Physiological levels of ATP negatively regulate proteasome function

Intracellular protein degradation by the ubiquitin-proteasome system is ATP dependent, and the optimal ATP concentration to activate proteasome function in vitro is -100 μM. IntraceUular ATP levels are generally in the low millimolar range, but ATP at a level within this range was shown to inhibit proteasome peptidase activities in vitro. Here, we report new evidence that supports a hypothesis that intracellular ATP at the physiological levels bidirectionally regulates 26S proteasome proteolytic function in the cell. First, we confirmed that ATP exerted bidirectional regulation on the 26S proteasome in vitro, with the optimal ATP concentration （between 50 and 100μM） stimulating proteasome chymotrypsin-like activities. Second, we found that manipulating intracellular ATP levels also led to bidirectional changes in the levels of proteasome-specific protein substrates in cultured cells. Finally, measures to increase intracellular ATP enhanced, while decreasing intraceHular ATP attenuated the ability of proteasome inhibition to induce cell death. These data strongly suggest that endogenous ATP within the physiological concentration range can exert a negative impact on proteasome activities, allowing the cell to rapidly upregulate proteasome activity on ATP reduction under stress conditions.

Bilirubin inhibits the anticancer activity of sorafenib by blocking MCL-1 degradation in hepatocellular carcinoma cells

Objective:Sorafenib is a first-line drug for advanced hepatocellular carcinoma(HCC).Unfortunately,most patients with HCC do not respond to sorafenib,mainly because of the frequent development of drug resistance.Bilirubin is an end metabolite of heme catabolism and an indicator of liver function,but its direct role in regulating the anticancer activity of sorafenib in HCC cells is unclear.In the current study,we aimed to investigate the mechanism of action of bilirubin in sorafenib-mediated tumor suppression in HCC.Methods:A retrospective observational cohort of 100 patients receiving sorafenib was conducted to evaluate the potential role of bilirubin in predicting the prognosis of patients with HCC.Human HCC cell lines were treated with sorafenib in the absence or presence of bilirubin,and cell proliferation,apoptosis,and signaling pathways were assayed.The antagonistic effect of bilirubin toward sorafenib was assessed in nude mice bearing HCC xenografts.Results:Serum levels of bilirubin(including total,direct,and indirect bilirubin)negatively correlated with the overall survival of patients with HCC treated with sorafenib(P<0.05).Both in vitro and in vivo analyses demonstrated that bilirubin significantly abrogated sorafenib-mediated proliferation inhibition and apoptosis induction in HCC cells(P<0.05).Mechanically,bilirubin inhibited sorafenib-induced activation of GSK-3βand subsequent downstream MCL-1 degradation.Conclusions:Our study provides experimental evidence of the antagonistic effect of bilirubin toward sorafenib-mediated anticancer activity in HCC,and it suggests that bilirubin could be used to predict the efficacy of sorafenib treatment.

NO hydrogenation to NH3 over FeCu/TiO_(2) catalyst with improved activity

Ammonia is crucial in industry and agriculture, but its production is hindered by environmental concerns and energy-intensive processes. Hence, developing an efficient and environmentally friendly catalyst is imperative. In this study, we employed a straightforward and efficient impregnation technique to create various Cu-doped catalysts. Notably, the optimized 10Fe-8Cu/TiO_(2) catalyst exhibited exceptional catalytic performance in converting NO to NH3, achieving an NO conversion rate exceeding 80% and an NH3 selectivity exceeding 98% at atmospheric pressure and 350 °C. We employed in situ diffuse reflectance Fourier transform infrared spectroscopy and conducted density functional theory calculations to investigate the intermediates and subsequent adsorption. Our findings unequivocally demonstrate that Cu doping enhances the rate-limiting hydrogenation step and lowers the energy barrier for NH3 desorption, thereby resulting in improved NO conversion and enhanced selectivity toward ammonia. This study presents a pioneering approach toward energy-efficient ammonia synthesis and recycling of nitrogen sources.

KCTD4 interacts with CLIC1 to disrupt calcium homeostasis and promote metastasis in esophageal cancer

Increasing evidences suggest the important role of calcium homeostasis in hallmarks of cancer,but its function and regulatory network in metastasis remain unclear.A comprehensive investigation of key regulators in cancer metastasis is urgently needed.Transcriptome sequencing(RNA-seq)of primary esophageal squamous cell carcinoma(ESCC)and matched metastatic tissues and a series of gain/loss-of-function experiments identified potassium channel tetramerization domain containing 4(KCTD4)as a driver of cancer metastasis.KCTD4 expression was found upregulated in metastatic ESCC.High KCTD4 expression is associated with poor prognosis in patients with ESCC and contributes to cancer metastasis in vitro and in vivo.Mechanistically,KCTD4 binds to CLIC1 and disrupts its dimerization,thus increasing intracellular Ca^(2+)level to enhance NFATc1-dependent fibronectin transcription.KCTD4-induced fibronectin secretion activates fibroblasts in a paracrine manner,which in turn promotes cancer cell invasion via MMP24 signaling as positive feedback.Furthermore,a lead compound K279-0738 significantly suppresses cancer metastasis by targeting the KCTD4-CLIC1 interaction,providing a potential therapeutic strategy.Taken together,our study not only uncovers KCTD4 as a regulator of calcium homeostasis,but also reveals KCTD4/CLIC1-Ca^(2+)-NFATc1-fibronectin signaling as a novel mechanism of cancer metastasis.These findings validate KCTD4 as a potential prognostic biomarker and therapeutic target for ESCC.

Bilirubin inhibits lung carcinogenesis by up-regulating cystatin A expression in tumor-infiltrating macrophages

As one of the leading causes of cancer deaths worldwide,the pathogenesis of lung cancer is still not completely understood.Bilirubin,a product of heme metabolism,has long been considered a waste product of the body.Increasing evidence suggests that bilirubin has additional antioxidant,anti-inflammatory,and proteasome inhibitory activities.However,the specific role of bilirubin in the formation and development of lung cancer has not been elucidated.

Stabilization of MYC G-quadruplex DNA by ruthenium(II)complex overcomes imatinib resistance in chronic myeloid leukemia cells harboring T315I mutation

The key pathogenesis of chronic myeloid leukemia(CML)is the formation of BCR-ABL fusion gene,encoding a 210 kDa Bcr-Abl tyrosine kinase,which is crucial for the occurrence and development of CML.Imatinib(IM)is the first targeted anticancer drug approved by FDA for the treatment of CML;however,some patients,especially those in accelerated phase and blastic phase,develop primary or secondary drug resistance to IM.Particularly,the most challenging resistance is caused by T315I mutation of Bcr-Abl,which represents approximately 15%–20%of all acquired mutations and renders cell resistant to a variety of tyrosine kinase inhibitors.1,2 Thus,there is an urgent need to develop novel strategies to overcome Bcr-Abl T315I-meidated IM resistance.

Error Sensitivity Analysis in 10–30-Day Extended Range Forecasting by Using a Nonlinear Cross-Prediction Error Model

Extended range forecasting of 10-30 days, which lies between medium-term and climate prediction in terms of timescale, plays a significant role in decision-making processes for the prevention and mitigation of disastrous met- eorological events. The sensitivity of initial error, model parameter error, and random error in a nonlinear cross- prediction error （NCPE） model, and their stability in the prediction validity period in 1 0-30-day extended range fore- casting, are analyzed quantitatively. The associated sensitivity of precipitable water, temperature, and geopotential height during cases of heavy rain and hurricane is also discussed. The results are summarized as follows. First, the initial error and random error interact. When the ratio of random error to initial error is small （10＂5-10-2）, minor vari- ation in random error cannot significantly change the dynamic features of a chaotic system, and therefore random er- ror has minimal effect on the prediction. When the ratio is in the range of 10-1-2 （i.e., random error dominates）, at- tention should be paid to the random error instead of only the initial error. When the ratio is around 10 2-10-1, both influences must be considered. Their mutual effects may bring considerable uncertainty to extended range forecast- ing, and de-noising is therefore necessary. Second, in terms of model parameter error, the embedding dimension m should be determined by the factual nonlinear time series. The dynamic features of a chaotic system cannot be depic- ted because of the incomplete structure of the attractor when m is small. When m is large, prediction indicators can vanish because of the scarcity of phase points in phase space. A method for overcoming the cut-off effect （m 〉 4） is proposed. Third, for heavy rains, precipitable water is more sensitive to the prediction validity period than temperat- ure or geopotential height; however, for hurricanes, geopotential height is most sensitive, followed by precipitable water.

Effects of the chemical structure of surfactants on the stability of naphthenic oil-based metalworking fluids

In this study,various nonionic surfactants(NS) with different ethylene oxide(EO) numbers and tail lengths and its binary blends with anionic surfactants(AS) were used as emulsifiers for naphthenic oil to form the microemulsion metalworking fluids(MWFs),and the effects of them on the stability of the emulsion system were investigated by formulation triangle method.The results indicated that binary complex surfactants of NS and AS as emulsifiers exhibited better emulsifying effect than that of single NS.NS with different EO numbers and tail lengths presented various emulsifying effects.NS(EO=10)exhibited the greatest number of stable formulations,especially the TX-10,but no linear relationship existed between the number of stable formulations and the tail length of NS.In addition,aromatic primary alcohol ethoxy late(APAE) series surfactants containing benzene groups similar to the cycloalkanes in the naphthenic oil so that presented the best emulsifying affect and the greatest number of stable formulations.The co-surfactant of sodium dodecyl benzene sulfonate(SDBS) binary blends with NS exerted the best synergistic effect,and the stable formulations numbers were ranged from 5 to 7,next sodium stearate(SS) comes last followed by sodium dodecyl sulfate(SDS-1) and sodium dodecyl sulfonate(SDS-2).