Cyy-272, an indazole derivative, effectively mitigates obese cardiomyopathy as a JNK inhibitor.

Obesity has shown a global epidemic trend. The high-lipid state caused by obesity can maintain the heart in a prolonged low-grade inflammatory state and cause ventricular remodeling, leading to a series of pathologies, such as hypertrophy, fibrosis, and apoptosis, which eventually develop into obese cardiomyopathy. Therefore, prolonged low-grade inflammation plays a crucial role in the progression of obese cardiomyopathy, making inflammation regulation an essential strategy for treating this disease. Cyy-272, an indazole derivative, is an anti-inflammatory compound independently synthesized by our laboratory. Our previous studies revealed that Cyy-272 can exert anti-inflammatory effects by inhibiting the phosphorylation and activation of C-Jun N-terminal kinase (JNK), thereby alleviating lipopolysaccharide (LPS)-induced acute lung injury (ALI). The current study aimed to evaluate the potential of Cyy-272 to mitigate the occurrence and progression of obese cardiomyopathy through the inhibition of the JNK signaling pathway. Our results indicate that the compound Cyy-272 has encouraging therapeutic effects on obesity-induced cardiac injury. It significantly inhibits inflammation in cardiomyocytes and heart tissues induced by high lipid concentrations, further alleviating the resulting hypertrophy, fibrosis, and apoptosis. Mechanistically, the protective effect of Cyy-272 on obese cardiomyopathy can be attributed to its direct inhibition of JNK protein phosphorylation. In conclusion, we identified a novel compound, Cyy-272, capable of alleviating obese cardiomyopathy and confirmed that its effect is achieved through direct inhibition of JNK.

[Carbon Dioxide Mitigation Co-effect Analysis of Structural Adjustment Measures in the "2+26" Cities in the Jing-Jin-Ji Region and Its Surroundings].

The Three-Year Action Plan for Winning the Blue Sky Defense Battle states that structural adjustments of industrial, energy, transportation, and land use are important to significantly reduce CO2 and air pollutant emissions. This co-effect is evident but has not been quantified at the city-cluster level. This study developed an emission inventory for the "2+26" cities of the Jing-Jin-Ji region and its surroundings and quantitatively analyzed the impacts of measures in the Three-Year Action Plan for Winning the Blue Sky Defense Battle on the emissions of CO2 and major air pollutants using Greenhouse Gas and Air Pollution Interactions and Synergies in the "2+26" cities model (GAINS-JJJ). The results showed that in the "2+26" cities, the emission reductions in CO2, primary PM2.5, SO2, NOx, and NH3 under policy scenario 2020 were 29.1 Mt (equivalent to 2% of the emissions in 2017), 203.8 (21%), 281.8 (27%), 485.5 (17%), and 34.3 kt (3%), respectively, relative to 2017. In terms of the cities or sectors, the higher the pollutant emissions, the higher the reduction achieved. The CO2 mitigation co-effect results showed that industrial adjustment measures, such as eliminating backward production capacity, upgrades on industrial boilers, and phasing out small and polluting factories, contributed the most to the co-effect of CO2 emission reduction, whereas NOx presented the highest co-effects, with CO2 among the different air pollutants.

Myricetin exhibits anti-glioma potential by inducing mitochondrial-mediated apoptosis, cell cycle arrest, inhibition of cell migration and ROS generation.

The Editors of JBUON issue an Expression of Concern to 'Myricetin exhibits anti-glioma potential by inducing mitochondrial-mediated apoptosis, cell cycle arrest, inhibition of cell migration and ROS generation', by Hu-Guang Li, Jun-Xia Chen, Jun-Hui Xiong, Jin-Wei Zhu, JBUON 2016;21(1):182-190; PMID:27061547. Following the publication of the above article, readers drew to our attention that part of the data was possibly unreliable. We sent emails to the authors with a request to provide the raw data to prove the originality, but received no reply. Therefore, as we continue to work through the issues raised, we advise readers to interpret the information presented in the article with due caution. We thank the readers for bringing this matter to our attention. We apologize for any inconvenience it may cause.

Myricetin exhibits anti-glioma potential by inducing mitochondrial-mediated apoptosis, cell cycle arrest, inhibition of cell migration and ROS generation.

PURPOSE: To study the antiproliferative effects of myricetin in human glioma U251 cells together with assessing its effects on cell cycle, apoptosis, apoptosis-related proteins, reactive oxygen species (ROS) generation and cell migration. METHODS: Cell viability of human glioma cells after myricetin treatment was assessed by MTT assay. Phase-contrast and confocal fluorescence microscopies were used to assess the morphological changes that occured in these cells following myricetin treatment. Flow cytometry using propidium iodide (PI) and Annexin-V FITC as probes was employed to evaluate the effects on cell cycle arrest and apoptosis induction, respectively. The effect of myricetin on intracellular ROS production was measured by flow cytometry with a fluorescent probe CM-DCFH2-DA. RESULTS: Myricetin induced a dose-dependent as well as time-dependent growth inhibitory effect in U251 human glioma cells. Myricetin treatment resulted in U251 cells detachment from adjacent cells making clusters of cells floating in the medium. Detached cells had irregular shape and incapable to maintain their membranes intact. Apoptotic cell death was induced by myricetin treatment as witnessed by fluorescence microscopy. The percentage of early and late apoptotic cells increased from 0.41% and 8.2% to 23.1% and 10.2%, 25.2% and 19.4%, to finally 36.2% and 28.4% after treatment with 15 µM, 60 µM and 120 µM of myricetin, respectively. We also observed a dose-dependent increase in Bax and Bad levels and a dose-dependent decrease in Bcl-2 and Bcl-xl expression levels following myricetin treatment. Cell cycle arrest in G2/M phase of the cell cycle was also induced by the drug treatment. A concentration-dependent ROS generation was also witnessed and a 3-fold increase of ROS production was seen after 60 µM myricetin treatment. CONCLUSION: Myricetin exerts anticancer effects in U251 human glioma cells by inducing mitochondrial-mediated apoptosis, G2/M phase cell cycle arrest, ROS generation and inhibition of cell migration.

Association of THBS1 rs1478605 T>C in 5'-untranslated regions with the development and progression of gastric cancer.

Thrombospondin 1 (THBS1) plays an important role in angiogenesis and tumor progression. The aim of the present study was to investigate the effects of single-nucleotide polymorphisms (rs1478605 and rs3743125) in the untranslated regions of the THBS1 gene on the development and progression of gastric cancer. In the case-control study, 275 gastric cancer patients and 275 cancer-free controls were successfully genotyped using polymerase chain reaction-restriction fragment length polymorphism. The data demonstrated that THBS1 rs1478605 genotypic distributions significantly differed between the patient and control groups (P=0.005). Carriers of the CC genotype exhibited a decreased risk of developing gastric cancer compared to the carriers of the CT and TT genotypes [adjusted odd ratio (OR), 0.56; 95% confidence interval (CI), 0.39-0.79; P=0.001]. The CC genotype of rs1478605 was negatively associated with gastric cancer lymph node metastasis (OR, 0.41; 95% CI, 0.23-0.71; P=0.001) and was associated with a reduced risk of lymph node metastasis in male patients (OR, 0.27; 95% CI, 0.14-0.52; P<0.001). The THBS1 CT haplotype was associated with a reduced risk of developing gastric cancer (OR, 0.56; 95% CI, 0.33-0.93; P=0.02). By contrast, no association was observed between THBS1 rs3743125 and the development and progression of gastric cancer. These results suggest that THBS1 rs1478605 represents a potential molecular marker for gastric cancer.

Overexpression of thrombospondin-1 in stromal myofibroblasts is associated with tumor growth and nodal metastasis in gastric carcinoma.

BACKGROUND AND OBJECTIVES: The roles of thrombospondin-1 (THBS-1) in tumor growth and metastasis are complicated and its function as a cancer inhibitor or promoter remains controversial. This clinical study investigated the functional roles of THBS-1 in gastric carcinoma by examining the expression patterns of THBS-1 protein and mRNA levels during gastric cancer development. METHODS: Eighty-two gastric carcinomas were included in this study. THBS-1, α-smooth muscle actin, and CD34 proteins were localized by immunohistochemical staining, and the levels of THBS-1 mRNA were quantified by real-time polymerase chain reaction. RESULTS: THBS-1 mRNA expression in gastric carcinoma tissues was significantly higher than in adjacent non-cancerous stomach tissues (P = 0.03). Tumor THBS-1 mRNA expression level was significantly related to lymph node metastasis (P = 0.031), tumor size (P = 0.021) and patient age (P = 0.005). THBS-1 protein was mainly located in stromal myofibroblasts, and was undetectable in tumor cells. Myofibroblasts may be mainly derived from stromal fibroblasts in gastric cancer. The abundance of myofibroblasts was positively correlated with tumor growth and nodal metastasis in gastric carcinoma (P = 0.03, P = 0.0008, respectively). CONCLUSIONS: This clinical study revealed that overexpression of THBS-1 in stromal myofibroblasts is associated with tumor growth and nodal metastasis in gastric carcinoma. THBS-1 may activate latent transforming growth factor-ß1 to stimulate fibroblasts to differentiate into myofibroblasts, though further studies are needed to validate this hypothesis. These results suggest that THBS-1 and myofibroblasts may serve as novel targets for strategies aimed at protection against and treatment of gastric carcinoma.

Polymorphism of THBS1 rs1478604 A>G in 5-untranslated region is associated with lymph node metastasis of gastric cancer in a Southeast Chinese population.

Thrombospondin-1 plays an important role in cancer development and progression. This study investigated if a correlation exists between single-nucleotide polymorphisms (SNPs) in the Thrombospondin-1 gene (THBS1) and gastric cancer. We conducted a case-control study on a randomly recruited population of 283 patients and 283 healthy individuals from the city of Fuzhou in Southeast China. Individuals were genotyped for four SNPs (rs1478604 A>G, rs2228261 C>T, rs2292305 T>C, and rs3743125 C>T) in THBS1 using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. THBS1 genotypic distributions between the case and control groups were tested for correlations with cancer development. Comparisons between the case and control groups showed no significant differences in the genotypic distributions of rs1478604 A>G, rs2228261 C>T, and rs3743125 C>T. However, we found a statistically significant association between homozygous CC of THBS1 rs2292305 T>C and development of highly differentiated carcinoma (HDC). The rs1478604 A>G variant was found to be associated with invasion and lymph node metastasis in gastric cancer. After logistic regression and stratification analysis, rs1478604 A>G was more strongly associated with lymph node metastasis in HDC gastric cancer. The power to detect an effect for rs1478604 A>G in HDC was 90%. These findings indicate that the THBS1 rs1478604 A>G variant is linked with differential risks for gastric cancer nodal metastasis. These results support further investigation of THBS1 as a potential therapeutic target in gastric cancer.

Association of a MYCL1 single nucleotide polymorphism, rs3134613, with susceptibility to diffuse-type gastric cancer and with differentiation of gastric cancer in a southeast Chinese population.

A MYCL1 single nucleotide polymorphism, rs3134613, has been reported to play an important role in many cancers. However, its involvement in gastric cancer is controversial. The aim of the study was to investigate the influence of rs3134613 on the development and progression of gastric cancer in a southeast Chinese population. Genotypes were analyzed by polymerase chain reaction-restriction fragment length polymorphism in 317 gastric cancer patients and 200 cancer-free controls. Data show that the risk of diffuse-type gastric cancer in carriers with the T allele (T/T or G/T genotype) was higher than that in carriers with the G/G genotype (adjusted odds ratio [OR] = 2.601, 95% confidence interval [CI] = 1.431-4.895, p = 0.003). The risk of diffuse-type gastric cancer in T allele carriers was higher than that in G allele carriers (adjusted OR = 1.594, 95% CI = 1.157-2.286, p = 0.009). The risk of poorly differentiated cancer in carriers with the T allele (T/T or G/T genotype) was higher than that in carriers with the G/G genotype (adjusted OR = 1.963, 95% CI = 1.156-3.325, p = 0.015). The results demonstrate that rs3134613 is associated with susceptibility to diffuse-type gastric cancer and with differentiation of gastric cancer. rs3134613 may be used as a potential marker to identify individuals who are at high risk of diffuse-type gastric cancer.

[Analysis of mitochondrial gene mutations in pedigrees of Leber's hereditary optic neuropathy].

The purpose of the study is to investigate the frequency of common pathogenic primary mitochondrial DNA mutations in pedigrees of Leber's hereditary optic neuropathy (LHON). Mutations were determined by polymerase chain reaction (PCR), single-stranded conformational polymorphism (SSCP) and DNA sequencing. Twenty-two patients with suspicion of LHON and twenty-one their maternal relatives underwent molecular genetic evaluation. Seventy-one normal individuals underwent molecular genetic evaluation as control at the same time. Members from 13 families with suspicion of LHON,11 families had nucleotide position nt11778 G-->A mutations. Another 2 families had nt14484 T-->C mutations. It is concluded that the point mutations at nucleotides 11778 and 14484 are primary LHON mutations,but the point mutation of nt14484 is rare in Chinese.

[Role of NADH-cytochrome b(5) reductase in biosynthesis of thyroid hydrogen peroxide].

The activity of NADH-cytochrome b(5) reductase (b(5)R) and the levels of hydrogen peroxide in the thyroid of patients with Graves' disease (GD) and normal controls were measured with potassium ferricyanide as substrate and with the homovanillic acid fluorescence assay. The activity of b(5)R and the level of H2O2 in GD thyroid were definitely higher than those in normal control, but the activity of catalase in GD thyroid was not significantly different from that in normal thyroid. After addition of p-chloromercuribenzoate, a b(5)R inhibitor, the activity of b(5)R in GD and normal thyroid decreased by 85%, the level of H2O2 decreased by 50%, and protein-bound iodine (PBI) formation by 52%. There is a positive correlation between the level of H2O2 and the activity of b(5)R. Our data indicate that b(5)R participates in thyroid hydrogen peroxide biosynthesis, and is an important enzyme in the production of H2O2.