larger than that of injected group. The expression of GPX-4 was lower in the control group than in the injection group (p = 0.016). Conclusions: The intraperitoneal administration of FT-H to Apo-E(-/-) mice resulted in lower blood glucose and lipid levels; reduced iron and iron metabolism protein deposition in the aorta; reduced indices of their ferroptosis, oxidation and inflammatory aggregation; and reduced collagen deposition in the aorta, which delayed the process of aortic atherosclerosis in mice.

The Relation of the Iron Metabolism Index to the Vulnerability Index of Carotid Plaque with Different Degrees of Stenosis.

OBJECTIVE: To investigate the differences in serum iron index and iron metabolizing protein expression in plaques in patients with different degrees of carotid artery stenosis and the relationship with plaque traits. METHODS: A total of 100 patients eligible for carotid endarterectomy (CEA) from August 2021 to February 2022 were included. Patients completed a computed tomography (CTA) scan for patient grouping and a magnetic resonance imaging (MRI) for precise quantification of carotid plaque traits within 1 week prior to surgery. Clinical indicators associated with the progression of carotid stenosis to occlusion were analyzed using ordered logistic regression. Twenty carotid plaques were analyzed immunohistochemically to investigate the relationship between plaque traits and the iron metabolism indexes. RESULTS: No significant correlation between high serum ferritin (SF), unsaturated iron binding capacity (UIBC) and progression of carotid stenosis (OR 1.100, 95% CI 0.004-0.165, p = 0.039; OR 1.050, 95% CI 0.005-0.094, p = 0.031). SF and serum transferrin receptor (sTfR) were correlated with normalized wall index (NWI) (R = 0.470, p = 0.036; R = 0.449, p = 0.046), and the results of multiple linear regression suggested that SF and sTfR remained associated with NWI (R = 0.630, R2 = 0.397, Adjusted R2 = 0.326, p = 0.014). In plaques, H-type ferritin (H-FT) was correlated with NWI and lipid-rich necrotic core (LRNC) volume (R = 0.502, p = 0.028; R = 0.468, p = 0.043). Transferrin receptor 1 (TfR1) was correlated with LRNC volume and intraplaque hemorrhage (IPH) volume (R = 0.538, p = 0.017; R = 0.707, p = 0.001). CONCLUSIONS: There were statistical differences in the expression of iron metabolism proteins in carotid plaques with different degrees of stenosis. Serum iron metabolism index (SF and sTfR) and expression of iron metabolizing proteins (H-FT and TfR1) in plaques were positively correlated with carotid plaque vulnerability index (NWI, LRNC volume).

Gain of Spontaneous clpX Mutations Boosting Motility via Adaption to Environments in Escherichia coli.

Motility is finely regulated and is crucial to bacterial processes including colonization and biofilm formation. There is a trade-off between motility and growth in bacteria with molecular mechanisms not fully understood. Hypermotile Escherichia coli could be isolated by evolving non-motile cells on soft agar plates. Most of the isolates carried mutations located upstream of the flhDC promoter region, which upregulate the transcriptional expression of the master regulator of the flagellum biosynthesis, FlhDC. Here, we identified that spontaneous mutations in clpX boosted the motility of E. coli largely, inducing several folds of changes in swimming speed. Among the mutations identified, we further elucidated the molecular mechanism underlying the ClpXV78F mutation on the regulation of E. coli motility. We found that the V78F mutation affected ATP binding to ClpX, resulting in the inability of the mutated ClpXP protease to degrade FlhD as indicated by both structure modeling and in vitro protein degradation assays. Moreover, our proteomic data indicated that the ClpXV78F mutation elevated the stability of known ClpXP targets to various degrees with FlhD as one of the most affected. In addition, the specific tag at the C-terminus of FlhD being recognized for ClpXP degradation was identified. Finally, our transcriptome data characterized that the enhanced expression of the motility genes in the ClpXV78F mutations was intrinsically accompanied by the reduced expression of stress resistance genes relating to the reduced fitness of the hypermotile strains. A similar pattern was observed for previously isolated hypermotile E. coli strains showing high expression of flhDC at the transcriptional level. Hence, clpX appears to be a hot locus comparable to the upstream of the flhDC promoter region evolved to boost bacterial motility, and our finding provides insight into the reduced fitness of the hypermotile bacteria.

Escherichia coli segments its controls on carbon-dependent gene expression into global and specific regulations.

How bacteria adjust gene expression to cope with variable environments remains open to question. Here, we investigated the way global gene expression changes in E. coli correlated with the metabolism of seven carbon substrates chosen to trigger a large panel of metabolic pathways. Coarse-grained analysis of gene co-expression identified a novel regulation pattern: we established that the gene expression trend following immediately the reduction of growth rate (GR) was correlated to its initial expression level. Subsequent fine-grained analysis of co-expression demonstrated that the Crp regulator, coupled with a change in GR, governed the response of most GR-dependent genes. By contrast, the Cra, Mlc and Fur regulators governed the expression of genes responding to non-glycolytic substrates, glycolytic substrates or phosphotransferase system transported sugars following an idiosyncratic way. This work allowed us to expand additional genes in the panel of gene complement regulated by each regulator and to elucidate the regulatory functions of each regulator comprehensively. Interestingly, the bulk of genes controlled by Cra and Mlc were, respectively, co-regulated by Crp- or GR-related effect and our quantitative analysis showed that each factor took turns to work as the primary one or contributed equally depending on the conditions.

The Protective Effect of Vanadium on Cognitive Impairment and the Neuropathology of Alzheimer's Disease in APPSwe/PS1dE9 Mice.

Alzheimer's disease (AD) is a widely distributed neurodegenerative disease characterized clinically by cognitive deficits and pathologically by formation of amyloid-ß (Aß) plaque and neurofibrillary tangles (NFTs) in the brain. Vanadium is a biological trace element that has a function to mimic insulin for diabetes. Bis(ethylmaltolato) oxidovanadium (IV) (BEOV) has been reported to have a hypoglycemic property, but its effect on AD remains unclear. In this study, BEOV was supplemented at doses of 0.2 and 1.0 mmol/L to the AD model mice APPSwe/PS1dE9 for 3 months. The results showed that BEOV substantially ameliorated glucose metabolic disorder as well as synaptic and behavioral deficits of the AD mice. Further investigation revealed that BEOV significantly reduced Aß generation by increasing the expression of peroxisome proliferator-activated receptor gamma and insulin-degrading enzyme and by decreasing ß-secretase 1 in the hippocampus and cortex of AD mice. BEOV also reduced tau hyperphosphorylation by inhibiting protein tyrosine phosphatase-1B and regulating the pathway of insulin receptor/insulin receptor substrate-1/protein kinase B/glycogen synthase kinase 3 beta. Furthermore, BEOV could enhance autophagolysosomal fusion and restore autophagic flux to increase the clearance of Aß deposits and phosphorylated tau in the brains of AD mice. Collectively, the present study provides solid data for revealing the function and mechanism of BEOV on AD pathology.