Identification of STAM-binding protein as a target for the treatment of gemcitabine resistance pancreatic cancer in a nutrient-poor microenvironment.

Pancreatic cancer (PC) is a highly malignant solid tumor whose resistance to gemcitabine (GEM) chemotherapy is a major cause of poor patient prognosis. Although PC is known to thrive on malnutrition, the mechanism underlying its chemotherapy resistance remains unclear. The current study analyzed clinical tissue sample databases using bioinformatics tools and observed significantly upregulated expression of the deubiquitinase STAMBP in PC tissues. Functional experiments revealed that STAMBP knockdown remarkably increases GEM sensitivity in PC cells. Multiple omics analyses suggested that STAMBP enhances aerobic glycolysis and suppresses mitochondrial respiration to increase GEM resistance in PC both in vitro and in vivo. STAMBP knockdown decreased PDK1 levels, an essential regulator of the aerobic glycolytic process, in several cancers. Mechanistically, STAMBP promoted the PDK1-mediated Warburg effect and chemotherapy resistance by modulating E2F1 via direct binding to E2F1 and suppressing its degradation and ubiquitination. High-throughput compound library screening using three-dimensional protein structure analysis and drug screening identified the FDA drug entrectinib as a potent GEM sensitizer and STAMBP inhibitor, augmenting the antitumor effect of GEM in a patient-derived xenograft (PDX) model. Overall, we established a novel mechanism, via the STAMBP-E2F1-PDK1 axis, by which PC cells become chemoresistant in a nutrient-poor tumor microenvironment.

Lactate Contributes to Remote Ischemic Preconditioning-Mediated Protection Against Myocardial Ischemia Reperfusion Injury by Facilitating Autophagy via the AMP-Activated Protein Kinase-Mammalian Target of Rapamycin-Transcription Factor EB-Connexin 43 Axis.

Remote ischemic preconditioning (RIPC) exerts a protective role on myocardial ischemia/reperfusion (I/R) injury by the release of various humoral factors. Lactate is a common metabolite in ischemic tissues. Nevertheless, little is known about the role lactate plays in myocardial I/R injury and its underlying mechanism. This investigation revealed that RIPC elevated the level of lactate in blood and myocardium. Furthermore, AZD3965, a selective monocarboxylate transporter 1 inhibitor, and 2-deoxy-d-glucose, a glycolysis inhibitor, mitigated the effects of RIPC-induced elevated lactate in the myocardium and prevented RIPC against myocardial I/R injury. In an in vitro hypoxia/reoxygenation model, lactate markedly mitigated hypoxia/reoxygenation-induced cell damage in H9c2 cells. Further studies suggested that lactate contributed to RIPC, rescuing I/R-induced autophagy deficiency by promoting transcription factor EB (TFEB) translocation to the nucleus through activating the AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR) pathway without influencing the phosphatidylinositol 3-kinase-Akt pathway, thus reducing cardiomyocyte damage. Interestingly, lactate up-regulated the mRNA and protein expression of connexin 43 (CX43) by facilitating the binding of TFEB to CX43 promoter in the myocardium. Functionally, silencing of TFEB attenuated the protective effect of lactate on cell damage, which was reversed by overexpression of CX43. Further mechanistic studies suggested that lactate facilitated CX43-regulated autophagy via the AMPK-mTOR-TFEB signaling pathway. Collectively, this research demonstrates that RIPC protects against myocardial I/R injury through lactate-mediated myocardial autophagy via the AMPK-mTOR-TFEB-CX43 axis.

E3 ubiquitin ligase UBR5 promotes gemcitabine resistance in pancreatic cancer by inducing O-GlcNAcylation-mediated EMT via destabilization of OGA.

Pancreatic cancer (PC) is among the deadliest malignancies, with an extremely poor diagnosis and prognosis. Gemcitabine (GEM) remains the first-line drug for treating PC; however, only a small percentage of patients benefit from current immunotherapies or targeted therapies. Resistance to GEM is prevalent and affects long-term survival. We found that ubiquitin-protein ligase E3 module N-recognition 5 (UBR5) is a therapeutic target against GEM resistance. UBR5 was markedly upregulated in clinical GEM-resistant PC samples and GEM-resistant PC cells. UBR5 knockdown markedly increased GEM sensitivity in GEM-resistant PC cell lines. UBR5-mediated GEM resistance was accompanied by activation of epithelial-mesenchymal transition (EMT) and could be mitigated by inhibiting EMT. Further analysis revealed that UBR5 promoted GEM resistance in PC cells by enhancing O-GlcNAcylation-mediated EMT. In addition, UBR5 knockdown resulted in increased O-GlcNAase (OGA) levels, an essential negatively regulated enzyme in the O-GlcNAcylation process. We identified a negative association between OGA and UBR5 levels, which further supported the hypothesis that O-GlcNAcylation-mediated GEM resistance induced by UBR5 is OGA-dependent in PC cells. Mechanistic studies revealed that UBR5 acts as an E3 ubiquitin ligase of OGA and regulates O-GlcNAcylation by binding and modulating OGA, facilitating its degradation and ubiquitination. Additionally, high-throughput compound library screening using three-dimensional protein structure analysis and drug screening identified a Food and Drug Administration drug, Y-39983 dihydrochloride, as a potent GEM sensitiser and UBR5 inhibitor. The combination of Y-39983 dihydrochloride and GEM attenuated tumour growth in a mouse xenograft tumour model. Collectively, these data demonstrated that UBR5 plays a pivotal role in the sensitisation of PC to GEM and provides a potential therapeutic strategy to overcome GEM resistance.

SLC35F2-SYVN1-TRIM59 axis critically regulates ferroptosis of pancreatic cancer cells by inhibiting endogenous p53.

Pancreatic cancer cells undergo intricate metabolic reprogramming to sustain their survival and proliferation. p53 exhibits a dual role in tumor cell ferroptosis. However, the precise role and mechanisms underlying wild-type p53 activation in promoting ferroptosis in pancreatic cancer cells remain obscure. In this study, we applied bioinformatics tools and performed an analysis of clinical tissue sample databases and observed a significantly upregulated expression of solute carrier family 35 member F2 (SLC35F2) in pancreatic cancer tissues. Our clinical investigations indicated that elevated SLC35F expression was related to adverse survival outcomes. Through multi-omics analyses, we discerned that SLC35F2 influences the transcriptome and inhibits ferroptosis in pancreatic cancer cells. Moreover, our findings reveal the pivotal involvement of p53 in mediating SLC35F2-mediated ferroptosis, both in vitro and in vivo. SLC35F2 inhibits ferroptosis by facilitating TRIM59-mediated p53 degradation. Further mechanistic investigations demonstrated that SLC35F2 competitively interacts with the E3 ubiquitin ligase SYVN1 of TRIM59, thereby stabilizing TRIM59 expression and consequentially promoting p53 degradation. Utilizing protein 3D structure analysis and drug screening, we identified irinotecan hydrochloride and lapatinib ditosylate as compounds targeting SLC35F2, augmenting the antitumor effect of imidazole ketone erastin (IKE) in a wild-type p53 patient-derived xenograft (PDX) model. However, in the p53 mutant PDX model, irinotecan hydrochloride and lapatinib ditosylate did not alter the sensitivity of the tumor xenograft model to IKE-triggered ferroptosis. In summary, our work establishes a novel mechanism wherein the SLC35F2-SYVN1-TRIM59 axis critically regulates ferroptosis of pancreatic cancer cells by inhibiting endogenous p53. Thus, SLC35F2 emerges as a promising therapeutic target for treating pancreatic cancer.

Widespread global disparities between modelled and observed mid-depth ocean currents.

The mid-depth ocean circulation is critically linked to actual changes in the long-term global climate system. However, in the past few decades, predictions based on ocean circulation models highlight the lack of data, knowledge, and long-term implications in climate change assessment. Here, using 842,421 observations produced by Argo floats from 2001-2020, and Lagrangian simulations, we show that only 3.8% of the mid-depth oceans, including part of the equatorial Pacific Ocean and the Antarctic Circumpolar Current, can be regarded as accurately modelled, while other regions exhibit significant underestimations in mean current velocity. Knowledge of ocean circulation is generally more complete in the low-latitude oceans but is especially poor in high latitude regions. Accordingly, we propose improvements in forecasting, model representation of stochasticity, and enhancement of observations of ocean currents. The study demonstrates that knowledge and model representations of global circulation are substantially compromised by inaccuracies of significant magnitude and direction, with important implications for modelled predictions of currents, temperature, carbon dioxide sequestration, and sea-level rise trends.

RBX1 regulates PKM alternative splicing to facilitate anaplastic thyroid carcinoma metastasis and aerobic glycolysis by destroying the SMAR1/HDAC6 complex.

BACKGROUND: Anaplastic thyroid carcinoma (ATC) is one of the most aggressive malignancies, frequently accompanied by metastasis and aerobic glycolysis. Cancer cells adjust their metabolism by modulating the PKM alternative splicing and facilitating PKM2 isoform expression. Therefore, identifying factors and mechanisms that control PKM alternative splicing is significant for overcoming the current challenges in ATC treatment. RESULTS: In this study, the expression of RBX1 was largely enhanced in the ATC tissues. Our clinical tests suggested that high RBX1 expression was significantly related to poor survival. The functional analysis indicated that RBX1 facilitated the metastasis of ATC cells by enhancing the Warburg effect, and PKM2 played a key role in RBX1-mediated aerobic glycolysis. Furthermore, we confirmed that RBX1 regulates PKM alternative splicing and promotes the PKM2-mediated Warburg effect in ATC cells. Moreover, ATC cell migration and aerobic glycolysis induced by RBX1-mediated PKM alternative splicing are dependent on the destruction of the SMAR1/HDAC6 complex. RBX1, as an E3 ubiquitin ligase, degrades SMAR1 in ATC through the ubiquitin-proteasome pathway. CONCLUSION: Overall, our study identified the mechanism underlying the regulation of PKM alternative splicing in ATC cells for the first time and provides evidence about the effect of RBX1 on cellular adaptation to metabolic stress.

The spatiotemporal response of China's vegetation greenness to human socio-economic activities.

Climate change and human socioeconomic activities both strongly impact long-term vegetation greenness. It is more a challenge to evaluate the impacts of socioeconomic activities on vegetative greenness than climate change, partially due to the lack of appropriate quantitative indicators of the former. Here we examined the relationship between the remote sensing nighttime light (NTL) data and the Normalized Difference Vegetation Index (NDVI), which in this study are used as the proxies of socioeconomic activities and vegetation greenness, respectively. We first eliminated the vegetation greenness changes in response to climate change and calculated the human-activities-induced NDVI (HNDVI). After explored the spatiotemporal patterns of the HNDVI and NTL data across China from 1998 to 2018, we studied the relationship between the HNDVI and NTL at the grid and county levels, respectively. Our results show that the mean adjusted DN values of the NTL data (NTLI) continuously increase (+0.2938) across our study area from 1998 to 2018, whereas the HNDVI values fluctuate with a general upward trend (+0.0018). Most grids (91.2%) with increased HNDVI were found in rural areas, particularly in the Northeast forest shelterbelt and the Loess Plateau. By contrast, the HNDVI values in rapidly urbanized areas in Chinese major urban agglomerations mainly show a downward trend, especially in the Yangtze River Delta (YRD) urban agglomeration. The relationships between the NTLI and HNDVI are inconsistent over time and across space, which could be attributed to land use conditions, afforestation projects in rural areas, and greening activities in urban areas over different periods and regions.

USP28 facilitates pancreatic cancer progression through activation of Wnt/ß-catenin pathway via stabilising FOXM1.

Ubiquitination is an important post-translational modification that can be reversed by a family of enzymes called deubiquitinating enzymes (DUBs). Ubiquitin-specific protease 28 (USP28), a member of the DUBs family, functions as a potential tumour promoter in various cancers. However, the biological function and clinical significance of USP28 in pancreatic cancer (PC) are still unclear. Here, we showed that PC tumours had higher USP28 expression compared with that of normal pancreatic tissues, and high USP28 level was significantly correlated with malignant phenotype and shorter survival in patients with PC. Overexpression of USP28 accelerated PC cell growth, whereas USP28 knockdown impaired PC cell growth both in vitro and in vivo. Further, we found that USP28 promoted PC cell growth by facilitating cell cycle progression and inhibiting apoptosis. Mechanistically, USP28 deubiquitinated and stabilised FOXM1, a critical mediator of Wnt/ß-catenin signalling. USP28-mediated stabilisation of FOXM1 significantly promoted nucleus ß-catenin trans-activation, which in turn led to the activation of the Wnt/ß-catenin pathway. Finally, restoration of FOXM1 expression abolished the anti-tumour effects of USP28-silencing. Thus, USP28 contributes to PC pathogenesis through enhancing the FOXM1-mediated Wnt/ß-catenin signalling, and could be a potential diagnostic and therapeutic target for PC cases.

The growth of plants and indigenous bacterial community were significantly affected by cadmium contamination in soil-plant system.

Concentrations of heavy metals continue to increase in soil environments as a result of both anthropogenic activities and natural processes. Cadmium (Cd) is one of the most toxic heavy metals and poses health risks to both humans and the ecosystem. Herein, we explore the impacts of Cd on a soil-plant system composed of oilseed rapes (Brassica napus and Brassica juncea) and bacteria. The results showed that Cd accumulation within tissues of two species of oilseed rapes enhanced with increasing concentrations of Cd in soils, and Cd treatment decreased their chlorophyll content and suppressed rapeseeds growth. Meanwhile, Cd stress induced the changes of antioxidative enzymes activities of both B. napus and B. juncea. Response to Cd of bacterial community was similar in soil-two species of oilseed rapes system. The impact of Cd on the bacterial communities of soils was greater than bacterial communities of plants (phyllosphere and endophyte). The α-diversity of bacterial community in soils declined significantly under higher Cd concentration (30 mg/kg). In addition, soil bacterial communities composition and structure were altered in the presence of higher Cd concentration. Meanwhile, the bacterial communities of bulk soils were significantly correlated with Cd, while the variation of rhizosphere soils bacterial communities were markedly correlated with Cd and other environmental factors of both soils and plants. These results suggested that Cd could affect both the growth of plants and the indigenous bacterial community in soil-plant system, which might further change ecosystem functions in soils.

Anti-inflammatory activity of different isolated sites of Chloranthus serratus in complete Freund's adjuvant-induced arthritic rats.

Chloranthus serratus is a traditional Chinese medicine for treating arthritis and bruises. The aim of the present study was to investigate the anti-arthritic activities and possible associated mechanisms of different isolated sites of Chloranthus serratus (DISC) in adjuvant-induced arthritis (AA) rats. The therapeutic effects of the extracts were assessed through changes in body weights, swelling rates, arthritis indexes (AI) and organ indexes. The levels of nitric oxide (NO), malondialdehyde and superoxide dismutase were determined using one-step method, TBA method and hydroxylamine method, respectively; the levels of TNF-α, IL-1ß, IL-6, prostaglandin E2, macrophage inhibitor factor-1, VEGF, immunoglobulin (Ig) G, IgM and IFN-γ in serum were determined using ELISA. Pathological changes and positive expression of VEGF in the ankle joints were investigated using hematoxylin-eosin staining and immunohistochemical staining, respectively. DISC treatment increased the weight gains and thymus indexes, and decreased the swelling rates, spleen indexes and AI in AA rats. The water isolated site (WA) and ethyl acetate isolated site (EA) significantly reversed complete Freund's adjuvant (CFA)-induced changes in the levels of NO, IL-6, TNF-α, IgG and IFN-γ, while the n-butanol isolated site (NB) only reversed the changes in IL-6 and IgG contents. Some changes in the chloroform isolated site group showed the same trend as those in the model group. The extracts relieved synovial hyperplasia, inflammatory cell infiltration and articular surface defects, and reduced the positive expression rate of VEGF in the synovial tissues of the AA rats to varying degrees. The WA exhibited the most marked effects, followed by the EA and NB, indicating that WA had optimal therapeutic effects on CFA-induced arthritic rats, which may be mediated by the oxidative stress and inhibition of inflammatory factors. C. serratus may serve as a potential candidate for the treatment of rheumatoid arthritis.

RING-finger protein 6 enhances c-Myc-mediated Warburg effect by promoting MAD1 degradation to facilitate pancreatic cancer metastasis.

Aerobic glycolysis (the Warburg effect) promotes tumor metastasis; hence, drugs targeting its regulators are being developed. c-Myc, a critical transcription factor that regulates the Warburg effect, is involved in the tumorigenesis of many cancers, including pancreatic cancer (PC). However, the upstream regulating mechanisms of c-Myc in PC are unclear. Herein, we reported that E3 ubiquitin ligase RING-finger protein 6 (RNF6) was upregulated in PC tissues, and an elevated RNF6 level was closely associated with metastasis and poor prognosis in patients with PC. In functional experiments, RNF6 over-expression accelerated the metastatic ability of PC cells, whereas RNF6 knockdown impaired PC cell motility and invasiveness along with metastasis in an orthotopic mouse model. Furthermore, we found that RNF6 promoted PC cell metastasis by enhancing c-Myc-mediated aerobic glycolysis. Mechanistically, RNF6 increased the expression level of c-Myc by catalyzing the ubiquitination of Max-dimerization protein-1 (MAD1), a cellular antagonist of c-Myc. Lastly, RNF6 promoted the degradation of MAD1 via the ubiquitin-proteasome pathway, and this reduction in the MAD1 levels enabled c-Myc to promote the Warburg effect in PC. Our results demonstrate that RNF6 may be a novel biomarker in PC carcinogenesis, thereby indicating that targeting the RNF6/MAD1/c-Myc axis is a potential strategy for PC therapy.

Use of Comparative Transcriptomics Combined With Physiological Analyses to Identify Key Factors Underlying Cadmium Accumulation in Brassica juncea L.

The contamination of soils with cadmium (Cd) has become a serious environmental issue that needs to be addressed. Elucidating the mechanisms underlying Cd accumulation may facilitate the development of plants that accumulate both high and low amounts of Cd. In this study, a combination of phenotypic, physiological, and comparative transcriptomic analyses was performed to investigate the effects of different Cd concentrations (0, 5, 10, 30, 50 mg/kg) on Brassica juncea L. Our results suggest that B. juncea L. seedlings had a degree of tolerance to the 5 mg/kg Cd treatment, whereas higher Cd stress (10-50 mg/kg) could suppress the growth of B. juncea L. seedlings. The contents of soluble protein, as well as MDA (malondialdehyde), were increased, but the activities of CAT (catalase) enzymes and the contents of soluble sugar and chlorophyll were decreased, when B. juncea L. was under 30 and 50 mg/kg Cd treatment. Comparative transcriptomic analysis indicated that XTH18 (xyloglucan endotransglucosylase/hydrolase enzymes), XTH22, and XTH23 were down-regulated, but PME17 (pectin methylesterases) and PME14 were up-regulated, which might contribute to cell wall integrity maintenance. Moreover, the down-regulation of HMA3 (heavy metal ATPase 3) and up-regulation of Nramp3 (natural resistance associated macrophage proteins 3), HMA2 (heavy metal ATPase 2), and Nramp1 (natural resistance associated macrophage proteins 1) might also play roles in reducing Cd toxicity in roots. Taken together, the results of our study may help to elucidate the mechanisms underlying the response of B. juncea L. to various concentrations of Cd.

Vaccinia-related kinase 2 blunts sorafenib's efficacy against hepatocellular carcinoma by disturbing the apoptosis-autophagy balance.

Hepatocellular carcinoma (HCC) is a lethal malignancy with limited treatment options. Sorafenib is the only Food and Drug Administration (FDA)-approved first-line targeted drug for the treatment of advanced HCC. However, its effect on patient survival is limited. Recently, studies have demonstrated that the imbalance between apoptosis and autophagy plays a critical role in chemoresistance, and it is hypothesised that restoring the balance between these processes is a potential treatment strategy for improving chemoresistance in cancer. However, there is currently no evidence supporting this hypothesis. We aimed to investigate if vaccinia-related kinase 2 (VRK2), a serine/threonine protein kinase, confers sorafenib resistance in HCC cells. Here, we found that VRK2 was enriched in sorafenib-resistant HCC cells and patient-derived xenografts. Both in vivo and in vitro evidences showed that VRK2 blunts the efficacy of sorafenib against hepatocellular carcinoma by disturbing the balance between apoptosis and autophagy. Mechanistically, VRK2 promotes the phosphorylation of Bcl-2 by activating JNK1/MAPK8, thereby enhancing the dissociation of Bcl-2 from Beclin-1 and promoting the formation of the Beclin-1-Atg14-Vps34 complex, which facilitates autophagy. Furthermore, VRK2-induced phosphorylation of Bcl-2 promotes the interaction of Bcl-2 with BAX, thereby inhibiting apoptosis. In conclusion, targeting VRK2 for modulation of the balance between autophagy and apoptosis may be a novel strategy for overcoming sorafenib resistance in HCC.

Anti-inflammatory activity of the water extract of Chloranthus serratus roots in LPS-stimulated RAW264.7 cells mediated by the Nrf2/HO-1, MAPK and NF-κB signaling pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Chloranthus serratus is a traditional Chinese medicine for treating arthritis and bruises. AIM OF THE STUDY: To investigate the dose-effect relationship and molecular mechanisms of the water extract of C. serratus roots (WECR) in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. MATERIALS AND METHODS: The cell viability was detected by CCK-8 method. One-step method, DCFH-DA fluorescence probe method and immunofluorescence method were used to detect nitric oxide (NO), reactive oxygen species (ROS) and p65 nuclear transcription, respectively. Interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and prostaglandin E2 (PGE2) were detected by enzyme linked immunosorbent assay. Inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) mRNA were detected by quantitative real-time PCR. Western blotting was taken to determine the contents of the relevant proteins in the nuclear transcription factor E2 related factor 2/heme oxygenase-1 (Nrf2/HO-1), mitogen-activated protein kinases (MAPK) and nuclear factor-kappa B (NF-κB) pathways. RESULTS: The concentrations of 3, 30 and 300 µg/mL were optimized as low, medium and high concentrations of the WECR, respectively, and 1 µg/mL was selected as the optimal concentration of LPS to activate macrophages. The dose of the positive drug dexamethasone was 0.13 mg/mL. The WECR could not only inhibit LPS-induced cell differentiation and the overexpression of NO, IL-6, TNF-α, PGE2 and ROS but also promote the expression of Nrf2 and HO-1, and down-regulate the phosphorylation levels of ERK, JNK, p38 and p65. After the WECR treatment, the expression levels of iNOS and COX-2 mRNA and nuclear translocation of p65 were all inhibited. CONCLUSIONS: The WECR exerts its anti-inflammatory activity by inhibiting the MAPK and NF-κB pathways, activating the Nrf2/HO-1 pathway and down-regulating inflammatory factor levels in a dose-dependent manner.

E3 ubiquitin ligase UBR5 promotes pancreatic cancer growth and aerobic glycolysis by downregulating FBP1 via destabilization of C/EBPα.

Pancreatic cancer is one of the most fatal cancers in humans. While it thrives in a state of malnutrition, the mechanism by which pancreatic cancer cells adapt to metabolic stress through metabolic reprogramming remains unclear. Here, we showed that UBR5, an E3 ubiquitin ligase, was significantly upregulated in pancreatic cancer patient samples compared to the levels in adjacent normal tissues. Levels of UBR5 were closely related to a malignant phenotype and shorter survival among pancreatic cancer patients. Multivariate analyses also revealed that UBR5 overexpression was an independent predictor of poor outcomes among patients with pancreatic cancer. Functional assays revealed that UBR5 contributes to the growth of pancreatic cancer cells by inducing aerobic glycolysis. Furthermore, we demonstrated that UBR5 knockdown increased levels of fructose-1,6-bisphosphatase (FBP1), an important negative regulator in the process of aerobic glycolysis in many cancers. We found a significant negative correlation between levels of UBR5 and FBP1, further demonstrating that UBR5-induced aerobic glycolysis is dependent on FBP1 in pancreatic cancer cells. Mechanistically, UBR5 regulates FBP1 expression by modulating C/EBPα, directly binding to C/EBPα, and promoting its ubiquitination and degradation. Together, these results identify a mechanism used by pancreatic cancer cells to survive the nutrient-poor tumour microenvironment and also provide insight regarding the role of UBR5 in pancreatic cancer cell adaptation to metabolic stresses.

FAT10 promotes the progression of bladder cancer by upregulating HK2 through the EGFR/AKT pathway.

The ubiquitin-like protein FAT10 and the hexokinase protein HK2 play vital regulatory roles in several cellular processes. However, the relationship between these two proteins and their role in the pathogenesis of bladder cancer are not well understood. Here, we found that FAT10 and HK2 protein levels were markedly higher in bladder cancer tissues than in normal adjacent tissues. In addition, RNAi-mediated silencing of FAT10 led to reduced HK2 levels and suppressed bladder cancer progression in vivo and in vitro. The results of our in vivo and in vitro experiments revealed that HK2 is critical for FAT10-mediated progression of bladder cancer. The current study demonstrated that FAT10 enhanced the progression of bladder cancer by positively regulating HK2 via the EGFR/AKT pathway. Based on our findings, FAT10 is believed to stabilize EGFR expression by modulating its degradation and ubiquitination. The results of the current study indicate that there is a correlation between FAT10 and HK2 in the progression of bladder cancer. In addition, we identified a new pathway that may be involved in the regulation of HK2. These findings implicate dysfunction of the FAT10, EGFR/AKT, and HK2 regulatory circuit in the progression of bladder cancer.

Mapping the exposure and sensitivity to heat wave events in China's megacities.

The rising temperature makes the weather becoming more extreme. Understanding how extreme hot temperature-heat wave events (HWEs)-are likely to alter individual heat exposure and sensitivity is crucial for developing climate change mitigation and adaptation strategies. Despite the importance, little is known about the real-time impacts of HWEs on individual daily life in developing nations, like China. To fill this gap, we adopt over 1544 thousand Weibo (Chinese Twitter) social media data, coupled with meteorological conditions people face when posting, to assess the heat exposure and people's sensitivity to HWEs across 31 mega-cities in China. The results show the hotspot of Weibo heat is coincident with the extremely hot temperature, with a correlation of 0.7 (p < 0.05). The intensities, frequencies, and durations of HWEs in both geographical and social media space have high spatial heterogeneity. Its spatial variation can be explained by the type of climate zone and the unique geographical environment. The cities with extreme hot weather are more likely to adapt to the heatwave and less sensitivity to HWEs. The proposed framework, which integrates the real-time social media semantic analysis, statistical method, and spatial techniques, provides a new paradigm to assess the HWEs exposure and sensitivity analysis in China.

Oxidative stress-mediated hepatotoxicity in rats induced by ethanol extracts of different parts of Chloranthus serratus.

CONTEXT: Chloranthus serratus (Thunb.) Roem. et Schult. (Chloranthaceae) is an herb widely used as a folk medicine treating inflammatory diseases, although it is toxic. OBJECTIVE: To investigate hepatotoxicity and related mechanisms induced by ethanol extracts of different parts of C. serratus in rats. MATERIALS AND METHODS: Sprague Dawley rats were divided into control (Con), ethanol extract of roots (ER), stems (ES), and leaves (EL) groups, and acute oral toxicity studies were conducted. The rats received doses of 4.14, 3.20, and 1.16 g/kg/d extracts for 14 days, respectively. Liver index, liver function and oxidative stress biomarkers, liver pathology, ultrastructure, TNF-α, ICAM-1, and Nrf2/HO-1 proteins expression levels were determined. RESULTS: The LD50 of ER, ES, and EL were higher than 10.35, 8.05, and 2.90 g/kg/p.o., respectively. The liver indexes in the extract groups increased significantly. EL dramatically increased TP, GLB, AST, ALT, ALP, TBA, MDA, ICAM-1, and TNF-α levels (p < 0.01), and induced the most obvious pathological and ultrastructural changes. ES and EL obviously decreased the T-SOD, GSH, CAT, and CHOL levels. Nrf2 and HO-1 proteins expression was reduced significantly in ES (0.77 ± 0.06, 2.33 ± 0.20) and EL (0.23 ± 0.04, 2.14 ± 0.16) groups, and reduced slightly in ER (1.08 ± 0.10; 3.39 ± 0.21) group. DISCUSSION AND CONCLUSION: ES and EL induce stronger hepatotoxicity than ER through oxidative stress and the Nrf2/HO-1 pathway, and the root is a better medicinal part, which provides a basis for clinical research, safe applications, and reasonable development of C. serratus.

Anti-inflammatory effects of the root, stem and leaf extracts of Chloranthus serratus on adjuvant-induced arthritis in rats.

Context: Chloranthus serratus [(Thunb.) Roem. et Schult, (Chloranthaceae)] is a folk medicine used for the treatment of rheumatoid arthritis.Objective: The aim of this study was to investigate anti-arthritic effects of the ethanol extracts of the roots (ER), stems (ES) and leaves (EL) of C. serratus on adjuvant arthritis rats and related mechanisms.Materials and methods: The rats were immunized by intradermal injection of complete Freund's adjuvant (CFA, 0.18 mL) into the right hind feet, and received intragastric administrations of the ER, ES and EL (2.07, 1.61 and 0.58 g/kg/d, respectively) for 14 days. The anti-arthritic activity was assessed by swelling rates, serum indicators, antioxidant capacity, histopathological and immunohistochemical analyses.Results: The LD50 of the ER, ES and EL was higher than 10.35, 8.05 and 2.90 g/kg/p.o., respectively. Extract treatments decreased swelling rates, tumour necrosis factor-alpha (TNF-α), vascular endothelial growth factor (VEGF), interleukin 1 beta (IL-1ß), migration inhibitory factor 1 (MIF-1), immunoglobulin G (IgG) and immunoglobulin M (IgM) levels and positive expression of VEGF in the arthritic rats (p < 0.01 or p < 0.05). The ER significantly decreased NO (3.91 ± 0.61 µmol/L), IL-6 (75.67 ± 16.83 pg/mL) and malondialdehyde (MDA) (2.28 ± 0.32 nmol/mL) contents and clearly increased IFN-γ (2082 ± 220.93 pg/mL) and superoxide dismutase (SOD) (601.98 ± 38.40 U/mL) levels. The ES and EL did not reverse the changes in some indicators. All the extracts alleviated inflammatory cell infiltration and synovial cell proliferation. Among them, the ER was the most pronounced.Discussion and conclusions: ER exerts the most promising effects, as shown by inhibiting the releases of inflammatory cytokines and enhancing antioxidant capacity, which provides a scientific basis for further research on C. serratus and its clinical applications.

ROCK2 mediates osteosarcoma progression and TRAIL resistance by modulating O-GlcNAc transferase degradation.

Osteosarcoma is a common bone tumor, with a poor prognosis. New combinatorial therapies that sensitize anticancer drug-resistant osteosarcoma cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) are, therefore, required. The GTPase RhoA effector, Rho-associated coiled-coil forming protein kinase 2 (ROCK2), is well known for its roles in various types of cancer; however, its involvement osteosarcoma has not yet been scrutinized. In this study, we analyzed ROCK2 expression, clinicopathological features, and prognosis in osteosarcoma patients. Apoptosis, colony formation, and cell proliferation were analyzed using flow cytometry, colony formation assays, and CCK8 assays, respectively. Proteomics analysis was used to evaluate osteosarcoma progression. We found that adjacent tissues had lower ROCK2 expression levels than osteosarcoma tissues and the level of expression was related to osteosarcoma tumor size and prognosis. Osteosarcoma prognosis was associated with ROCK2 expression level, which served as an independent marker in multivariate analysis. ROCK2 silencing inhibited proliferation in vivo and in vitro and triggered apoptotic osteosarcoma cell death. ROCK2 inhibited the TRAIL-mediated apoptotic pathway in osteosarcoma cells and promoted activation. Mechanistically, ROCK2 affected osteosarcoma progression and TRAIL resistance by modifying O-GlcNAcylation through O-GlcNAc transferase degradation. Taken together, our results demonstrated a unique mechanism whereby ROCK2 influences osteosarcoma progression and TRAIL resistance, hence improving osteosarcoma management.