Recent anthropogenic curtailing of Yellow River runoff and sediment load is unprecedented over the past 500 y.

The Yellow River (YR) is the fifth-longest and the most sediment-laden river in the world. Frequent historical YR flooding events, however, have resulted in tremendous loss of life and property, whereas in recent decades YR runoff and sediment load have fallen sharply. To put these recent changes in a longer-term context, we reconstructed natural runoff for the middle reach of the YR back to 1492 CE using a network of 31 moisture-sensitive tree-ring width chronologies. Prior to anthropogenic interference that started in the 1960s, the lowest natural runoff over the past 500 y occurred during 1926 to 1932 CE, a drought period that can serve as a benchmark for future planning of YR water allocation. Since the late 1980s, the low observed YR runoff has exceeded the natural range of runoff variability, a consequence of the combination of decreasing precipitation and increasing water consumption by direct and indirect human activities, particularly agricultural irrigation. This reduced runoff has resulted in an estimated 58% reduction of the sediment load in the upper reach of the YR and 29% reduction in the middle reach.

Maximum July-August temperatures for the middle of the southern Tien Shan inferred from tree-ring latewood maximum densities.

Long-term temperature reconstructions are urgently needed to prolong meteorological climatic data, which are too short to evaluate the anthropogenic effect on climate change since the Industrial Revolution. The maximum latewood chronology (MXD) of Picea schrenkiana in the middle of the southern Tien Shan was established, and it showed a strong correlation with the mean maximum temperature of the current July to August (TmaxJA), with r = 0.773 (p < 0.001, 1959-2016), which implies that a high temperature in the late growing season could increase the cell wall thickness and lead to high latewood density. Then, the TmaxJA of the middle of the southern Tien Shan was reconstructed over the period of 1720-2018. Three MXD chronologies from Kyrgyzstan significantly correlated with our TmaxJA reconstruction at the interannual scale, and they also showed similar variations on decadal scales. None of these MXD series showed a warming trend in the past century, which was also found in several MXD series from different regions of the world. Spatial correlation analysis revealed that our TmaxJA reconstruction showed significant correlations with that in eastern Asia, southern Europe, and north-western Africa, forming a teleconnection called the Silk Road Pattern. However, moving correlation analysis between our TmaxJA reconstruction and Hokkaido temperature series indicated that this teleconnection was unstable in the past 3 centuries. The volcanic eruptions from the mid-high latitudes in the Northern Hemisphere showed a stronger cooling effect than those from the Southern Hemisphere and the low latitudes of the Northern Hemisphere. The summer North Atlantic Oscillation was also shown to affect the temperature in the Tien Shan to a certain extent.

Clitocine potentiates TRAIL-mediated apoptosis in human colon cancer cells by promoting Mcl-1 degradation.

Among anti-cancer candidate drugs, TRAIL might be the most specific agent against cancer cells due to its low toxicity to normal cells. Unfortunately, cancer cells usually develop drug resistance to TRAIL, which is a major obstacle for its clinical application. One promising strategy is co-administrating with sensitizer to overcome cancer cells resistance to TRAIL. Clitocine, a natural amino nucleoside purified from wild mushroom, is recently demonstrated that can induce apoptosis in multidrug-resistant human cancer cells by targeting Mcl-1. In the present study,we found that pretreatment with clitocine dramatically enhances TRAIL lethality in its resistant human colon cancer cells by inducing apoptosis. More importantly, combination of clitocine and TRAIL also effectively inhibits xenograft growth and induces tumor cells apoptosis in athymic mice. The disruption of the binding between Mcl-1 and Bak as well as mitochondrial translocation of Bax mediated by clitocine are identified as the key underlying mechanisms, which leading to mitochondrial membrane permeabilization. Enforced exogenous Mcl-1 can effectively attenuate clitocine/TRAIL-induced apoptosis by suppressing the activation of intrinsic apoptotic pathway. Furthermore, clitocine regulates Mcl-1 expression at the posttranslational level as no obvious change is observed on mRNA level and proteasome inhibitor MG132 almost blocks the Mcl-1 suppression by clitocine. In fact, more ubiquitinated Mcl-1 was detected under clitocine treatment. Our findings indicate that clitocine is potentially an effective adjuvant agent in TRAIL-based cancer therapy.

Clitocine targets Mcl-1 to induce drug-resistant human cancer cell apoptosis in vitro and tumor growth inhibition in vivo.

Drug resistance is a major reason for therapy failure in cancer. Clitocine is a natural amino nucleoside isolated from mushroom and has been shown to inhibit cancer cell proliferation in vitro. In this study, we observed that clitocine can effectively induce drug-resistant human cancer cell apoptosis in vitro and inhibit tumor xenograft growth in vivo. Clitocine treatment inhibited drug-resistant human cancer cell growth in vitro in a dose- and time-dependent manner. Biochemical analysis revealed that clitocine-induced tumor growth inhibition is associated with activation of caspases 3, 8 and 9, PARP cleavage, cytochrome c release and Bax, Bak activation, suggesting that clitocine inhibits drug-resistant cancer cell growth through induction of apoptosis. Analysis of apoptosis regulatory genes indicated that Mcl-1 level was dramatically decreased after clitocine treatment. Over-expression of Mcl-1 reversed the activation of Bax and attenuated clitocine-induced apoptosis, suggesting that clitocine-induced apoptosis was at least partially by inducing Mcl-1 degradation to release Bax and Bak. Consistent with induction of apoptosis in vitro, clitocine significantly suppressed the drug-resistant hepatocellular carcinoma xenograft growth in vivo by inducing apoptosis as well as inhibiting cell proliferation. Taken together, our data demonstrated that clitocine is a potent Mcl-1 inhibitor that can effectively induce apoptosis to suppress drug-resistant human cancer cell growth both in vitro and in vivo, and thus holds great promise for further development as potentially a novel therapeutic agent to overcome drug resistance in cancer therapy.

Analysis of alkaline phosphatase and γ-glutamyltransferase after radiofrequency ablation of primary liver cancer: A retrospective study.

BACKGROUND: Changes in alkaline phosphatase (ALP) and γ-glutamyltransferase (GGT) levels in patients with primary liver cancer (PLC) after radiofrequency ablation (RFA). Hepatocellular carcinoma is a malignant tumor with high incidence worldwide. As a common local treatment, RFA has attracted much attention for its efficacy and influence on liver function. AIM: To investigate the effect of serum ALP and GGT levels on the prognosis of patients with PLC treated by RFA. METHODS: The preoperative clinical data of 165 patients who were pathologically or clinically diagnosed with PLC and who received RFA in our hospital between October 2018 and June 2023 were collected. The chi-square test was used to compare the data between groups. The Kaplan-Meier method and Cox regression were used to analyze the associations between serum ALP and GGT levels and overall survival, progression-free survival (PFS) and clinical characteristics of patients before treatment. RESULTS: The 1-year survival rates of patients with normal (≤ 135 U/L) and abnormal (> 135 U/L) serum ALP before treatment were 91% and 79%, respectively; the 2-year survival rates were 90% and 68%, respectively; and the 5-year survival rates were 35% and 18%, respectively. The difference between the two groups was statistically significant (P = 0.01). Before treatment, the 1-year survival rates of patients with normal serum GGT levels (≤ 45 U/L) and abnormal serum GGT levels (> 45 U/L) were 95% and 87%, the 2-year survival rates were 85% and 71%, and the 5-year survival rates were 37% and 21%, respectively. The difference between the two groups was statistically significant (P < 0.001). Serum ALP [hazard ratio (HR) = 1.766, 95% confidence interval (95%CI): 1.068-2.921, P = 0.027] and GGT (HR = 2. 312, 95%CI: 1.367-3.912, P = 0.002) is closely related to the overall survival of PLC patients after RF ablation and is an independent prognostic factor. The 1-year PFS rates were 72% and 50%, the 2-year PFS rates were 52% and 21%, and the 5-year PFS rates were 14% and 3%, respectively. The difference between the two groups was statistically significant (P < 0001). The 1-year PFS rates were 81% and 56% in patients with normal and abnormal serum GGT levels before treatment, respectively; the 2-year PFS rates were 62% and 35%, respectively; and the 5-year PFS rates were 18% and 7%, respectively, with statistical significance between the two groups (P < 0.001). The serum ALP concentration (HR = 1. 653, 95%CI: 1.001-2.729, P = 0.049) and GGT (HR = 1.949, 95%CI: 1.296-2.930, P = 0.001) was closely associated with PFS after RFA in patients with PLC. The proportion of male patients with abnormal ALP levels is high, the Child-Pugh grade of liver function is poor, and the incidence of ascites is high. Among GGT-abnormal patients, the Child-Pugh grade of liver function was poor, the tumor stage was late, the proportion of patients with tumors ≥ 5 cm was high, and the incidence of hepatic encephalopathy was high. CONCLUSION: Serum ALP and GGT levels before treatment can be used to predict the prognosis of patients with PLC after RFA, and they have certain guiding significance for the long-term survival of patients with PLC after radiofrequency therapy.

Erratum to: Verticillin A inhibits colon cancer cell migration and invasion by targeting c-Met.

The online version of the original article can be found at https://doi.org/10.1631/jzus.B2000190 Erratum to: J Zhejiang Univ-Sci B (Biomed & Biotechnol) 2020 21(10):779-795 https://doi.org/10.1631/jzus.B2000190.

Cytotoxic Effect of Graphene Oxide Nanoribbons on Escherichia coli.

The biological and environmental toxicity of graphene and graphene derivatives have attracted great research interest due to their increasing applications. However, the cytotoxic mechanism is poorly understood. Here, we investigated the cytotoxic effect of graphene oxide nanoribbons (GORs) on Escherichia coli (E. coli) in an in vitro method. The fabricated GORs formed long ribbons, 200 nm wide. Based on the results of the MTT assay and plate-culture experiments, GORs significantly inhibited the growth and reproduction of E. coli in a concentration-dependent manner. We found that GORs stimulated E. coli to secrete reactive oxygen species, which then oxidized and damaged the bacterial cell membrane. Moreover, interaction between GORs and E. coli cytomembrane resulted in polysaccharide adsorption by GORs and the release of lactic dehydrogenase. Furthermore, GORs effectively depleted the metal ions as nutrients in the culture medium by adsorption. Notably, mechanical cutting by GORs was not obvious, which is quite different from the case of graphene oxide sheets to E. coli.

Verticillin A inhibits colon cancer cell migration and invasion by targeting c-Met.

Verticillin A is a diketopiperazine compound which was previously isolated from Amanita flavorubescens Alk (containing parasitic fungi Hypomyces hyalines (Schw.) Tul.). Here, we initially found, by wound healing assay and Transwell assay in vitro, that verticillin A possesses an inhibitory effect against the migration and invasion of the human colon cancer cell. Subsequently, c-mesenchymal-epithelial transition factor (c-Met) was identified as a molecular target of verticillin A by screening key genes related to cell migration. Verticillin A-mediated c-Met suppression is at the transcriptional level. Further study demonstrated that verticillin A suppressed c-MET phosphorylation and decreased c-MET protein level. In addition, verticillin A inhibited the phosphorylation of c-MET downstream molecules including rat sarcoma (Ras)-associated factor (Raf), extracellular signal-regulated kinase (ERK), and protein kinase B (AKT). Overexpression of Erk partially reversed the verticillin A-mediated anti-metastasis action in the human colon cancer cell. More importantly, verticillin A also inhibited cancer cell metastasis in vivo. Thus, verticillin A can significantly inhibit the migration and invasion of colon cancer cells by targeting c-Met and inhibiting Ras/Raf/mitogen-activated extracellular signal-regulated kinase (MEK)/ERK signaling pathways. Therefore, we determined that verticillin A is a natural compound that can be further developed as an anti-metastatic drug in human cancers.

Imperatorin induces Mcl-1 degradation to cooperatively trigger Bax translocation and Bak activation to suppress drug-resistant human hepatoma.

Imperatorin is a small molecule nature compound isolated from the root of Angelica dahurica, and has been shown to exhibit multiple bioeffector functions, including anti-cancer activity. However, the molecular mechanism underlying imperatorin in suppression of tumor growth is unknown. In this study, we aimed at elucidating the molecular mechanisms underlying imperatorin function and determining the efficacy of imperatorin in suppression of drug-resistant human liver cancer. We observed that imperatorin suppresses tumor cell growth through inducing apoptosis, and imperatorin is more effective in induction of multidrug-resistant human liver cancer cells in vitro. We further determined that imperatorin induces apoptosis through both extrinsic and intrinsic apoptosis pathway. At the molecular level, we identified Mcl-1 as the molecular target of imperatorin and determined that imperatorin induces proteosome-dependent Mcl-1 degradation to release Bak and Bax to trigger apoptosis in liver cancer cells. Consistent with its in vitro apoptosis induction activity, imperatorin exhibited potent activity against multidrug-resistant liver cancer xenograft growth in vivo. Taken together, we determined that imperatorin is a Mcl-1 degradation inducer that can effectively suppress multidrug-resistant human liver cancer growth in vivo, and thus holds great promise for development as an effective small molecule anti-cancer agent in human liver cancer therapy to overcome drug resistance.

Clitocine induces apoptosis and enhances the lethality of ABT-737 in human colon cancer cells by disrupting the interaction of Mcl-1 and Bak.

ABT-737 is a novel anti-apoptotic Bcl-2 family protein inhibitor with high affinity to Bcl-2, Bcl-xl and Bcl-w but relatively low affinity to Mcl-1/A1. Therefore, high level Mcl-1 usually confers human tumor cell resistance to ABT-737. At the present study, we observed that clitocine can induce apoptosis in six tested human colon cancer cell lines accompanied by suppression of Mcl-1. More interestingly, clitocine significantly enhances the ABT-737-mediated lethality by inducing apoptosis. At the molecular level we determined Mcl-1 is the potential target through which clitocine can sensitize human colon cancer cells to ABT-737 induced apoptosis. Knocking-down of Mcl-1 is sufficient to increase cancer cell susceptibility to ABT-737 while its over-expression can significantly reverse this susceptibility. We also determined that clitocine may activate Bak by disrupting the interaction between Mcl-1 and Bak to induce mitochondrial membrane permeabilization. Furthermore, silence of Bak with the specific siRNA effectively attenuates the apoptosis induction by co-treatment of clitocine and ABT-737. Finally, clitocine in combination with ABT-737 significantly suppress the xenograft growth in animal model. Collectively, our studies suggest clitocine can induce apoptosis and potentiate ABT-737 lethality in human colon cancer cells by disrupting the interaction of Mcl-1 and Bak to trigger apoptosis.