Ribosomal protein S3 mediates drug resistance of proteasome inhibitor: potential therapeutic application in multiple myeloma.

Multiple myeloma (MM) remains incurable due to drug resistance. Ribosomal protein S3 (RPS3) has been identified as a non-Rel subunit of NF-κB. However, the detailed biological roles of RPS3 remain unclear. Here, we report for the first time that RPS3 is necessary for MM survival and drug resistance. RPS3 was highly expressed in MM, and knockout of RPS3 in MM inhibited cell growth and induced cell apoptosis both in vitro and in vivo. Overexpression of RPS3 mediated the proteasome inhibitor resistance of MM and shortened the survival of MM tumor-bearing animals. Moreover, our present study found an interaction between RPS3 and the thyroid hormone receptor interactor 13 (TRIP13), an oncogene related to MM tumorigenesis and drug resistance. We demonstrated that the phosphorylation of RPS3 was mediated by TRIP13 via PKCδ, which played an important role in activating the canonical NF-κB signaling and inducing cell survival and drug resistance in MM. Notably, the inhibition of NF-κB signaling by the small-molecule inhibitor targeting TRIP13, DCZ0415, was capable of triggering synergistic cytotoxicity when combined with bortezomib in drug-resistant MM. This study identifies RPS3 as a novel biomarker and therapeutic target in MM.

Design and synthesis of cantharidin derivative DCZ5418 as a TRIP13 inhibitor with anti-multiple myeloma activity in vitro and in vivo.

Natural product cantharidin can inhibit multiple myeloma cell growth in vitro, while serious adverse effects limited its clinical application. Therefore, the structural modification of cantharidin is needed. Herein, inspired by the structural similarity of the aliphatic endocyclic moiety in cantharidin and TRIP13 inhibitor DCZ0415, we designed and synthesized DCZ5418 and its nineteen derivatives. The molecular docking study indicated that DCZ5418 had a similar binding mode to TRIP13 protein as DCZ0415 while with a stronger docking score. Moreover, the bioassay studies of the MM-cells viability inhibition, TRIP13 protein binding affinity and enzyme inhibiting activity showed that DCZ5418 had good anti-MM activity in vitro and definite interaction with TRIP13 protein. The acute toxicity test of DCZ5418 showed less toxicity in vivo than cantharidin. Furthermore, DCZ5418 showed good anti-MM effects in vivo with a lower dose administration than DCZ0415 (15 mg/kg vs 25 mg/kg) on the tumor xenograft models. Thus, we obtained a new TRIP13 inhibitor DCZ5418 with improved safety and good activity in vivo, which provides a new example of lead optimization by using the structural fragments of natural products.

Carbon flux dynamics and influencing factors in a semi-arid dune ecosystem of northern China.

The dune ecosystem plays a significant role in the global carbon cycle. The Horqin Sandy Land is a typical semi-arid fragile ecosystem in northern China. Understanding the magnitudes and dynamics of carbon dioxide fluxes within this region is essential for understanding the carbon balance. Used 6 years (2013-2018) measurements from an eddy-covariance system, we analyzed the dynamic patterns of net ecosystem carbon exchange (NEE), gross primary production (GPP), and ecosystem respiration (Reco) of the dune ecosystem in Horqin Sandy Land and examined their responses to climate factors with a focus on the precipitation. The results showed that the NEE of the dune ecosystem fluctuated from -166 to 100 gCO2·m-2·year-1 across the 6 growing seasons, with an average of -56 gCO2·m-2·year-1. The precipitation was not a key factor influencing the carbon flux variability. During the mid-growth stage, GPP was primarily affected by the effective precipitation frequency (R2 ranging from 0.65 to 0.85, P < 0.05), followed by fractional vegetation cover (R2 ranging from 0.65 to 0.68, P < 0.05). However, in the early and late growth stages, temperature predominantly drove the carbon flux (R2 = 0.75, P < 0.01). The interannual variability of carbon flux can be predominantly elucidated by phenological indicators such as CO2 uptake (CUstart), end of CO2 uptake (CUend), CO2 uptake period (CUP), and Spring lag. The results demonstrated the dune ecosystem is a weak carbon sink in semi-arid ecosystems. Furthermore, we emphasized the significance of effective precipitation frequency in regulating carbon fluxes. Our results provide a foundational understanding of the carbon balance in semi-arid ecosystems.

Dihydrocelastrol induces antitumor activity and enhances the sensitivity of bortezomib in resistant multiple myeloma by inhibiting STAT3-dependent PSMB5 regulation.

Multiple myeloma (MM) is characterized by excessive aggregation of B-cell-derived malignant plasma cells in the hematopoietic system of bone marrow. Previously, we synthesized an innovative molecule named dihydrocelastrol (DHCE) from celastrol, a triterpene purified from medicinal plant Tripterygium wilfordii. Herein, we explore the therapeutic properties and latent signal transduction mechanism of DHCE action in bortezomib (BTZ)-resistant (BTZ-R) MM cells. In this study, we first report that DHCE shows antitumor activities in vitro and in vivo and exerts stronger inhibitory effects than celastrol on BTZ-R cells. We find that DHCE inhibits BTZ-R cell viability by promoting apoptosis via extrinsic and intrinsic pathways and suppresses BTZ-R MM cell proliferation by inducing G0/G1 phase cell cycle arrest. In addition, inactivation of JAK2/STAT3 and PI3K/Akt pathways are involved in the DHCE-mediated antitumor effect. Simultaneously, DHCE acts synergistically with BTZ on BTZ-R cells. PSMB5, a molecular target of BTZ, is overexpressed in BTZ-R MM cells compared with BTZ-S MM cells and is demonstrated to be a target of STAT3. Moreover, DHCE downregulates PSMB5 overexpression in BTZ-R MM cells, which illustrates that DHCE overcomes BTZ resistance through increasing the sensitivity of BTZ in resistant MM via inhibiting STAT3-dependent PSMB5 regulation. Overall, our findings imply that DHCE may become a potential therapeutic option that warrants clinical evaluation for BTZ-R MM.

Soluble uric acid induces myocardial damage through activating the NLRP3 inflammasome.

Uric acid crystal is known to activate the NLRP3 inflammasome and to cause tissue damages, which can result in many diseases, such as gout, chronic renal injury and myocardial damage. Meanwhile, soluble uric acid (sUA), before forming crystals, is also related to these diseases. This study was carried out to investigate whether sUA could also activate NLRP3 inflammasome in cardiomyocytes and to analyse the mechanisms. The cardiomyocyte activity was monitored, along with the levels of mature IL-1ß and caspase-1 from H9c2 cells following sUA stimulus. We found that sUA was able to activate NLRP3 inflammasome, which was responsible for H9c2 cell apoptosis induced by sUA. By elevating TLR6 levels and then activating NF-κB/p65 signal pathway, sUA promoted NLRP3, pro-caspase 1 and pro-IL-1ß production and provided the first signal of NLRP3 inflammasome activation. Meanwhile, ROS production regulated by UCP2 levels also contributed to NLRP3 inflammasome assembly and subsequent caspase 1 activation and mature IL-1ß secretion. In addition, the tlr6 knockdown rats suffering from hyperuricemia showed the lower level of IL-1ß and an ameliorative cardiac function. These findings suggest that sUA activates NLRP3 inflammasome in cardiomyocytes and they may provide one therapeutic strategy for myocardial damage induced by sUA.

[Soluble Uric Acid Activates NLRP3 Inflammasome in Myocardial Cells Through Down-regulating UCP2].

OBJECTIVE: To determine the H9C2 cell damage and NLRP3 inflammasome activation trigged by soluble uric acid (UA). METHODS: H9C2 cells were treated with UA. The cellular damage was examined after 12 h, 24 h and 48 h of treatment using MTS and lactic dehydrogenase (LDH). The apoptosis of H9C2 cells was analyzed by flow cytometry (FCM). NLRP3 inflammasome activation was reflected by the protein levels of NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC) and Caspase-1 detected by Western blot. The mitochondria and cytoplasm were separated and the release of cytochrome C was detected by Western blot to analyze the damage of mitochondria. The impacts of NAC, a ROS inhibitor, on the cell viability and NLRP3 inflammasome activation were analyzed. The expression of UCP2 was detected by Western blot and immunofluorescence (IF). RESULTS: Dose response and time dependent effects of UA on cellular damage and cell apoptosis was observed. UA up-regulated the expression of NLRP3 inflammasome-related molecules. UA damaged the mitochondria. NAC improved the cell viability and inhibited NLRP3 inflammasome activation. UA down-regulated the expression of UCP2. CONCLUSION: Soluble UA can down-regulate the expression of UCP2, damage the mitochondria and activate NLRP3 inflammasome, resulting in cellular damage of H9C2 cells.

TI17, a novel compound, exerts anti-MM activity by impairing Trip13 function of DSBs repair and enhancing DNA damage.

BACKGROUND: Thyroid hormone receptor interacting protein 13 (Trip13) is an AAA-ATPase that regulates the assembly or disassembly protein complexes and mediates Double-strand breaks (DSBs) repair. Overexpression of Trip13 has been detected in many cancers and is associated with myeloma progression, disease relapse and poor prognosis inmultiple myeloma (MM). METHODS: We have identified a small molecular, TI17, through a parallel compound-centric approach, which specifically targets Trip13. To identify whether TI17 targeted Trip13, pull-down and nuclear magnetic resonance spectroscopy (NMR) assays were performed. Cell counting kit-8, clone formation, apoptosis and cell cycle assays were applied to investigate the effects of TI17. We also utilized a mouse model to investigate the effects of TI17 in vivo. RESULTS: TI17 effectively inhibited the proliferation of MM cells, and induced the cycle arrest and apoptosis of MM cells. Furthermore, treatment with TI17 abrogates tumor growth and has no apparent side effects in mouse xenograft models. TI17 specifically impaired Trip13 function of DSBs repair and enhanced DNA damage responses in MM. Combining with melphalan or HDAC inhibitor panobinostat triggers synergistic anti-MM effect. CONCLUSIONS: Our study suggests that TI17 could be acted as a specific inhibitor of Trip13 and supports a preclinical proof of concept for therapeutic targeting of Trip13 in MM.

Berberine derivative DCZ0358 induce oxidative damage by ROS-mediated JNK signaling in DLBCL cells.

The most common neoplasm among adult lymphomas is diffuse large B-cell lymphoma (DLBCL), typically characterized by pain-free and progressive lymph node enlargement. Due to high heterogeneity of DLBCL, 30-40 % of patients are resistant to R-CHOP standard chemoimmunotherapy. DCZ0358 is a new compound designed and synthesized from berberine by our group and the molecular mechanism by which it inhibited DLBCL growth has attracted our widespread attention. In this study, we employed the CCK8 assay to reveal that DCZ0358 inhibited proliferation in a dependent manner of time and dosage of DLBCL cells. Moreover, flowcytometry and western blot results showed that DCZ0358 downregulated the expression of CDK4, CDK6 and CyclinD1 to block cell cycle progression in G0/G1 phase. Furthermore, DCZ0358 enhanced mitochondrial membrane potential depolarization, promoted mitochondrial permeability transport pore openness, increased cytoplastic Ca2+ levels and decreased intracellular adenosine triphosphate production, which led to mitochondrial dysfunction. In particular, DCZ0358 treatment triggered cell apoptosis and elevated intracellular reactive oxygen species (ROS) levels, which subsequently mediated JNK pathway activation. Further research indicated the pre-treatment with ROS scavenger N-acetylcysteine (NAC) and JNK inhibitor SP600125 could partially attenuate apoptosis and DNA damage triggered by DCZ0358. Most importantly, DCZ0358 exhibited synergistic anti-tumor effects when combined with etoposide, a common clinical anti-DLBCL drug, both in vitro and certainly in vivo. Above results demonstrated anti-tumor molecular mechanism of DCZ0358 in DLBCL cells and highlighted the ROS/JNK/DNA damage pathway as a potential target in therapies, which have implications for the development of more effective clinical treatments for DLBCL.

[Characteristics of humidity and temperature variations and CO2 exchange of mobile dunes at different space-time scales in Horqin sandy land, China].

Terrestrial carbon cycle plays a key role in driving climate change and ecosystem carbon balance. Understanding the variations of humidity and temperature and CO2 exchanges are meaningful to reveal the law and mechanism of regional carbon cycles in deserts. We examined the near surface humidity, temperature variations, and CO2 exchanges by eddy covariance and Bowen ratio systems in a typical mobile dune of Horqin sandy land. We analyzed the relationships between water-heat and CO2 exchanges of 0 to 10 m vertical height at daily and seasonal scales were analyzed. The results showed that the vertical variations of near surface temperature ranged from 0.4 ℃ to 2 ℃ and decreased with the increases of height from April to September, but with an opposite pattern in other months. The seasonal variation of air relative humidity was greater than 40%. During the growing season of 2018, the averaged daily net ecosystem carbon exchange (NEE) was -0.02 mg·m-2·s-1. The annual averaged daily NEE was 0.003 mg·m-2·s-1, indicating that the mobile dunes were carbon sources at the whole year scale. The vertical differences of temperature and humidity well fitted the NEE. The inflexion points of the fitting curve were at 10% humidity and 0.5 ℃ temperature, respectively. At the scalem of the year, the NEE fitting result of temperature was better than that of humidity, with the inflexion points at 17 ℃ and 65% humidity, respectively. In the growing season, the near surface vertical temperature difference was negative, which would inhibit CO2 absorption of mobile dunes. The circumstances of high humidity would promote the absorption of atmospheric CO2. Across different time and vertical height, the variations of humidity and temperature were closely related to CO2 exchanges, which affected carbon sink and source of mobile dunes. Carbon budget was more sensitive to temperature than humidity.

[Deep water leakage from semi-mobile dunes in semi-arid regions and its response to rainfall patterns]. / åŠå¹²æ—±åœ°åŒºåŠæµåŠ¨æ²™ä¸˜æ°´åˆ†æ·±å±‚æ¸—æ¼é‡åŠå ¶å¯¹é™é›¨æ ¼å±€çš„å“åº”.

As the main source of soil moisture supply in desertified areas, rainfall has a profound impact on soil moisture changes and plays an important role in deep soil moisture replenishment. Based on the Hydrus-1D model with optimized parameters, we analyzed the dynamic change process of the leakage in the 200 cm deep layer of the semi-mobile dunes in Horqin Sandy Land and its response to the rainfall patterns. The results showed that the averaged leakage replenishment of semi-mobile dunes was 254.31 mm from April to October each year during 2016 to 2019, accoun-ting for 61.8% of the rainfall in the same period. Deep leakage mainly occurred from June to August, accounting for 72.8% of the total. The leakage rate was distributed between 0.03-2.70 mm·h-1, with the maximum leakage rate occurring under heavy rainfall and frequent rainfall events. The deep soil water supplied by rainfall infiltration was affected by the amount of rainfall, rainfall intensity, duration of precipitation and soil moisture content in the earlier period. Precipitation events with long duration and small rainfall intensity were more conducive to deep water lea-kage, with a significant positive correlation between the leakage and rainfall (R2=0.85). 16-18 mm rainfall was the threshold for the leakage of 200 cm soil depth. The high-frequency rainfall event usually reached peak after 17-38 hours, with the entire leakage process being more than 164 hours. Accurate estimation of deep leakage has theoretical and practical significance for water resource assessment and ecological construction in desertified areas.

Dataset on outdoor behavior-system and spatial-pattern in the third place in cold area-based on the perspective of new energy structure.

The data presented in this paper are related to the research article entitled "Exploration of Outdoor Behavior System and Spatial Pattern in the Third Place in Cold Area- based on the perspective of new energy structure" (Ren, 2016) [1]. The dataset was from a field sub-time extended investigation to residents of Power Home Community in Inner Mongolia of China that belongs to cold region of ID area according to Chinese design code for buildings. This filed data provided descriptive statistics about environment-behavior symbiosis system, environment loading, behavior system, spatial demanding and spatial pattern for all kinds of residents (Older, younger, children). The field data set is made publicly available to enable critical or extended analyzes.