METTL3 facilitates multiple myeloma tumorigenesis by enhancing YY1 stability and pri-microRNA-27 maturation in m6A-dependent manner.

Multiple myeloma (MM) is a pernicious plasma cell disorder and has a poor prognosis. N6-methyladenosine (m6A) is an abundant epigenetic RNA modification and is important in cancer progression. Nevertheless, the function of m6A and its regulator METTL3 in MM are rarely reported. Here, we identified the m6A "writers", METTL3, was enhanced in MM and found that Yin Yang 1 (YY1) and primary-miR-27a-3p were the potential target for METTL3. METTL3 promoted primary-miR-27a-3p maturation and YY1 mRNA stability in an m6A manner. YY1 also was found to facilitate miR-27a-3p transcription. METTL3 affected the growth, apoptosis, and stemness of MM cells through accelerating the stability of YY1 mRNA and the maturation of primary-miR-27a-3p in vitro and in vivo. Our results reveal the key function of the METTL3/YY1/miR-27a-3p axis in MM and may provide fresh insights into MM therapy.

Strong bacterial stochasticity and fast fungal turnover in Taihu Lake sediments, China.

Understanding the assembly and turnover of microbial communities is crucial for gaining insights into the diversity and functioning of lake ecosystems, a fundamental and central issue in microbial ecology. The ecosystem of Taihu Lake has been significantly jeopardized due to urbanization and industrialization. In this study, we examined the diversity, assembly, and turnover of bacterial and fungal communities in Taihu Lake sediment. The results revealed strong bacterial stochasticity and fast fungal turnover in the sediment. Significant heterogeneity was observed among all sediment samples in terms of environmental factors, especially ORP, TOC, and TN, as well as microbial community composition and alpha diversity. For instance, the fungal richness index exhibited an approximate 3-fold variation. Among the environmental factors, TOC, TN, and pH had a more pronounced influence on the bacterial community composition compared to the fungal community composition. Interestingly, species replacement played a dominant role in microbial beta diversity, with fungi exhibiting a stronger pattern. In contrast, stochastic processes governed the community assembly of both bacteria and fungi, but were more pronounced for bacteria (R2 = 0.7 vs. 0.5). These findings deepen the understanding of microbial assembly and turnover in sediments under environmental stress and provide essential insights for maintaining the multifunctionality of lake ecosystems.

Adsorption and desorption of heavy metals at water sediment interface based on bayesian model.

Estuarine areas are not only the main gathering point for human sewage but also the place where one-way and two-way fluids interact, thus forming a complex and changeable geochemical physical field. Here, heavy metals (HMs) are adsorbed and desorbed due to physical, chemical, and biochemical processes. However, the adsorption and desorption behavior of HMs in the aquatic environment is complex, and physicochemical processes occurring in the estuarine sediment-water interface control the direction and boundaries of the system. This study analyzed the migration and distribution of HMs in rivers and lakes, and established a Bayesian network model to quantitatively understand the impact of nutrients and key environmental factors on the adsorption-desorption behavior of HMs in lake and estuaries, as well as the competitive relationship between environmental factors. The influence of environmental factors and the occurrence of HMs are both important model inputs. Our findings indicated that the migration risk of Cd in Qinghai Lake was high. Environmental factors such as Cation exchange capacity (CEC), Organic matter (OM), Soluble fluoride (SFL), and pH play the most important role in the adsorption and desorption of HMs. Our findings also indicated that the exchange and activity of HMs in sediments were much higher than in the overlying water. The organic matter content was the most complex environmental factor affecting HMS adsorption and desorption at the water-sediment interface. Additionally, the mass concentration of dissolved oxygen (DO) has a linear relationship with bioavailable HMs in river and lake sediments, but has no linear relationship with the concentration of water-soluble HMs. Interestingly, there are synergistic effects between environmental factors, which directly or indirectly affect the release of bioavailable HMs. However, it is important to determine whether the effects of different environmental factors on the exchange of bioavailable HMs are negative or positive. Our findings suggested that Bayesian network (BN) signals (positive or negative) could provide insights into the transfer direction of metals in the water-sediment interface.

Distribution, risk and bioavailability of metals in sediments of Lake Yamdrok Basin on the Tibetan Plateau, China.

Total contents of metals in soil and sediments on the Tibetan Plateau of China have been widely analyzed, but existing information is insufficient to effectively evaluate metal ecological risk because of a lack of metal bioavailability data. In this study, distribution, potential risk, mobility and bioavailability of metals in sediments of Lake Yamdrok Basin in Tibet of China were explored by combined use of total digestion, sequential extraction and the diffusive gradient in thin-films (DGT). Average concentrations of Cr, Ni, Cu, Zn, As, Cd and Pb in surface sediments were 31.25, 30.31, 22.00, 45.04, 31.32, 0.13 and 13.39 mg/kg, respectively. Higher levels of metals were found near the inflowing rivers. Residual form was dominant in Cr, Ni, Zn, Cd and Pb, and reducible form was dominant in As and Cd. Metals in surface sediments showed a low enrichment degree overall, but Cd and As had higher ecological risk levels than the other metals. Furthermore, there was a larger average proportion of exchangeable form of As (20.4%) and Cd (9.0%) than the other metals (1.7%-3.3%), implying their higher mobility and release risk. Average DGT-labile concentrations of Cr, Ni, Cu, Zn, As, Cd and Pb were 0.5, 4.5, 0.7, 25.1, 60.0, 0.22 and 1.0 µg/L, respectively. The DGT-labile As was significantly correlated with extractable As forms (p< 0.01), suggesting that extractable As in sediments acts as a "mobile pool" for bioavailable As. These results suggest potential risks of As and Cd, especially As, deserve further attention in Lake Yamdrok Basin.

A Bayesian Network Meta-Analysis Comparing the Efficacies of Eleven Novel Therapies with the Common Salvage Regimen for Relapsed or Refractory Acute Myeloid Leukemia.

BACKGROUND/AIMS: Acute myeloid leukemia (AML) is a relapsed and refractory hematological malignancy with a lower morbidity but higher mortality. In addition to hematopoietic stem cell transplantation, chemotherapy is used as the front-line treatment. However, the diversity of available agents and the inconsistency of outcomes of relevant trials render treatment decision-making tough. Network meta-analysis (NMA) is an efficient statistical framework that makes a comprehensive comparison and provides a valuable clinical reference. METHODS: All the potential trials were retrieved from the medical database and screened according to the inclusion and exclusion criteria. The main characteristics of each trial as well as the primary outcomes, including complete remission (CR), overall response rate (ORR), overall survival (OS), and event-free survival (EFS), were extracted. In addition, the network graph was plotted to illustrate the connections among the trials involved. Comparison results in the network were exhibited in a forest plot. Furthermore, the surface under the cumulative ranking curve (SUCRA) was introduced to rank the treatments for each endpoint. RESULTS: A total of 11 trials were selected from 1,625 identifications. No significant difference in the common treatment was observed for the endpoints CR and ORR. In terms of OS, CPX-351 (HR: 0.77, 95% CrI: 0.63, 0.94) and HiDAC plus MK-8776 (HR: 0.80, 95% CrI: 0.68, 0.93) showed a superiority over the common salvage regimen in the short term, while HiDAC plus MK-8776 (HR: 0.80, 95% CrI: 0.70, 0.93) and Ara-C plus vosaroxin (HR: 0.86, 95% CrI: 0.74, 0.99) outperformed the common salvage regimen for the 3-year OS. In addition, clofarabine plus Ara-C (HR: 0.61, 95% CrI: 0.53, 0.69) and CPX-351 (HR: 0.71, 95% CrI: 0.60, 0.83) were confirmed to be efficacious in enhancing the rate of EFS. CONCLUSION: Referring to the network outcome and SUCRA value, clofarabine plus Ara-C (CR: 79.05%, ORR: 80.02%) and Ara-C plus vosaroxin (CR: 75.42%, ORR: 73.43%) were potentially the top two choices for both CR and ORR. CPX-351 (1-year OS: 91.36%), HiDAC plus MK-8776 (3-year OS: 94.23%) and clofarabine plus Ara-C (1-year EFS: 97.34%) yielded the highest probabilities to be the optimal choices for 1-year OS, 3-year OS and 1-year EFS, respectively.

Arsenate biotransformation by Microcystis aeruginosa under different nitrogen and phosphorus levels.

The arsenate (As(V)) biotransformation by Microcystis aeruginosa in a medium with different concentrations of nitrogen (N) and phosphorus (P) has been studied under laboratory conditions. When 15µg/L As(V) was added, N and P in the medium showed effective regulation on arsenic (As) metabolism in M. aeruginosa, resulting in significant differences in the algal growth among different N and P treatments. Under 0.2mg/L P treatment, increases in N concentration (4-20mg/L) significantly stimulated the cell growth and therefore indirectly enhanced the production of dimethylarsinic acid (DMA), the main As metabolite, accounting for 71%-79% of the total As in the medium. Meanwhile, 10-20mg/L N treatments accelerated the ability of As metabolization by M. aeruginosa, leading to higher contents of DMA per cell. However, As(V) uptake by M. aeruginosa was significantly impeded by 0.5-1.0mg/L P treatment, resulting in smaller rates of As transformation in M. aeruginosa as well as lower contents of As metabolites in the medium. Our data demonstrated that As(V) transformation by M. aeruginosa was significantly accelerated by increasing N levels, while it was inhibited by increasing P levels. Overall, both P and N play key roles in As(V) biotransformation processes.

Characterization of phosphate solubilizing bacteria in the sediments of eutrophic lakes and their potential for cyanobacterial recruitment.

Microbes may induce endogenous phosphorus (P) migration from lacustrine sediment. This study focused on the role of phosphate-solubilizing bacteria (PSB) disturbance in affecting the sediment P release and further contributing to cyanobacterial recruitment in Meiliang Bay, Lake Taihu. Gluconic acid was the main mechanism of phosphate solubilizing by PSB. The dominant PSB (Burkholderia) isolated from eutrophic lake sediments was used as a representative to investigate the effects of disturbance on endogenous P release using diffusive gradients in thin films (DGT) and high-resolution dialysis (HR-Peeper). The results show that soluble reactive phosphorus (SRP) and iron (Fe (II)) concentrations could reach 0.51 mg L-1 and 33.56 mg L-1 in pore water, respectively. And the sediment DGT-P and DGT-Fe were relatively reduced by PSB. Subsequent the chlorophyll a (Chl a) concentrations reached peaks of 344.8 µg L-1 in overlying water. The abundance of the dominant PSB (Burkholderia-Caballeronia-Paraburkholderia) were significantly associated with Chl a (P < 0.05) and algal effective state phosphorus (AAP) (P < 0.05), respectively. PSB mainly regulates AAP leaching to pore water and then diffusing across the sediment-water interface to the overlying water, producing the effect of cyanobacteria recruitment. The results provide new insights into early management of cyanobacterial resuscitation in a large eutrophic lake.

Removal efficacy of fly ash composite filler on tailwater nitrogen and phosphorus and its application in constructed wetlands.

Constructed wetlands (CWs) have been widely used in tailwater treatment. However, it is difficult to achieve considerable removal efficiency of nitrogen and phosphorus in tailwater solely by CWs-an efficient green wetland filler is also important. This study investigated 160 domestic sewage treatment facilities (DSTFs) in rural areas from two urban areas in Jiaxing for TP and NH3-N and found that TP and NH3-N concentrations in rural domestic sewage (RDS) in this plain river network are still high. Therefore, we selected a new synthetic filler (FA-SFe) to enhance nitrogen and phosphorus reduction, and we discuss the importance of filler in constructed wetlands. Experiments revealed the adsorption capacity of the new filler: the maximum adsorption amounts of TP and NH3-N reached 0.47 g m-2 d-1 and 0.91 g m-2 d-1, respectively. The application potential of FA-SFe was verified in actual wastewater treatment, with the removal rates of ammonia nitrogen and TP reaching 71.3% and 62.7%, respectively. This study provides a promising pathway for nitrogen and phosphorus removal from rural tailwaters.

Study on the management efficiency of lanthanum/iron co-modified attapulgite on sediment phosphorus load.

Attapulgite co-modified by lanthanum-iron (MT-LHMT) was used to study its effectiveness and mechanism in controlling phosphorus release from sediments. MT-LHMT has high adsorption capacity for phosphate and the maximum adsorption capacity of MT-LHMT to phosphate can reach 75.79 mg/g. The mechanism mainly involved electrostatic action, surface precipitation and ligand exchange between MT-LHMT bonded hydroxyl and phosphate to form La-O-P and Fe-O-P inner-sphere complexes. MT-LHMT has excellent adsorption performance in the pH range of 3-8. In addition to HCO3-, CO32- and HA- had a negative effect on the phosphorus removal of MT-LHMT, while NO3-, Cl-, SO42-, K+, Ca2+ and Mg2+ had a positive or no effect on phosphorus removal. MT-LHMT significantly reduced the risk of phosphorus release from overlying water in different dose effects and covering methods, as well as the unstable inactivation of flowing phosphorus, sediment dissolved reactive phosphorus (DRP) and available phosphorus with medium diffusion gradient in thin film in the sediment-water interface (Labile-PDGT). The MT-LHMT capping wrapped with fabric can reduce the risk of nitrogen release from sediment to overlying water more than only MT-LHMT capping. The results of this study showed that the MT-LHMT capping wrapped with fabric has high potential and can be used as an active capping material to manage the nitrogen and phosphorus load in surface water.

Characterization of phosphorus sorption and microbial community in lake sediments during overwinter and recruitment periods of cyanobacteria.

The release of endogenous phosphorus from lacustrine sediment is a key element of freshwater eutrophication. The microbes in sediments may affect phosphorus migration and transformation during the growth of cyanobacteria, which may lead to the release of phosphorus from sediments and contribute to water eutrophication. To study phosphorus sorption and the microbial community structure in the overlying water and the vertical depth of sediments, samples in Meiliang Bay were collected during the dormancy and resuscitation phases of cyanobacteria. The results showed that there were high total phosphorus (TP) concentrations in the overlying water and sediment, with maximum values reached 0.24 mg L-1 and 1059 mg kg-1, respectively. Fitting by modified Langmuir model indicated that the partitioning coefficients (KP) was, from greatest to least: bottom sediment (maximum of 0.923 L g-1) > middle sediment (0.571 L g-1) > surface sediment (0.262 L g-1). During the cyanobacteria resuscitation stage, the relative abundance of Proteobacteria (18.37%-33.56%), Chloroflexi (9.57%-17.76%), Cyanobacteria (0.38%-2.62%), and the Nitrospirota phylum Thermodesulfovibrionia (4.61%-10.14%) were higher than the dormant period of cyanobacteria, and bacteria with phosphorus-solubilizing (27.27%-52.01%) accounted for the majority. The redundancy analysis (RDA) found that the structure of the microbial communities in sediments was significant correlation with organic phosphorus (OP) (P = 0.002) during recruitment period of cyanobacteria, which would accelerate the conversion of OP into soluble inorganic phosphorus and then gets released from sediment to water. The most predominant phylum among phosphorus-solubilizing bacteria (PSB) is Proteobacteria, followed by Actinobacteriota, which were positively correlated with equilibrium phosphorus concentration (EPC0) (P < 0.05) during the cyanobacterial resuscitation phase. The sediments from the cyanobacteria resuscitation phase had phosphorus release risk and highlighted the significant role of the bacterial community.

[Distribution and Potential Ecological Risk Assessment of Heavy Metals in Sediments of Lake Qinghai].

Lake Qinghai is the largest closed saltwater lake in China. In recent years, because of the rapid development of industry, agriculture, and tourism, the lake has been increasingly affected by human activities, which has attracted the attention of many scholars. In order to understand the distribution of heavy metals in the surface sediments of Lake Qinghai, the contents of Zn, Cu, Pb, Co, Ni, As, Cd, and Cr were investigated, the metal fractions were extracted, and the sources, as well as potential ecological risks, were analyzed. The results showed that:① the ω(As) (13.21 mg·kg-1) and ω(Cd) (0.21 mg·kg-1) in the surface sediments of Lake Qinghai were 1.13 and 1.53 times higher than the environmental background values, respectively, and the other heavy metal contents were all lower than the environmental background values. There were similar spatial distribution characteristics of analyzed metals except for As, with higher values measured in the northwestern area of the lake and the 151 Terminal. ② Except for Cd, the analyzed heavy metals mainly existed in the form of the residual state; by contrast, Cd mainly existed in the form of the bioavailable state, which has high potential toxicity to aquatic organisms. ③ Combined with the results of the correlation and principal component analysis, the metals including Zn, Cu, Pb, Co, Ni, Cd, and Cr were thought to mainly come from the natural environment, whereas the source of As was related to human activities, such as agricultural production. ④ According to potential risk analyses, the average of the metal potential ecological risk factors was 76.57, which indicated a slight ecological hazard level. However, it should be noted that the potential ecological hazard level and release risk of Cd at each site were higher than those of the other metals, especially in the regions nearing the estuary of Heima River, Lake Gahai, and the sand island, which showed higher levels of enrichment and potential release risk. Therefore, further attention should be paid to the potential impacts of Cd in sediments of these regions on the water environment and ecosystem.

Prevention and treatment of doxorubicin-induced cardiotoxicity by dexrazoxane and schisandrin B in rabbits.

The cost of dexrazoxane, a drug used to provide protection from doxorubicin-induced cardiotoxicity, limits its use in low-income countries. We aimed to see whether schisandrin B, an inexpensive drug, could provide protection equivalent to that provided by dexrazoxane. New Zealand white rabbits were randomly divided into groups and treated with saline, doxorubicin, doxorubicin + dexrazoxane, or doxorubicin + schisandrin B. Doxorubicin-induced damage and the protective effects were studied by recording the echocardiographic parameters and serum levels of superoxide dismutase, malondialdehyde, cardiac troponin I, and brain natriuretic peptide and observing the histology and degree of apoptosis. Schisandrin B had dose-dependent effects in decreasing the magnitude of doxorubicin-induced indicators of cardiomyopathy to a degree that approximated the decrease produced by dexrazoxane treatment. Schisandrin B might be a useful, low-cost alternative drug for this application.

Lnc NEAT1/miR-29b-3p/Sp1 form a positive feedback loop and modulate bortezomib resistance in human multiple myeloma cells.

The overall survival of multiple myeloma (MM) patients significantly improved with the use of proteasome inhibitor such as bortezomib. However, resistance to sorafenib limits its use. Bortezomib-resistant MM cells were generated and their bortezomib-resistant properties were confirmed by cell viability and apoptosis assays. To explore functions and underlying mechanisms of long non-coding RNA nuclear paraspeckle assembly transcript 1 (NEAT1) on bortezomib resistance in MM, MTT assays, flow cytometry analyses, dual luciferase report gene assays, RNA pulldown assays and chromatin immunoprecipitation assays were carried out. NEAT1 and specific protein 1 (Sp1) was upregulated while miR-29b-3p was down regulated in bortezomib-resistant MM cells. NEAT1 promoted Sp1 expression by sponging miR-29b-3p and then enhanced the tolerance of MM cells to bortezomib. Sp1 targeted to NEAT1 promoter region promoting NEAT1 transcription and formed a positive feedback loop. NEAT1 and Sp1 levels were higher and miR-29b-3p was levels were lower in bortezomib-resistant MM patients. NEAT1/miR-29b-3p/Sp1 feedback loop enhanced the tolerance of MM cells to bortezomib. These results indicate potentially valuable targets for overcoming bortezomib resistance for MM.

Study on antimony mobility in a contaminated shallow lake sediment using the diffusive gradients in thin films technique.

Antimony is a priority environmental contaminant. Increasing attention is being paid to the behaviors and mobilities of the various Sb species in the environment. Sb speciation in the environment and the mobilities of Sb species at mining sites have been studied well, but Sb speciation and mobility in shallow lakes requires further study. Here, we studied Sb behavior in sediment of a shallow lake in the plain rivers network in Taihu Basin that suffers continual Sb inputs from textile plants. The diffusive gradients in thin films techniques (DGT) made of zirconium oxide based binding resin gel (ZrO-Chelex), agarose diffusive gel and polyvinylidene fluoride filter were deployed in water and sediment to obtain a high-resolution record in situ. The results indicated that (1) pollutants released by textile plants caused relatively high Sb(Ⅲ), Sb(Ⅴ) and organoantimony concentrations in the eutrophic shallow lake, (2) Sb was seldomly mobile in the oxic layer where Sb(Ⅲ) was sorbed on Fe(Ⅲ) oxides and gradually formed Fe-Sb complexes in the sediment, but in the anoxic environment (oxidation-reduction potential: 366 - -344 mv) Sb(V), Fe(Ⅱ) and P (V) were simultaneously released to resupply the porewater, (3) the release of Sb from solid phase is decided by the redox condition, and the rate of release is dependent on the labile Sb content of the sediment. The mobility of Sb should be given sufficient attention when the potential ecological risk of metal(loid)s in shallow lakes and wetlands sediment are evaluated.

Recent Progress of Exosomes in Multiple Myeloma: Pathogenesis, Diagnosis, Prognosis and Therapeutic Strategies.

Multiple myeloma (MM) is a hematological malignancy that is still incurable. The bone marrow microenvironment (BMM), with cellular and non-cellular components, can create a favorable environment for the survival, proliferation and migration of MM cells, which is the main reason for the failure of MM therapies. Many studies have demonstrated that exosomes play an important role in the tumor-supportive BMM. Exosomes are nanoscale vesicles that can be released by various cells. Some exosomes contribute to the pathogenesis and progression of MM. MM-derived exosomes act on different cells in the BMM, thereby creating an environment conducive to the survival and growth of MM cells. Owing to the important roles of exosomes in the BMM, targeting the secretion of exosomes may become an effective therapeutic strategy for MM. In addition, the abnormal expression of "cargos" in the exosomes of MM patients may be used to diagnose MM or used as part of a screen for the early prognoses of MM patients. Exosomes also have good biological properties, including safety, biocompatibility, stability and biodegradability. Therefore, the encapsulation of anti-cancer drugs in exosomes, along with surface modifications of exosomes with targeting molecules, are very promising strategies for cancer therapies-particularly for MM. In addition, DC-derived exosomes (DC-EXs) can express MHC-I, MHC-II and T cell costimulatory molecules. Therefore, DC-EXs may be used as a nanocarrier to deliver cancer vaccines in MM. This review summarizes the recent progress of exosome research regarding the pathogenesis of, diagnosis of, prognosis of and therapeutic strategies for MM.

[Schisandrin B prevents doxorubicin-induced cardiotoxicity in rabbits].

OBJECTIVE: To study the effect of dexrazoxane in preventing doxorubicin-induced cardiotoxicity in rabbit-models and its mechanism. METHODS: Thirty one New Zealand white rabbits were randomly divided into two groups, doxorubicin (DOX) group and doxorubicin + dexrazoxane group. The cardiotoxicity was assessed by measuring serum superoxide dismutase (SOD), malondialdehyde (MDA), cardiac troponin I (cTnI), brain natriuretic peptide (BNP), left ventricular ejection function (LVEF), and left ventricular fractional shortening (LVFS), before and 4 and 10 weeks after intervention. Pathological changes in cardiac tissues and the apoptosis of myocardial cells were examined at the end of the experiment. Results Doxorubicin increased serum MDA, cTnI and BNP and decreased SOD, LVEF and LVFS (P < 0.05). Dexrazoxane (DEX) inhibited the increase of MDA, cTnI and BNP, and the decrease of LVEF and LVFS (P < 0.05). The rabbits treated with doxorubicin + dexrazoxane had slighter pathological changes in myocardium and apoptotic myocardial cells than those treated with DOX. CONCLUSION: Dexrazoxane prevents doxorubicin-induced cardiotoxicity through decreasing oxygen free radical production, cutting down lipid peroxidation, and depressing cardiocyte apoptosis.

MicroRNA-27 Inhibits Autophagy and Promotes Proliferation of Multiple Myeloma Cells by Targeting the NEDD4/Notch1 Axis.

Multiple myeloma (MM) is a malignant tumor disease that seriously affects the health of patients. Previous studies have shown the crucial role of autophagy in the development of MM. Therefore, the study aimed to study the effect of miR-27 on autophagy in MM via NEDD4/Notch1 axis. RT-qPCR or western blot analysis was used to detect the expression of miR-27, NEDD4, and Notch1 in bone marrow tissues and CD138+ plasma cells of patients and MM cells. After gain- and loss-of-function assays in MM cells, proliferation and invasion were assessed by clone formation and Transwell assays. Meanwhile, expression of autophagy-related proteins was measured by western blot analysis, followed by evaluation of autophagosomes and autophagic flow. The targeting relationship was evaluated by luciferase reporter assay, whereas the binding of NEDD4 to Notch1 protein was analyzed by co-immunoprecipitation. The ubiquitination level of Notch1 protein was detected. A nude mouse tumor model was established to determine the role of miR-27 in MM in vivo. miR-27 and Notch1 upregulation and NEDD4 downregulation were observed in bone marrow tissues and CD138+ plasma cells of patients and MM cells. miR-27 negatively targeted NEDD4, while NEDD4 could specifically bind to Notch1 protein to increase Notch1 ubiquitin degradation in MM cells. miR-27 or Notch1 overexpression or NEDD4 silencing diminished autophagy but enhanced proliferation and invasion of MM cells. miR-27 upregulation promoted the formation of subcutaneous tumor in nude mice. Collectively, miR-27 elevated Notch1 expression by targeting NEDD4 and promoted the development of MM by inhibiting cell autophagy, which provides a new idea and basis for MM treatment.

Inhibition of Multiple Myeloma Using 5-Aza-2'-Deoxycytidine and Bortezomib-Loaded Self-Assembling Nanoparticles.

PURPOSE: The aim of this study was to explore the use of self-assembling nanoparticles loaded with two chemotherapy drugs for the treatment of multiple myeloma. MATERIALS AND METHODS: Nanoparticle systems were developed based on amine polyethylene glycol-polycaprolactone (NH2-PEG-PCL) to encapsulate 5-Aza-2'-deoxycytidine and Bortezomib using the self-assemble method. Morphological changes were observed by transmission electron microscopy (TEM), and the size, drug release, long-term stability, and release of reactive oxygen species (ROS) were analyzed. The MTT assay was used to evaluate the effects of drug-loaded nanoparticles (PEG-PCL-DAC-BTZ) in inhibiting the proliferation of multiple myeloma cells (U266 and LP-1), and the TUNEL assay and Western blotting were used to measure the induction of cell apoptosis. RESULTS: Based on the diameter of NH2-PEG-PCL and PEG-PCL-DAC-BTZ, the drug-loaded nanoparticles were successfully prepared. TEM revealed that PEG-PCL-DAC-BTZ was spherically shaped. More than 90% of the drugs were released after 72 h, and PEG-PCL-DAC-BTZ maintained a good stability. U266 and LP-1 cells treated with PEG-PCL-DAC-BTZ showed the highest growth inhibition, release of ROS, and cell apoptosis compared to those treated with unloaded nanoparticles and chemotherapy drugs alone. CONCLUSION: The drug-loaded nanoparticles are a good foundation for the treatment of multiple myeloma as they showed a slow release profile, good stability, and superior anti-cancer effects in vitro.

Arsenic distribution and speciation in multiphase media of a lake basin, Tibet: The influences of environmental factors on arsenic biogeochemical behavior in the cold arid plateau lake.

Widespread arsenic (As) has been found in surface media on the Tibetan Plateau, but few studies of As species have been performed because of the difficult sampling conditions. In this study, As distribution and speciation in multiphase media (including surface water, interstitial water, and sediment) in Lake Yamdrok Basin in Tibet in wet and dry seasons were investigated to allow the biogeochemical behavior of As in the cold arid plateau lake to be understood. The total As (TAs) (mainly containing arsenate (As(V)) and arsenite (As(III))) concentrations were generally higher in surface and interstitial water in the lake zones than in Inflowing rivers. Among the four lake zones, significantly higher As concentrations were found in Chen Co, Yamdrok Tso, and Kongmo Co than in Bajiu Co, and surface sediments from the former three lake zones contained relatively high concentrations of the labile As. Redox potential (Eh) in sediments and HCO3 concentration in surface water primarily controlled labile As mobilization through reductive dissolution of As-bearing iron (hydr)oxides and oxyanion competition for As adsorption sites, and therefore affected the As distributions in aqueous phases. As(III) concentrations in interstitial water accounted for 41% ± 33% of TAs, and positively correlated with the arsenate-reducing microbe population in sediments. In contrast, As(V) was predominant in surface water (accounting for 95% ± 8% of TAs), and even trace amounts of dimethylarsinic acid (DMA) was found in wet season. Notably, lower Eh values in dry season triggered a marked increase in the As concentrations in interstitial water, and this probably increased the risk of As contamination of surface water.

Increased expression of miR-27 predicts poor prognosis and promotes tumorigenesis in human multiple myeloma.

Multiple myeloma (MM) is an incurable hematological malignancy characterized by abnormal infiltration of plasma cells in the bone marrow. MicroRNAs (miRNAs) have emerged as crucial regulators in human tumorigenesis and tumor progression. miR-27, a novel cancer-related miRNA, has been confirmed to be implicated in multiple types of human tumors; however, its biological role in MM remains largely unknown. The present study aimed to characterize the biological role of miR-27 in MM and elucidate the potential molecular mechanisms. Here we found that miR-27 was significantly up-regulated in MM samples compared with normal bone marrow samples from healthy donors. Moreover, the log-rank test and Kaplan-Meier survival analysis displayed that MM patients with high miR-27 expression experienced a significantly shorter overall survival than those with low miR-27 expression. In the current study, we transfected MM cells with miR-27 mimics or miR-27 inhibitor to manipulate its expression. Functional studies demonstrated that miR-27 overexpression promoted MM cell proliferation, facilitated cell cycle progression, and expedited cell migration and invasion; whereas miR-27 knockdown inhibited cell proliferation, induced cell cycle arrest, and slowed down cell motility. Mechanistic studies revealed that Sprouty homolog 2 (SPRY2) was a direct target of miR-27 and that rescuing SPRY2 expression reversed the promoting effects of miR-27 on MM cell proliferation, migration, and invasion. Besides, miR-27 ablation suppressed tumorigenecity of MM cells in mouse xenograft models. Collectively, our data indicate that miR-27 exerts its oncogenic functions in MM by targetting SPRY2 and that miR-27 may be used as a promising candidate target in MM treatment.