Glutamine provides carbon and nitrogen to support the proliferation of cancer cells. However, the precise reason why cancer cells are particularly dependent on glutamine remains unclear. In this study, we report that glutamine modulates the tumor suppressor F-box and WD repeat domain-containing 7 (FBW7) to promote cancer cell proliferation and survival. Specifically, lysine 604 (K604) in the sixth of the 7 substrate-recruiting WD repeats of FBW7 undergoes glutaminylation (Gln-K604) by glutaminyl tRNA synthetase. Gln-K604 inhibits SCFFBW7-mediated degradation of c-Myc and Mcl-1, enhances glutamine utilization, and stimulates nucleotide and DNA biosynthesis through the activation of c-Myc. Additionally, Gln-K604 promotes resistance to apoptosis by activating Mcl-1. In contrast, SIRT1 deglutaminylates Gln-K604, thereby reversing its effects. Cancer cells lacking Gln-K604 exhibit overexpression of c-Myc and Mcl-1 and display resistance to chemotherapy-induced apoptosis. Silencing both c-MYC and MCL-1 in these cells sensitizes them to chemotherapy. These findings indicate that the glutamine-mediated signal via Gln-K604 is a key driver of cancer progression and suggest potential strategies for targeted cancer therapies based on varying Gln-K604 status.
Glutamine/metabolism* ; Myeloid Cell Leukemia Sequence 1 Protein/genetics* ; Humans ; Proto-Oncogene Proteins c-myc/genetics* ; Cell Proliferation ; Signal Transduction ; Neoplasms/pathology* ; F-Box-WD Repeat-Containing Protein 7/genetics* ; Cell Survival ; Cell Line, Tumor ; Apoptosis

Fabry disease, a rare genetic disorder affecting multiple organs, has understudied correlations among enzyme activity, genotype, and clinical manifestations in patients of different sexes with classical and late-onset phenotypes. In this study, clinical data, α-Gal A activity, and GLA gene test results of 311 patients, who were categorized by classical and late-onset phenotypes, ⩽5% and > 5% of the normal mean value of enzyme activity, and truncated and nontruncated mutation groups, were collected. The common clinical manifestations of Fabry disease included acroparesthesia, hypohidrosis/anhidrosis, neuropsychiatric system, and renal and cardiovascular involvement. Multiorgan involvement was higher in males and classical phenotype patients. In both sexes, classical patients commonly presented with acroparesthesia and multiorgan involvement, whereas late-onset patients showed renal, neuropsychiatric, and cardiovascular involvement. Male and classical patients had lower enzyme activity than female and late-onset patients, respectively. Classical males with enzyme activity of ⩽5% of the normal mean level showed higher multiorgan involvement frequency than those with enzyme activity of > 5%, whereas no significant difference was observed among females. Ninety-five gene mutation sites were detected, with significant phenotype heterogeneity in patients with the same mutation. No significant difference in enzyme activity or clinical manifestations was observed between truncated and nontruncated mutations. Overall, male patients with Fabry disease, regardless of classical or late-onset phenotype, have a higher frequency of multiple-organ involvement and lower α-Gal A activity than female patients. α-Gal A activity was closely correlated with clinical symptoms in males but weakly correlated with clinical manifestations in females. The clinical manifestations of patients with the same mutation are heterogeneous, and the correlation between gene mutation and enzyme activity or clinical manifestation is weak.
Adolescent ; Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; Age of Onset ; alpha-Galactosidase/metabolism* ; China ; Fabry Disease/enzymology* ; Genotype ; Mutation ; Phenotype ; Sex Factors ; East Asian People/genetics*

Aconitum kusnezoffii is a perennial herbaceous medicinal plant of the family Ranunculaceae, with unique medicinal value. Damping off is one of the most important seedling diseases affecting A. kusnezoffii, occurring widely and often causing large-scale seedling death in the field. To clarify the species of the pathogen causing damping off in A. kusnezoffii and to formulate an effective control strategy, this study conducted pathogen identification, research on biological characteristics, and evaluation of fungicide inhibitory activity. Through morphological characteristics, cultural traits, and phylogenetic tree analysis, the pathogen causing damping off in A. kusnezoffii was identified as Rhizoctonia solani, belonging to the AG5 anastomosis group. The optimal temperature for mycelial growth of the pathogen was 25-30 ℃, with OA medium as the most suitable medium, pH 8 as the optimal pH, and sucrose and yeast as the best carbon and nitrogen sources, respectively. The effect of light on mycelial growth was not significant. In evaluating the inhibitory activity of 45 chemical fungicides, including 30% hymexazol, and 4 biogenic fungicides, including 0.3% eugenol, it was found that 30% thifluzamide and 50% fludioxonil had significantly better inhibitory effects on R. solani than other tested agents, with EC_(50) values of 0.129 6,0.220 6 μg·mL~(-1), respectively. Among the biogenic fungicides, 0.3% eugenol also showed an ideal inhibitory effect on the pathogen, with an EC_(50) of 1.668 9 μg·mL~(-1). To prevent the development of resistance in the pathogen and to reduce the use of chemical fungicides, it is recommended that the three fungicides above be used in rotation during production. These findings provide a theoretical basis for the accurate diagnosis and effective control strategy for R. solani causing damping off in A. kusnezoffii.
Fungicides, Industrial/pharmacology* ; Plant Diseases/microbiology* ; Rhizoctonia/growth & development* ; Aconitum/microbiology* ; Phylogeny ; Mycelium/growth & development*

OBJECTIVE: To investigate the effect and mechanism of Shuangshi Tonglin Capsules (SSTL) in the treatment of prostate fibrosis (PF). METHODS: Human prostate stromal cells (WPMY-1) were used for in vitro experiments to establish PF cell models induced with estradiol (E₂). The cell proliferation, migration and clonogenic capacity were determined by cell counting kit-8, scratch assay, and crystal violet staining, respectively. Sprague-Dawley rats were used for in vivo experiments. The changes in histomorphology and organ index of rat prostate by SSTL were determined. Pathologic changes and collagen deposition changes in rat prostate were observed by haematoxylin and eosin (HE) and Masson staining. Enzyme-linked immunosorbent assay kits were used to determine changes in rat PF markers fibroblast growth factor-23 (FGF-23), E₂ and prostate specific antigen (PSA). Mechanistically, changes in oxidative stress indicators by SSTL were determined in WPMY-1 cells and PF rats. Then the expressions of nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) and transforming growth factor-β1 (TGF-β1)/Smad pathway-related proteins as well as Nrf2 and TGF-β1 mRNA were further detected by Western blot or quantitative real-time polymerase chain reaction both in vivo and in vitro. RESULTS: In the efficacy study, SSTL significantly reduced the proliferation, migration, and clonogenic ability of cells, improved the morphology of the glandular tissue, significantly reduced the prostate index, reduced glandular fibrous tissue and collagen deposition, and resulted in a significant decrease in the levels of FGF-23, E₂ and PSA (P<0.01 or P<0.05). In the mechanistic study, SSTL ameliorated oxidative stress by significantly increasing superoxide dismutase and glutathione peroxidase levels and decreasing malondialdehyde level in WPMY-1 cells and rats (P<0.01 or P<0.05). SSTL significantly elevated the expressions of Nrf2, HO-1, NAD(P)H quinone oxidoreductase 1 (NQO-1), and Smad7 proteins in both cells and rats, and significantly decreased the expressions of TGF-β1, collagen I, α-smooth muscle actin and Smad4 proteins (P<0.01 or P<0.05). SSTL also elevated the content of Nrf2 mRNA and decreased the content of TGF-β1 mRNA in cells and rats (P<0.01 or P<0.05). The Nrf2 inhibitor ML385 was added in in vitro experiments to further validate the pathway relevance. CONCLUSION SSTL was effective in improving PF in vivo and in vitro, and its mechanism of action may function through the Nrf2/TGF-β1 signaling pathway.
Male ; NF-E2-Related Factor 2/metabolism* ; Animals ; Drugs, Chinese Herbal/therapeutic use* ; Signal Transduction/drug effects* ; Transforming Growth Factor beta1/metabolism* ; Rats, Sprague-Dawley ; Humans ; Fibrosis ; Prostate/drug effects* ; Cell Proliferation/drug effects* ; Capsules ; Cell Movement/drug effects* ; Oxidative Stress/drug effects* ; Rats

OBJECTIVE: To explore the functional roles and underlying mechanisms of neferine in the context of angiotensin II (Ang II)-induced hypertension and vascular dysfunction. METHODS: Male mice were infused with Ang II to induce hypertension and randomly divided into treatment groups receiving neferine or a control vehicle based on baseline blood pressure using a random number table method. The hypertensive mouse model was constructed by infusing Ang II via a micro-osmotic pump (500 ng/kg per minute), and neferine (0.1, 1, or 10 mg/kg), valsartan (10 mg/kg), or double distilled water was administered intragastrically once daily for 6 weeks. A non-invasive blood pressure system, ultrasound, and hematoxylin and eosin staining were performed to assess blood pressure and vascular changes. RNA sequencing and network pharmacology were employed to identify differentially expressed transcripts (DETs) and pathways. Vascular ring tension assay was used to test vascular function. A7R5 cells were incubated with neferine for 24 h and then treated with Ang II to record the real-time Ca²⁺ concentration by confocal microscope. Immunohistochemistry (IHC) and Western blot were used to evaluate vasorelaxation, calcium, and the extracellular signal-regulated kinase (ERK)1/2 pathway. RESULTS: Neferine treatment effectively mitigated the elevation in blood pressure, pulse wave velocity, aortic thickening in the abdominal aorta of Ang II-infused mice (P<0.05). RNA sequencing and network pharmacology analysis identified 355 DETs that were significantly reversed by neferine treatment, along with 25 potential target genes, which were further enriched in multiple pathways and biological processes, such as ERK1 and ERK2 cascade regulation, calcium pathway, and vascular smooth muscle contraction. Further investigation revealed that neferine treatment enhanced vasorelaxation and reduced Ca²⁺-dependent contraction of abdominal aortic rings, independent of endothelium function (P<0.05). The underlying mechanisms were mediated, at least in part, via suppression of receptor-operated channels, store-operated channels, or voltage-operated calcium channels. Neferine pre-treatment demonstrated a reduction in intracellular Ca²⁺ release in Ang II stimulated A7R5 cells. IHC staining and Western blot confirmed that neferine treatment effectively attenuated the upregulation of p-ERK1/2 both in vivo and in vitro, which was similar with treatment of ERK1/2 inhibitor PD98059 (P<0.05). CONCLUSIONS Neferine remarkably alleviates Ang II-induced elevation of blood pressure, vascular dysfunction, and pathological changes in the abdominal aorta. This beneficial effect is mediated by the modulation of multiple pathways, including calcium and ERK1/2 pathways.
Animals ; Angiotensin II ; Male ; Benzylisoquinolines/therapeutic use* ; Network Pharmacology ; Blood Pressure/drug effects* ; Sequence Analysis, RNA ; Mice ; Hypertension/chemically induced* ; Mice, Inbred C57BL ; Calcium/metabolism*

Objective: To investigate the independent prognostic factors affecting disease-free survival(DFS) after radical surgery in Ⅱ and Ⅲ adenocarcinoma of gastroesophageal junction(AEG) patients, and to construct a nomogram prediction model. Methods : A retrospective analysis was conducted on a cohort comprising 326 patients who were diagnosed with AEG. Chi-square test was used for categorical variable analysis. The survival analysis was drawn by Kaplan-Meier method and tested by log-rank method. Univariate and multivariate Cox regression analyses identified independent prognostic factors, and based on these factors, a nomogram was constructed to predict 3-year and 5-year DFS in AEG patients. The calibration curves evaluated the performance of nomogram. Results: Among 326 AEG patients, 281 were in the young group(<70 years old) and 45 were in the old group(≥70 years old). Kaplan-Meier curve showed that patients with advanced age, TNM stage Ⅰ-Ⅱ and no history of hepatitis B had longer DFS. Univariate and multivariate analysis showed that age, TNM stage and history of hepatitis B were independent prognostic factors for DFS. The 3-year and 5-year correction curves showed that the prediction efficiency of nomogram was good. The decision curve analysis showed that the model had a good clinical net benefit. Conclusion Age, TNM stage and history of hepatitis B are independent prognostic factors for DFS in AEG patients. The nomogram constructed and validated can be used to predict DFS in AEG patients.

Objective:To investigate the effects of Juglone on the apoptosis of osteosarcoma(OS)cells(U2OS and MG63 cells)through the cysteinyl aspartate specific proteinase-3(Caspase-3)/gasdermin E(GSDME)-mediated pyroptosis pathway.Methods:The U2OS and MG63 cells were cultured in vitro and divided into control group,different concentrations(5,10 and 20 μmol·L-1)of Juglone groups and Caspase-3 inhibitor Z-DEVD-FMK group(10 μmol·L-1 Juglone+30 μmol·L-1 Z-DEVD-FMK).The survival rates of cells in various groups were assessed by cell counting kit-8(CCK-8)assay,and the apoptotic rates were detected by flow cytometry.Lactate dehydrogenase(LDH)release assay was used to measure the release rates of LDH from the cells.Western blotting method was used to detect the expression levels of apoptosis-related proteins including B-cell lymphoma-2(Bcl-2),Bcl-2-associated X protein(Bax),cleaved-Caspase-3 and poly(ADP-ribose)polymerase(PARP)and pyroptosis-related proteins including GSDME full form(GSDME-F)and GSDME N-terminal(GSDME-N).The levels of interleukin-1β(IL-1β)and interleukin-18(IL-18)in the cell supernataut in various groups were measured by enzyme-linked immunosorbent assay(ELISA)method.Results:Compared with control group,the survival rates of cells in 5,10,and 20 μmol·L-1Juglone groups were significantly decreased(P＜0.05 or P＜0.01),and the 50％inhibitory concentration(IC50)values of U2OS cells and MG63 cells were 8.4 and 10.2 μmol·L-1,respectively.Compared with control group,the apoptotic rates and LDH release rates of U2OS and MG63 cells in 5 and 10 μmol·L-1Juglone groups were significantly increased(P＜0.05 or P＜0.01).Compared with control group,the expression levels of Bax,cleaved-Caspase-3,and cleaved-PARP proteins in 5 and 10 μmol·L-1 Juglone groups were significantly increased(P＜0.01),while the expression levels of Bcl-2 protein were significantly decreased(P＜0.01).Compared with control group,the levels of IL-1β and IL-18 in cell supernatant in 5 and 10 μmol·L-1Juglone groups were increased(P＜0.01).Compared with control group,the expression levels of cleaved-Caspase-3 and GSDME-N proteins in 5 and 10 μmol·L-1 Juglone groups were significantly increased(P＜0.01),while there was no difference in the expression level of GSDME-F protein(P＞0.05).Compared with 10 μmol·L-1 Juglone group,the expression levels of cleaved-Caspase-3 and GSDME-N in Z-DEVD-FMK group were significantly decreased(P＜0.01),while there was no difference in the expression level of GSDME-F protein(P＞0.05).Conclusion:Juglone can induce the apoptosis of U2OS and MG63 cells and cause the Caspase-3/GSDME-mediated pyroptosis.

Objective To investigate the status of population dynamics and distribution changes of Aedes aegypti in Guangdong Province.Methods Continuous monitoring was conducted from May 2018 to July 2024 in Wushi Town and Qishui Town,Leizhou City,Zhanjiang City,Guangdong Province.Additionally,a survey of the distribution of Ae.aegypti along the Leizhou Peninsula coast was carried out.Results The density of Ae.aegypti in Zhanjiang showed a gradual decline from 2018 to 2024.The last detection of adult Ae.aegypti in Wushi Town was in September 2021,and the last larva was found in October 2023.No Ae.aegypti was detected in Qishui Town during surveys from 2021 to 2024.A survey of 18 coastal villages in the Leizhou Peninsula revealed no detections of Ae.aegypti.Conclusions This study provides a basis for understanding the distribution and population density fluctuations of Ae.aegypti,assessing its invasion risk,and scientifically conducting relevant prevention and control efforts.

Objective:To assess the effectiveness of a 6-month Ba Duan Jin exercise program in improving the balance of community-dwelling older adults.Methods:A two arms, parallel-group, cluster randomized controlled trial was conducted in 1 028 community residents aged 60-80 years in 40 communities in 5 provinces of China. Participants in the intervention group (20 communities, 523 people) received Ba Duan Jin exercise 5 days/week, 1 hour/day for 6 months, and three times of falls prevention health education, and the control group (20 communities, 505 people) received falls prevention health education same as the intervention group. The Berg balance scale (BBS) score was the leading outcome indicator, and the secondary outcome indicators included the length of time of standing on one foot (with eyes open and closed), standing in a tandem stance (with eyes open and closed), the closed circle test, and the timed up to test.Results:A total of 1 028 participants were included in the final analysis, including 731 women (71.11%) and 297 men (28.89%), and the age was (69.87±5.67) years. After the 3-month intervention, compared with the baseline data, the BBS score of the intervention group was significantly higher than the control group by 3.05 (95% CI: 2.23-3.88) points ( P<0.001). After the 6-month intervention, compared with the baseline data, the BBS score of the intervention group was significantly higher than the control group by 4.70 (95% CI: 4.03-5.37) points ( P<0.001). Ba Duan Jin showed significant improvement ( P<0.05) in all secondary outcomes after 6 months of exercise in the intervention group compared with the control group. Conclusions:This study showed that Ba Duan Jin exercise can improve balance in community-dwelling older adults aged 60-80. The longer the exercise time, the better the improvement.

Professor ZHOU Peng has deeply discussed the pathological characteristics of psoriasis vulgaris,emphasizing that the disease is usually manifested deficiency interweaved with excess,leading to frequent recurrence and persistent refractory,which may lead to psychological and emotional problems of patients.This paper further expounds the effect of blood stasis on the pathogenesis,progression and prognosis of psoriasis,and puts forward a new method of combining Lingnan fire needling and filiform needling acupuncture technique to treat psoriasis vulgaris with blood stasis syndrome.Professor ZHOU Peng believes that the treatment principle of this disease is"regulating the mind first,rectifying blood as a base,syndrome differentiating and eliminating pathogenic factors",aiming at comprehensively considering the etiology and symptoms,in order to achieve more effective treatment results.Combined with the analysis of dermoscopic signs,it provides a possible improvement direction for the treatment of psoriasis vulgaris from a new perspective.