Epigenetic Enzyme Mutations: Role in Tumorigenesis and Molecular Inhibitors

Epigenetic modifications, such as DNA methylation and histone modification, result in heritable changes in gene expression without changing the DNA sequence. Epigenetic regulatory enzymes such as DNA methyltransferases, histone methyltransferases, and histone deacetylases are involved in epigenetic modification. Studies have shown that the dysregulation caused by changes in the amino acid sequence of these enzymes is closely correlated with tumor onset and progression. In addition, certain amino acid changes in the metabolic enzyme isocitrate dehydrogenase (IDH) are linked to altered epigenetic modifications in tumors. Some small molecule inhibitors targeting these aberrant enzymes have shown promising anti-cancer efficacy in preclinical and clinical trials. For example, the small molecule inhibitor ivosidenib, which targets IDH1 with a mutation at R132, has been approved by the FDA for the clinical treatment of acute myeloid leukemia. In this review, we summarize the recurrent “hotspot” mutations in these enzymes in various tumors and their role in tumorigenesis. We also describe candidate inhibitors of the mutant enzymes which show potential therapeutic value. In addition, we introduce some previously unreported mutation sites in these enzymes, which may be related to tumor development and provide opportunities for future study

Assessment of the feasibility and coverage of a modified universal hearing screening protocol for use with newborn babies of migrant workers in Beijing

BACKGROUND: Although migrant workers account for the majority of newborns in Beijing, their children are less likely to undergo appropriate universal newborn hearing screening/rescreening (UNHS) than newborns of local non-migrant residents. We hypothesised that this was at least in part due to the inadequacy of the UNHS protocol currently employed for newborn babies, and therefore aimed to modify the protocol to specifically reflect the needs of the migrant population. METHODS: A total of 10,983 healthy babies born to migrant mothers between January 2007 and December 2009 at a Beijing public hospital were investigated for hearing abnormalities according to a modified UNHS protocol. This incorporated two additional/optional otoacoustic emissions (OAE) tests at 24–48 hours and 2 months after birth. Infants not passing a screening test were referred to the next test, until any hearing loss was confirmed by the auditory brainstem response (ABR) test. RESULTS: A total of 98.91% (10983/11104) of all newborn children underwent the initial OAE test, of which 27.22% (2990/10983) failed the test. 1712 of the failed babies underwent the second inpatient OAE test, with739 failing again; thus significantly decreasing the overall positive rate for abnormal hearing from 27.22% to 18.36% ([2990–973 /10983)]; p = 0). Overall, 1147(56.87%) babies underwent the outpatient OAE test again after1-month, of whom 228 failed and were referred for the second outpatient OAE test (i.e. 2.08% (228/10983) referral rate at 1month of age). 141 of these infants underwent the referral test, of whom 103 (73.05%) tested positive again and were referred for a final ABR test for hearing loss (i.e. final referral rate of 1.73% ([228-38/10983] at 2 months of age). Only 54 infants attended the ABR test and 35 (0.32% of the original cohort tested) were diagnosed with abnormal hearing. CONCLUSIONS: Our study shows that it is feasible and practical to achieve high coverage rates for screening hearing loss and decrease the referral rates in newborn babies of migrant workers, using a modification of the currently employed UNHS protocol

Promoting cellulase and hemicellulase production from Trichoderma orientalis EU7-22 by overexpression of transcription factors Xyr1 and Ace3.

The construction of hyper-production strains of cellulase is the prerequisite for the production of biofuels or biochemicals. Trichoderma orientalis EU7-22 with complete cellulase system shows the potential for cellulase production in industrial scale. To improve the cellulase production, two crucial transcription activators Xyr1 and Ace3 were constitutively overexpressed in EU7-22 strain. Cellulase, xylanase and protein secretion were significantly improved in the recombinant strain dxyA-8 under inducing culture, which were 2.34, 0.68 and 1.06 folds higher than those of EU7-22, respectively. Moreover, the FPase and CMCase activities were up to 2.55 IU/mL and 90.38 IU/mL with glucose as carbon source, which were 2.12 and 1.95 folds higher than those of EU7-22 under inducing condition, respectively. Reducing sugar released from pretreated spartina that hydrolyzed by crude enzyme from dxyA-8 had achieved 24% improvement. Therefore, overexpression of these transcription factors effectively promotes the production of cellulase and hemicellulase of Trichoderma orientalis EU7-22

Promoting cellulase and hemicellulase production from Trichoderma orientalis EU7-22 by overexpression of transcription factors Xyr1 and Ace3

Abstract(#br)The construction of hyper-production strains of cellulase is the prerequisite for the production of biofuels or biochemicals. Trichoderma orientalis EU7-22 with complete cellulase system shows the potential for cellulase production in industrial scale. To improve the cellulase production, two crucial transcription activators Xyr1 and Ace3 were constitutively overexpressed in EU7-22 strain. Cellulase, xylanase and protein secretion were significantly improved in the recombinant strain dxyA-8 under inducing culture, which were 2.34, 0.68 and 1.06 folds higher than those of EU7-22, respectively. Moreover, the FPase and CMCase activities were up to 2.55 IU/mL and 90.38 IU/mL with glucose as carbon source, which were 2.12 and 1.95 folds higher than those of EU7-22 under inducing condition, respectively. Reducing sugar released from pretreated spartina that hydrolyzed by crude enzyme from dxyA-8 had achieved 24% improvement. Therefore, overexpression of these transcription factors effectively promotes the production of cellulase and hemicellulase of Trichoderma orientalis EU7-22

Aggregation formation mediated anoikis resistance of BEL7402 hepatoma cells.

Anoikis resistance is the prerequisite of cancer cells metastasis. Elucidation of the mechanism of anoikis resistance remains a significant challenge. We reported here a model to mimic anoikis resistant process of hepatoma cells in vitro. Experimental results indicated cell to cell aggregation could mediate anoikis resistance of BEL7402 hepatoma cells. Further investigation of these aggregations indicated the biological properties changed greatly after the hepatoma cells lost their anchorage. Aggregation forming process could be separated into three distinct phases according to their biological characteristics, comprising of premature phase, mature phase and postmature phase. Mature phase aggregations have the premium state of cell viability and may mimic the metastatic cells in the circulating system. Biological properties of these three phases aggregations were studied in details including morphological alteration, cell viability and microarray expression profiles. It indicated there was a great upregulation of adhesion molecules during the process of aggregation formation and the cell to cell contact in the aggregation may be mediated independent of calcium involved adhesion pathway. This model might shed light on the anoikis resistance mechanism of hepatoma cells and help to develop new therapies that may target the anoikis resistant hepatoma cells in the metastasis process

Predictors for unfavorable prognosis after stroke with perforator artery disease

Background and purposePerforator artery disease (PAD) is an important subtype of ischemic stroke. The risk factors affecting the prognosis of patients with PAD are unclear. This study aimed to investigate the risk factors affecting the unfavorable prognosis of PAD.MethodsPatients with PAD were enrolled from Dushu Lake Hospital Affiliated to Soochow University and diagnosed as stroke with PAD during the period from September 2021 to July 2023 and followed up with a modified Rankin Scale (mRS) after 90 days, defining the mRS of 0–2 as a group with favorable prognosis, and 3–6 as a group with unfavorable functional outcome. Logistic regression was used to identify predictors for PAD. Multiple logistic regression analysis and receiver operating characteristics (ROC) were used to identify predictors of unfavorable prognosis.ResultsOf the 181 enrolled patients, 48 (26.5%) were identified with unfavorable prognosis. On multivariate analysis, increased age (OR = 1.076, 95% CI: 1.012 ~ 1.144, p = 0.019), higher National Institutes of Health Stroke Scale (NIHSS) score at admission (OR = 2.930, 95% CI: 1. 905 ~ 4.508, p < 0.001), and increased neutrophil-to-lymphocyte ratio (NLR) (OR = 3.028, 95% CI: 1.615 ~ 5.675, p = 0.001) were independent risk factors for unfavorable prognosis in patients with PAD, and the area under the receiver operating characteristic curve was 0.590, 0.905, and 0.798, and the multi-factor diagnostic model (Model 2) showed reliable diagnostic specificity and sensitivity (area under the curve = 0.956, p < 0.001, specificity 0.805, sensitivity 0.958, accuracy 0.845).ConclusionIncreased baseline NLR and NIHSS score and aging may be independent risk factors for unfavorable prognosis of patients with PAD. NLR can be used as a potential biological indicator to predict the prognosis of stroke with PAD

Neuroprotective Mechanisms of Lycium barbarum Polysaccharides Against Ischemic Insults by Regulating NR2B and NR2A Containing NMDA Receptor Signaling Pathways

Glutamate excitotoxicity plays an important role in neuronal death after ischemia. However, all clinical trials using glutamate receptor inhibitors have failed. This may be related to the evidence that activation of different subunit of NMDA receptor will induce different effects. Many studies have shown that activation of the intrasynaptic NR2A subunit will stimulate survival signaling pathways, whereas upregulation of extrasynaptic NR2B will trigger apoptotic pathways. A Lycium barbarum polysaccharide (LBP) is a mixed compound extracted from Lycium barbarum fruit. Recent studies have shown that LBP protects neurons against ischemic injury by anti-oxidative effects. Here we first reported that the effect of LBP against ischemic injury can be achieved by regulating NR2B and NR2A signaling pathways. By in vivo study, we found LBP substantially reduced CA1 neurons from death after transient global ischemia and ameliorated memory deficit in ischemic rats. By in vitro study, we further confirmed that LBP increased the viability of primary cultured cortical neurons when exposed to oxygen-glucose deprivation (OGD) for 4 h. Importantly, we found that LBP antagonized increase in expression of major proteins in the NR2B signal pathway including NR2B, nNOS, Bcl-2-associated death promoter (BAD), cytochrome C (cytC) and cleaved caspase-3, and also reduced ROS level, calcium influx and mitochondrial permeability after 4 h OGD. In addition, LBP prevented the downregulation in the expression of NR2A, pAkt and pCREB, which are important cell survival pathway components. Furthermore, LBP attenuated the effects of a NR2B co-agonist and NR2A inhibitor on cell mortality under OGD conditions. Taken together, our results demonstrated that LBP is neuroprotective against ischemic injury by its dual roles in activation of NR2A and inhibition of NR2B signaling pathways, which suggests that LBP may be a superior therapeutic candidate for targeting glutamate excitotoxicity for the treatment of ischemic stroke

Physical Mapping of a Novel Locus Conferring Leaf Rust Resistance on the Long Arm of Agropyron cristatum Chromosome 2P

Wheat leaf rust is one of the most common wheat diseases worldwide and can cause up to 40% wheat yield loss. To combat the growth and spread of leaf rust disease, continual exploration and identification of new and effective resistance genes are needed. Here, we report for the first time a locus conferring leaf rust resistance located on the long arm of Agropyron cristatum chromosome 2P in Triticum aestivum–A. cristatum 2P translocation lines. This study used 50 leaf rust races, including two Chinese major dominant leaf rust races, named by THT and PHT, and other 48 different leaf rust races collected from 11 provinces, 1autonomous region and 1 municipality of China to test the resistance to T. aestivum–A. cristatum 2P chromosome translocation lines and their backcross populations, the results indicated that the novel leaf rust resistance locus was immune or nearly immune to all tested leaf rust races. Four long arm translocation lines with different breakpoints of A. cristatum chromosome 2PL and their backcross populations were tested with leaf rust race THT at the seedling and adult stages and genotyped with 2P-specific STS markers. The results showed that the novel leaf rust resistance locus of the T. aestivum–A. cristatum 2P translocation lines was located in the chromosomal bin FL 0.66–0.86 of 2PL. Therefore, T. aestivum–A. cristatum 2P chromosome translocation lines conferring leaf rust resistance locus could provide a novel disease-resistance resource for future wheat breeding programs

Neuroprotective Mechanisms of Lycium barbarum Polysaccharides Against Ischemic Insults by Regulating NR2B and NR2A Containing NMDA Receptor Signaling Pathways

Glutamate excitotoxicity plays an important role in neuronal death after ischemia. However, all clinical trials using glutamate receptor inhibitors have failed. This may be related to the evidence that activation of different subunit of NMDA receptor will induce different effects. Many studies have shown that activation of the intrasynaptic NR2A subunit will stimulate survival signaling pathways, whereas upregulation of extrasynaptic NR2B will trigger apoptotic pathways. A Lycium barbarum polysaccharide (LBP) is a mixed compound extracted from Lycium barbarum fruit. Recent studies have shown that LBP protects neurons against ischemic injury by anti-oxidative effects. Here we first reported that the effect of LBP against ischemic injury can be achieved by regulating NR2B and NR2A signaling pathways. By in vivo study, we found LBP substantially reduced CA1 neurons from death after transient global ischemia and ameliorated memory deficit in ischemic rats. By in vitro study, we further confirmed that LBP increased the viability of primary cultured cortical neurons when exposed to oxygen-glucose deprivation (OGD) for 4 h. Importantly, we found that LBP antagonized increase in expression of major proteins in the NR2B signal pathway including NR2B, nNOS, Bcl-2-associated death promoter (BAD), cytochrome C (cytC) and cleaved caspase-3, and also reduced ROS level, calcium influx and mitochondrial permeability after 4 h OGD. In addition, LBP prevented the downregulation in the expression of NR2A, pAkt and pCREB, which are important cell survival pathway components. Furthermore, LBP attenuated the effects of a NR2B co-agonist and NR2A inhibitor on cell mortality under OGD conditions. Taken together, our results demonstrated that LBP is neuroprotective against ischemic injury by its dual roles in activation of NR2A and inhibition of NR2B signaling pathways, which suggests that LBP may be a superior therapeutic candidate for targeting glutamate excitotoxicity for the treatment of ischemic stroke