Establishment and maintenance of the polar site are important for root hair tip growth. We previously reported that Arabidopsis (Arabidopsis thaliana) MICROTUBULE-ASSOCIATED PROTEIN18 (MAP18) functions in controlling the direction of pollen tube growth and root hair elongation. Additionally, the Rop GTPase ROP2 was reported as a positive regulator of both root hair initiation and tip growth in Arabidopsis. Both loss of function of ROP2 and knockdown of MAP18 lead to a decrease in root hair length, whereas overexpression of either MAP18 or ROP2 causes multiple tips or a branching hair phenotype. However, it is unclear whether MAP18 and ROP2 coordinately regulate root hair growth. In this study, we demonstrate that MAP18 and ROP2 interact genetically and functionally. MAP18 interacts physically with ROP2 in vitro and in vivo and preferentially binds to the inactive form of the ROP2 protein. MAP18 promotes ROP2 activity during root hair tip growth. Further investigation revealed that MAP18 competes with RhoGTPase GDP DISSOCIATION INHIBITOR1/SUPERCENTIPEDE1 for binding to ROP2, in turn affecting the localization of active ROP2 in the plasma membrane of the root hair tip. These results reveal a novel function of MAP18 in the regulation of ROP2 activation during root hair growth.
Dynamin-related peptide 1 (Drpl)-mediated mitochondrial fission is an important process associated with cardiac dysfunction under different pathological conditions. The aim of the present study was to investigate the expression of Drpl during inflammatory myocardial injury. Sprague‑Dawley rats were treated intraperitoneally with lipopolysaccharides (LPS). Furthermore, cultured H9C2 cardiomyocytes were treated with LPS, interleukin‑6 (IL‑6) and tumor necrosis factor‑α (TNF‑α). Total and mitochondrial proteins were isolated from the heart tissue of rats and from the H9C2 cardiomyocytes. Expression levels of Drp1 and RhoA were analyzed by western blotting. Mitochondrial morphology was determined using confocal laser microscopy. The levels of mitochondrial Drp1 and phosphorylated‑Drp1 (p‑Drp1) Ser616 were revealed to be increased in rats 6 h after injection with LPS (5, 10 or 20 mg/kg). Furthermore, treatment with LPS and IL‑6 did not demonstrate a significant effect on the expression of total and mitochondrial Drp1 in H9C2 cardiomyocytes in vitro; however, treatment with TNF‑α (20 ng/ml) significantly enhanced the levels of mitochondrial Drp1 and p‑Drp1 Ser616. Following TNF‑α treatment, the expression of Ras homolog gene family member A (RhoA) was also revealed to increase. Treatment with both Y‑27632 and fasudil, [Rho kinase (ROCK) inhibitors], was demonstrated to attenuate the otherwise TNF‑α‑induced increase in p‑Drp1 Ser616 and mitochondrial Drp1. In addition, it was revealed that Y‑27632 and fasudil may also attenuate the TNF‑α‑induced increase in mitochondrial fragmentation and cell viability. Therefore, the findings of the present study suggest that TNF‑α is the predominant inducer of Drp1 S616 phosphorylation during sepsis. The results of the present study also suggest that the RhoA/ROCK pathway may be involved in the phosphorylation and mitochondrial translocation of Drp1, which leads to mitochondrial fragmentation.
Esophageal cancer and gastric cancer have shared risk factors and inherited susceptibility. Recent genome-wide association studies have identified multiple genetic loci associated with gastric cancer risk, which may also involve in the development of esophageal cancer. Herein, we evaluated the relationship of gastric cancer risk-related variants at 1q22, 3q13.3, 5p13.1, and 8q24 with the risk of esophageal squamous cell carcinoma (ESCC) in a Chinese population with a case–control study (2139 cases and 2273 controls). We found that the T allele of rs2294008, an intronic variant of the PSCA gene at 8q24 that was previously associated with an increased risk of gastric cancer, was inversely associated with a decreased risk of ESCC (odds ratio = 0.90; 95% confidence interval, 0.81–0.99; P = 0.034). Of interest, the association of rs2294008 with ESCC was consistent with that observed in esophageal adenocarcinoma and ESCC in Caucasian populations. However, no significant associations were observed for the other three variants at 1q22 (rs4072037), 3q13.31 (rs9841504), and 5p13.1 (rs13361707). Our findings suggest that the susceptibility locus of PSCA at 8q24 may be a double-edged sword, as modulator between the carcinogenesis processes of stomach and esophagus.
Immune checkpoint blockade (ICB) therapy has achieved breakthroughs in the treatment of advanced non-small cell lung cancer (NSCLC). Nevertheless, the low response due to immuno-cold tumor microenvironment (TME) largely limits the application of ICB therapy. Based on the glycolytic/cholesterol synthesis axis, a stratification framework for EGFR wild-type NSCLC was developed to summarize the metabolic features of immuno-cold and immuno-hot tumors. The cholesterol subgroup displays the worst prognosis in immuno-cold NSCLC with significant enrichment of the cholesterol gene signature, indicating targeting cholesterol synthesis is essential for the therapy for immuno-cold NSCLC. Statin, the inhibitor for cholesterol synthesis, can suppress the aggressiveness of NSCLC in vitro and in vivo and also drastically reverse immuno-cold to an inflamed phenotype in vivo which exhibited a higher response to ICB therapy. Moreover, both our in-house data and meta-analysis further support that statin can significantly enhance ICB efficacy. In terms of preliminary mechanisms, statin could transcriptionally inhibit PD-L1 expression and induce ferroptosis in NSCLC cells. Overall, we reveal the significance of cholesterol synthesis in NSCLC and demonstrate the improved therapeutic efficacy of ICB in combination with statin.These findings could provide a innovative clinical insight to treat NSCLC patients with immuno-cold tumors.
Objective: The present study investigated the clinical significance of mannose-binding lectin 2 (MBL2), cluster of differentiation 14 (CD14) and tumour necrosis factor-α (TNF-α) gene polymorphisms in patients with spinal tuberculosis (TB) in Chinese population. Methods: A total of 240 patients with spinal TB were enrolled in the present study from May 2013 to August 2016 at Hangzhou Red Cross Hospital. A total of 150 age- and sex-matched healthy subjects were enrolled as controls. The genomic DNA was extracted from the peripheral blood of all subjects, and the MBL2, CD14 and TNF-α gene polymorphisms were detected by direct DNA sequencing. Results: (1) Compared with controls, patients with spinal TB exhibited a significantly higher frequency of the XY genotype at the −221G>C polymorphism as well as the Q allele and PQ genotype or an association with the QQ genotype at the +4C>T polymorphism in the MBL2 gene. (2) Compared with controls, patients with spinal TB exhibited a significantly higher frequency of the T allele and TT genotype or an association with the CT genotype at the −159C>T polymorphism in the CD14 gene. (3) Compared with controls, patients with spinal TB exhibited a significantly higher frequency of the T allele and the CT genotype or an association with the TT genotype at the TNF-857 polymorphism in the TNF-α gene. Conclusion: The −221G>C polymorphism of MBL2, the −159C>T polymorphism of CD14 and the TNF-857 polymorphism of TNF-α are risk factors for spinal TB and may be involved in the development of spinal TB in the Chinese population. These factors are indicators of susceptibility to spinal TB and require clinical attention.
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