LW-213 induces cell apoptosis in human cutaneous T-cell lymphomas by activating PERK-eIF2α-ATF4-CHOP axis.

Cutaneous T-cell lymphoma (CTCL) is characterized by a heterogeneous group of extranodal non-Hodgkin lymphomas, in which monoclonal T lymphocytes infiltrate the skin. LW-213, a derivative of wogonin, was found to induce cell apoptosis in chronic myeloid leukemia (CML). In this study, we investigated the effects of LW-213 on CTCL cells and the underlying mechanisms. We showed that LW-213 (1-25 µM) dose-dependently inhibited human CTCL cell lines (Hut-102, Hut-78, MyLa, and HH) with IC50 values of around 10 µM, meanwhile it potently inhibited primary leukemia cells derived from peripheral blood of T-cell lymphoma patients. We revealed that LW-213-induced apoptosis was accompanied by ROS formation and the release of calcium from endoplasmic reticulum (ER) through IP3R-1channel. LW-213 selectively activated CHOP and induced apoptosis in Hut-102 cells via activating PERK-eIF2α-ATF4 pathway. Interestingly, the degree of apoptosis and expression of ER stress-related proteins were alleviated in the presence of either N-acetyl cysteine (NAC), an ROS scavenger, or 2-aminoethyl diphenylborinate (2-APB), an IP3R-1 inhibitor, implicating ROS/calcium-dependent ER stress in LW-213-induced apoptosis. In NOD/SCID mice bearing Hut-102 cell line xenografts, administration of LW-213 (10 mg/kg, ip, every other day for 4 weeks) markedly inhibited the growth of Hut-102 derived xenografts and prolonged survival. In conclusion, our study provides a new insight into the mechanism of LW-213-induced apoptosis, suggesting the potential of LW-213 as a promising agent against CTCL.

Role of nitroxyl (HNO) in cardiovascular system: From biochemistry to pharmacology.

Cardiovascular diseases are recognized to be a major cause of people morbidity and mortality. A host of stress signals contribute to the pathogenesis of cardiovascular disorders. Deficiency of hydrogen sulfide (H2S) or nitric oxide (NO) coordinately plays essential roles in the development of cardiovascular diseases. Recent studies have shown that interaction between the two gaseostransmitters, H2S and NO, may give rise to nitroxyl (HNO), one-electron-reduced product of NO. HNO is found to exhibit a variety of biological and pharmacological properties including positive inotropy and cardiovascular protective effects, etc. In this review, recent progresses regarding HNO generation, detection, biochemical and pharmacological functions are discussed.

LW-213, a newly synthesized flavonoid, induces G2/M phase arrest and apoptosis in chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell neoplasm characterized by an uncontrolled proliferation of moderately and well differentiated cells of the granulocytic lineage. LW-213, a newly synthesized flavonoid compound, was found to exert antitumor effects against breast cancer through inducing G2/M phase arrest. We investigated whether LW-213 exerted anti-CML effects and the underlying mechanisms. We showed that LW-213 inhibited the growth of human CML cell lines K562 and imatinid-resistant K562 (K562r) in dose- and time-dependent manners with IC50 values at the low µmol/L levels. LW-213 (5, 10, 15 µM) caused G2/M phase arrest of K562 and K562r cells via reducing the activity of G2/M phase transition-related proteins Cyclin B1/CDC2 complex. LW-213 treatment induced apoptosis of K562 and K562r cells via inhibiting the expression of CDK9 through lysosome degradation, thus leading to the suppression of RNAPII phosphorylation, down-regulation of a short-lived anti-apoptic protein MCL-1. The lysosome inhibitor, NH4Cl, could reverse the anti-CML effects of LW-213 including CDK9 degradation and apoptosis. LW-213 treatment also degraded the downstream proteins of BCR-ABL1, such as oncoproteins AKT, STAT3/5 in CML cells, which was blocked by NH4Cl. In primary CML cells and CD34+ stem cells, LW-213 maintained its pro-apoptotic activity. In a K562 cells-bearing mice model, administration of LW-213 (2.5, 5.0 mg/kg, ip, every other day for 4 weeks) dose-dependently prolonged the survival duration, and significantly suppressed huCD45+ cell infiltration and expression of MCL-1 in spleens. Taken together, our results demonstrate that LW-213 may be an efficient agent for CML treatment.

Feasibility of phase-contrast cine magnetic resonance imaging for measuring blood flow in the sheep fetus.

Phase-contrast cine MRI (PC-MRI) is the gold-standard noninvasive technique for measuring vessel blood flow and has previously been applied in the human fetal circulation. We aimed to assess the feasibility of using PC-MRI to define the distribution of the fetal circulation in sheep. Fetuses were catheterized at 119-120 days of gestation (term, 150 days) and underwent MRI at ∼123 days of gestation under isoflurane anesthesia, ventilated at a FIO2 of 1.0. PC-MRI was performed using a fetal arterial blood pressure catheter signal for cardiac triggering. Blood flows were measured in the major fetal vessels, including the main pulmonary artery, ascending and descending aorta, superior vena cava, ductus arteriosus, left and right pulmonary arteries, umbilical vein, ductus venosus, and common carotid artery and were indexed to estimated fetal weight. The combined ventricular output, pulmonary blood flow, and flow across the foramen ovale were calculated from vessel flows. Intraobserver and interobserver agreement and reproducibility was assessed. Blood flow measurements were successfully obtained in 61 out of 74 vessels (82.4%) interrogated in 9 fetuses. There was good intraobserver [R = 0.998, P < 0.0001; intraclass correlation (ICC) = 0.997] and interobserver agreement (R = 0.996, P < 0.0001; ICC = 0.996). Repeated MRI measurements showed good reproducibility (R = 0.989, P = 0.0002; ICC = 0.990). We conclude that PC-MRI using fetal catheters for gating triggers is feasible in the major vessels of late gestation fetal sheep. This approach may provide a useful new tool for assessing the circulatory characteristics of fetal sheep models of human disease, including fetal growth restriction and congenital heart disease.

Hydrogen Sulfide: Recent Progression and Perspectives for the Treatment of Diabetic Nephropathy.

Diabetic kidney disease develops in approximately 40% of diabetic patients and is a major cause of chronic kidney diseases (CKD) and end stage kidney disease (ESKD) worldwide. Hydrogen sulfide (H2S), the third gasotransmitter after nitric oxide (NO) and carbon monoxide (CO), is synthesized in nearly all organs, including the kidney. Though studies on H2S regulation of renal physiology and pathophysiology are still in its infancy, emerging evidence shows that H2S production by renal cells is reduced under disease states and H2S donors ameliorate kidney injury. Specifically, aberrant H2S level is implicated in various renal pathological conditions including diabetic nephropathy. This review presents the roles of H2S in diabetic renal disease and the underlying mechanisms for the protective effects of H2S against diabetic renal damage. H2S may serve as fundamental strategies to treat diabetic kidney disease. These H2S treatment modalities include precursors for H2S synthesis, H2S donors, and natural plant-derived compounds. Despite accumulating evidence from experimental studies suggests the potential role of the H2S signaling pathway in the treatment of diabetic nephropathy, these results need further clinical translation. Expanding understanding of H2S in the kidney may be vital to translate H2S to be a novel therapy for diabetic renal disease.

Relaxation properties of human umbilical cord blood at 1.5 Tesla.

PURPOSE: To characterize the MRI relaxation properties of human umbilical cord blood at 1.5 Tesla. METHODS: Relaxometry measurements were performed on cord blood specimens (N = 88, derived from six caesarean deliveries) spanning a broad range of hematocrits (Hct = 0.19-0.76) and oxygen saturations (sO2 = 4-100%), to characterize the dependence of T1 and T2 on these blood properties. Adult blood data (N = 31 specimens, derived from two volunteers) were similarly studied to validate our experimental methods by comparison with existing literature. Using biophysical models previously developed for adult blood, new model parameters were estimated, which relate Hct and sO2 to the observed cord blood relaxation times. RESULTS: Fitted biophysical models explained more than 90% of the variation in T1 and T2 . In general, T2 relaxation times of cord blood were longer (by up to 35%) than those of adult blood, whereas T1 relaxation times were slightly shorter (by up to 10%). CONCLUSIONS: The models and fitted parameters presented here can be used for calibration of future MRI investigations of fetal and neonatal blood physiology. This study is an important step in facilitating accurate, noninvasive assessments of fetal blood oxygen content, a valuable diagnostic parameter in the identification and treatment of fetal hypoxia. Magn Reson Med 77:1678-1690, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

The hemodynamics of late-onset intrauterine growth restriction by MRI.

BACKGROUND: Late-onset intrauterine growth restriction (IUGR) results from a failure of the placenta to supply adequate nutrients and oxygen to the rapidly growing late-gestation fetus. Limitations in current monitoring methods present the need for additional techniques for more accurate diagnosis of IUGR in utero. New magnetic resonance imaging (MRI) technology now provides a noninvasive technique for fetal hemodynamic assessment, which could provide additional information over conventional Doppler methods. OBJECTIVE: The objective of the study was to use new MRI techniques to measure hemodynamic parameters and brain growth in late-onset IUGR fetuses. STUDY DESIGN: This was a prospective observational case control study to compare the flow and T2 of blood in the major fetal vessels and brain imaging findings using MRI. Indexed fetal oxygen delivery and consumption were calculated. Middle cerebral artery and umbilical artery pulsatility indexes and cerebroplacental ratio were acquired using ultrasound. A score of ≥ 2 of the 4 following parameters defined IUGR: (1) birthweight the third centile or less or 20% or greater drop in the centile in estimated fetal weight; (2) lowest cerebroplacental ratio after 30 weeks less than the fifth centile; (3) ponderal index < 2.2; and (4) placental histology meets predefined criteria for placental underperfusion. Measurements were compared between the 2 groups (Student t test) and correlations between parameters were analyzed (Pearson's correlation). MRI measurements were compared with Doppler parameters for identifying IUGR defined by postnatal criteria (birthweight, placental histology, ponderal index) using receiver-operating characteristic curves. RESULTS: We studied 14 IUGR and 26 non-IUGR fetuses at 35 weeks' gestation. IUGR fetuses had lower umbilical vein (P = .004) and pulmonary blood flow (P = .01) and higher superior vena caval flow (P < .0001) by MRI. IUGR fetuses had asymmetric growth but smaller brains than normal fetuses (P < .0001). Newborns with IUGR also had smaller brains with otherwise essentially normal findings on MRI. Vessel T2s, oxygen delivery, oxygen consumption, middle cerebral artery pulsatility index, and cerebroplacental ratio were all significantly lower in IUGR fetuses, whereas there was no significant difference in umbilical artery pulsatility index. IUGR score correlated positively with superior vena caval flow and inversely with oxygen delivery, oxygen consumption, umbilical vein T2, and cerebroplacental ratio. Receiver-operating characteristic curves revealed equivalent performance of MRI and Doppler techniques in identifying IUGR that was defined based on postnatal parameters with superior vena caval flow area under the curve of 0.94 (95% confidence interval, 0.87-1.00) vs a cerebroplacental ratio area under the curve of 0.80 (95% confidence interval, 0.64-0.97). CONCLUSION: MRI revealed the expected circulatory redistribution in response to hypoxia in IUGR fetuses. The reduced oxygen delivery in IUGR fetuses indicated impaired placental oxygen transport, whereas reduced oxygen consumption presumably reflected metabolic adaptation to diminished substrate delivery, resulting in slower fetal growth. Despite brain sparing, placental insufficiency limits fetal brain growth. Superior vena caval flow and umbilical vein T2 by MRI may be useful new markers of late-onset IUGR.

Foetal blood flow measured using phase contrast cardiovascular magnetic resonance--preliminary data comparing 1.5 T with 3.0 T.

BACKGROUND: Phase contrast cardiovascular magnetic resonance (PC CMR) has emerged as a clinical tool for blood flow quantification but its use in the foetus has been hampered by the need for gating with the foetal heart beat. The previously described metric optimized gating (MOG) technique has been successfully used to measure foetal blood flow in late gestation foetuses on a 1.5 T CMR magnet. However, there is increasing interest in performing foetal cardiac imaging using 3.0 T CMR. We describe our pilot investigation of foetal blood flow measured using 3.0 T CMR. METHODS: Foetal blood flows were quantified in 5 subjects at late gestational age (35-38 weeks). Three were normal pregnancies and two were pregnancies with ventricular size discrepancy. Data were obtained at 1.5 T and 3.0 T using a previously described PC CMR protocol. After reconstruction using MOG, blood flow was quantified independently by two observers. Intra- and inter-observer reproducibility of flow measurements at the two field strengths was assessed by Pearson correlation coefficient (R(2)), linear regression and Bland Altman analysis. RESULTS: PC CMR flow measurements were obtained in 36 of 40 target vessels. Strong intra-observer agreement was obtained between measurements at each field strength (R(2) = 0.78, slope = 0.83 ± 0.11), with a mean bias of -1 ml/min/kg and 95% confidence limits of ±71 ml/min/kg. Inter-observer agreement was similarly high for measurements at both 1.5 T (R(2) = 0.86, slope = 0.95 ± 0.13, bias = 6 ± 52 ml/min/kg) and 3.0 T (R(2) = 0.88, slope = 0.94 ± 0.13, bias = 4 ± 47 ml/min/kg). Across all PC CMR measurements, SNR per pixel was expectedly higher at 3.0 T relative to 1.5 T (165 ± 50%). The relative differences in flow measurements between observers were low (range: 4-16%) except for pulmonary blood flow which showed much higher variability at 1.5 T (34%) versus that at 3.0 T (11%). This was attributed to the poorly visualized, small pulmonary vessels at 1.5 T, which made delineation inconsistent between observers. CONCLUSIONS: This is the first pilot study to measure foetal blood flow using PC CMR at 3.0 T. The flow data obtained were in good correlation with those measured at 1.5 T, both within and between observers. With increased SNR at 3.0 T, smaller pulmonary vessels were better visualized which improved inter-observer agreement of associated flows.

[Factors Influencing the Variation in Phytoplankton Functional Groups in Fuchunjiang Reservoir].

To explore the distribution characteristics, blooming risk mechanism and driving factors of phytoplankton community structure in Fuchunjiang Reservoir. The variation characteristics of phytoplankton, zooplankton and physicochemical indicators in Fuchunjiang Reservoir and its upper and lower reaches were investigated in 2020 and 2021. Based on the phytoplankton functional groups, non-metric multidimensional scale analysis, redundancy analysis and other statistical methods, the seasonal succession characteristics and driving factors of phytoplankton functional groups were analyzed. A total of 18 phytoplankton functional groups were identified, in of which 10 were predominant. The composition of phytoplankton functional groups in the Fuchunjiang Reservoir was significant different. Spatially, the upstream were dominated by group C and P while the represent species were Cyclotella and Aulacoseira,reflecting the mixed meso-eutrophic environments. However, group P was the main group in Fuchunjiang reservoir, and the dominance decreased gradually along the stream direction. Meanwhile, in the downstream, MP has an absolute advantage at Qiantang River estuary. It reflected the environmental characteristics of frequent disturbance and high turbidity of tide-sensing rivers. In addition, the predominant functional groups demonstrated strong seasonal variations. The dominant functional groups were diverse in summer and consisted of P+L0+J+M+S1+H1+MP. In addition to group P (Aulacoseira), which was dominant throughout the year, it also included several groups represented by cyanobacteria and chlorophyta, reflecting the environmental characteristics of changeable habitats and vigorous productivity. In autumn, the succession was dominated by H1 group represented by Dolichospermum and the representative function groups were P and H1, reflecting the hydrological background of reduced flow and static flow. In winter, the increase of Cyclotella led to the predominance of group C, which was dominated by P+C, reflecting the changing conditions of weakened water exchange and intensified eutrophication problems. In spring, the dominant functional groups were gradually enriched and were composed of C, D, P, and MP, which also reflected the changing environmental habitat characteristics which caused by increasing rainfall and air temperature. According to the results of the C-R-S growth strategy, the Fuchunjiang Reservoir has been in the R strategy for a long time, which was consistent with the habitat characteristics of Fuchunjiang Reservoir and its upper and lower reaches with high disturbance and low stress. In addition, C strategy and S strategy appeared in some reaches, reflecting the variability of water quality and hydrology. RDA analysis showed that water temperature, discharge, zooplankton biomass, permanganate index, total nitrogen and total phosphorus were significantly correlated with the seasonal succession of phytoplankton functional groups (P < 0.05), and temperature and flow pattern were probably the most critical factors for the succession. Studies have shown that the impact of hydrometeorological processes on phytoplankton in the Fuchunjiang Reservoir is crucial:high temperature and changing discharge during the summer may lead to cyanobacterial blooms in the Fuchunjiang reservoir; To reduce the risk of algal blooms, it is still necessary to increase the control of nitrogen and phosphorus load in rivers, and fully consider the coordination of water conservancy dispatch methods.

Polysulfide Protects Against Diabetic Cardiomyopathy Through Sulfhydration of Peroxisome Proliferator-Activated Receptor-γ and Sirtuin 3.

Aims: Diabetic cardiomyopathy (DCM) is characterized by cardiac dysfunction and heart failure. However, the effective therapy for DCM is still lacking. Polysulfide contains chains of sulfur atoms, and accumulative evidence has shown that it actively participates in mammalian physiology or pathophysiology. Nevertheless, the potential effects and mechanisms of polysulfide in DCM need further investigation. In the present study, Na2S4, a polysulfide donor, was employed to investigate the therapeutic effects of polysulfide in DCM. Results: Our results showed that Na2S4 protected cardiomyocytes against high glucose (HG)-induced cardiomyocyte injury. The pathological changes in DCM including cell death, oxidative stress, mitochondrial dysfunction and cardiac hypertrophy were improved by Na2S4 treatment. The left ventricular contractile function in streptozotocin (STZ)-induced diabetic mice was significantly improved by Na2S4. Mechanistically, Na2S4 upregulated and sulfhydrated peroxisome proliferator-activated receptor-γ (PPARγ) and sirtuin 3 (SIRT-3) in cardiomyocytes. Suppression of PPARγ or SIRT-3 with their specific inhibitors or blockade of sulfhydration abolished the protective effects of Na2S4. Moreover, mutations of PPARγ or SIRT-3 at specific cysteines diminished the benefits of Na2S4 in HG-challenged cardiomyocytes. Innovation and Conclusion: We demonstrated that Na2S4 prevented the development of DCM via sulfhydration of both PPARγ and SIRT-3. Our results imply that polysulfide may be a potential and promising agent to treat DCM. Antioxid. Redox Signal. 38, 1-17.

[Influence of Denitrification on Cyanobacterial Blooms Trends in Lake Taihu, China].

Denitrification is a major process in aquatic ecosystems, and it competes with cyanobacterial growth for nitrogen. However, the effect of denitrification on cyanobacterial blooms under the background of climate change remains unclear. This study explored the interaction between lake denitrification and formation of cyanobacterial blooms, using the historical water quality monitoring data of North Lake Taihu over five years from 2017 to 2021 and via incubation experiments of cyanobacteria and sediment denitrification. The monitoring data showed that algal biomass (Chla as a proxy) primarily peaked during summer and autumn. The seasonal variations in total N concentration showed a completely opposite trend than that of algal biomass, which peaked in winter and spring. Nitrate was the major component of dissolved inorganic nitrogen, and the nitrate concentration was approximately zero in summer and autumn. The total phosphorus concentration varied in the same way as the Chla concentration. The experimental results showed that Cyanobacteria did not grow when the temperature was below 20℃. In comparison, denitrification showed a significant linear relationship with temperatures between 10-25℃ (R2=0.99) and reached the maximum value of (62.98±21.36) µmol·(kg·h)-1 in Lake Taihu at 25℃. Additionally, the nitrate concentration threshold at the maximum denitrification rate was 4 mg·L-1. Cyanobacteria assimilate nitrate for growth, thereby reducing the concentration of nitrate required for denitrification. This study indicated that the advance in lake temperature warming due to climate change may result in earlier growth of cyanobacteria, thereby leading to large amounts of N being assimilated by algae before denitrification, further affecting the dynamics of cyanobacterial blooms. The present results are scientifically important for explaining the mechanism of cyanobacterial bloom rebound in Lake Taihu under the background of recent climate changes.

LW-213 induces immunogenic tumor cell death via ER stress mediated by lysosomal TRPML1.

Dying tumor cells release biological signals that exhibit antigenicity, activate cytotoxic T lymphocytes, and induce immunogenic cell death (ICD), playing a key role in immune surveillance. We demonstrate that the flavonoid LW-213 activates endoplasmic reticulum stress (ERS) in different tumor cells and that the lysosomal calcium channel TRPML1 mediates the ERS process in human cellular lymphoma Hut-102 cells. Apoptotic tumor cells induced by ERS often possess immunogenicity. Tumor cells treated with LW-213 exhibit damage-associated molecular patterns (DAMPs), including calreticulin translocation to the plasma membrane and extracellular release of ATP and HMGB1. When co-cultured with antigen-presenting cells (APCs), LW-213-treated tumor cells activated APCs. Two groups of C57BL/6J mice were inoculated with Lewis cells: a "vaccine group", which demonstrated that LW-213-treated tumor cells promote the maturation of dendritic cells and increase CD8+ T cells infiltration in the tumor microenvironment and a "pharmacodynamic group", treated with a combination of LW-213 and PD1/PD-L1 inhibitor (BMS-1), which reduced tumor growth and significantly prolonged the survival time of mice in the "pharmacodynamic group". Therefore, LW-213 can be developed as a novel ICD inducer, providing a new concept for antitumor immunotherapy.

[Antitumor effect research progress of shikonin and its derivatives].

Shikonin, the main active ingredient of Lithospermum, and its derivatives have been proved to have antitumor effects, and the anti-tumor mechanisms involve multiple targets. Based on recent literatures, this review focuses on the antitumor effects and its mechanisms. More emphases are given on the aspects of induction of apoptosis, induction of necrosis, acting on matrix metalloproteinase, acting on the protein tyrosine kinase and antiangiogenesis. The current status and problems of shikonin derivatives in antitumor effects are simply summarized and lookout for the development of antitumor drugs with shikonin as leading compounds.

[Changes in Algal Particles and Their Water Quality Effects in the Outflow River of Taihu Lake].

Connected rivers are a common engineering method to ensure the ecological health of urban water. However, for the lakes with serious cyanobacteria blooms, the algal particles are carried by the outflow of the lake and will have a significant impact on water quality. The location at which the Liangxi river meets Meiliang Bay of Lake Taihu was selected to explore the influence of the eutrophic lake on the connected rivers, and high-frequency monitoring was conducted in summer for three consecutive years to analyze the changes in the flux of cyanobacterial bloom particles in rivers and their impact on river water quality. The results show that:① The improvement of the algal cyanobacteria bloom in Meiliang Bay and the operation of the pressure-controlled algae well at the entrance of the river significantly reduced the concentration of chlorophyll a and the flux of algae particles in the Liangxi River. The average value of the concentration of chlorophyll a and the flux of algae particles in the river in summer 2019 were 54.34 µg·L-1 and 84.7 t·d-1, respectively, and significantly lower than those of 2017; ② Water diversion had a significant effect on improving the water quality of the receiving water. Except for DTP, the nitrogen and phosphorus concentrations of the remaining forms of the Liangxi River showed a downward trend from 2017 to 2019, indicating that the water quality of the Liangxi river improved after water transfer; ③ A large amount of cyanobacterial blooms entering the channel significantly increased the particulate nitrogen and phosphorus content of the water. From 2017 to 2019, the nitrogen and phosphorus in the Liangxi River were mainly PN and PP, accounting for 62.5% and 70.8% of TN and TP, respectively; ④ The water quality of the Beijing-Hangzhou Grand Canal and other connected rivers has not been affected by the algal particles in Meiliang Bay. In August 2019, the chlorophyll a content in the canal water decreased by 65% compared with that of June, indicating that cyanobacterial bloom particles have not accumulated in the Grand Canal; ⑤ On the premise that the cyanobacteria bloom in the lake has not been effectively improved, the algae particles carried by the water diversion will have an impact on the water quality and landscape of the local reach connecting the river.

[Effects of Land Use on Nutrient Concentrations in the Inflow River of Lake Taihu, China].

Land use is an important factor affecting non-point nutrient loading. Here, the Wuxi River basin was selected to analyze the influence of sub-basin land use on nutrient concentrations using remotely sensed land use data and monthly river water quality variables from October 2019 to September 2020. The results showed that the water quality of the river was closely related to land-use type. Specifically, dryland farmland, villages, and building land have a strong promoting influence on nitrogen, phosphorus, organic carbon, and phytoplankton chlorophyll a. The proportion of orchard land was also positively correlated with river nutrient concentrations. A negative correlation was observed between the proportion of forest land and nutrient concentrations. Moreover, the proportion of the water area in rivers and reservoirs was negatively correlated with the total dissolved nitrogen and nitrate concentrations in the river, and the proportion of the water area in natural pits and fishponds was negatively correlated with river nitrate and ammonia concentrations. Furthermore, the proportion of river and fishpond areas was positively correlated with the concentration of dissolved total phosphorus, dissolved organic carbon, and the permanganate index, while the proportion of the natural pond area was positively correlated with the concentration of particulate phosphorus and phytoplankton chlorophyll a. The influence of land-use types on water quality was also affected by distance from the river. This research indicates that the appropriate utilization of land and wetlands is key to controlling non-point nutrient loading in the river network, including Lake Taihu. Specifically, the self-purification capacity of wetland waters should be incorporated into nutrient control schemes, and special attention should be paid to the reduction of non-point source pollution in the drylands along the downstream riverbanks and urbanized areas.

[Long-term Changes and Drivers of Ecological Security in Shahe Reservoir, China].

Monthly datasets of ecological indicators from 2010 to 2020 in Shahe Reservoir, Tianmuhu, China, were examined to reveal the long-term variations in water ecological security and its driving factors. The results of Secchi disk depth(SD) measurements revealed significantly spatial variation(P<0.05) within the reservoir. The highest SD was recorded in the downstream-linked reservoir, and the lowest SD was recorded in the upstream tributaries. In contrast, the values of other water ecological indicators were higher in the upstream tributaries than in the transition region and the downstream-linked reservoir area. In summer and autumn, the SD was low, while the concentrations of total phosphorous(TP), chlorophyll a(Chl-a), the permanganate index, and cyanobacterial biomass(BMc) were high. During the thermal stratification period from May to September, the concentrations of 2-methylisoborneol(MIB) and Chl-a were highest at a depth of 4 m, while diatom biomass(BMb) and BMc reached their maximum at depths of 2 m and 0.5 m, respectively. Therefore, spatial and temporal variations should be fully considered when evaluating aquatic ecological security. Focusing on spring and summer, when the risk of water ecological security was high, Chl-a combined with SD and MIB along with their correlation with other water quality indexes, was used to evaluate and optimize the ecological security of Shahe Reservoir. The evaluation results showed that the aquatic ecological security of the reservoir was excellent over the last 10 years; however, annual fluctuations have been large and the evaluation scores were spatially variable. While seasonal sampling strategies focusing on three layers depths are economical and reliable for lake regions with thermal stratification, our results indicate that tailored monitoring may be required to determine the aquatic ecological security of lakes and reservoirs. In Shahe Reservoir, the decrease in the SD and the increase in MIB caused by high TP and algal blooms were the most important drivers of ecological service function in the reservoir. Furthermore, hydrometeorological factors may also play important roles in the aquatic ecological security of reservoirs.

[Spatial Differences and Influencing Factors of Denitrification and ANAMMOX Rates in Spring and Summer in Lake Taihu].

Denitrification and ANAMMOX are the main nitrogen removal processes in lakes, which are of great significance for maintaining the nitrogen balance. Lake Taihu is a large, shallow lake. There are great spatial and temporal differences in the nutrient levels and algal blooms, which will affect the rates of denitrification and ANAMMOX. In order to understand the spatial and temporal variations in the denitrification and ANAMMOX rates and their influencing factors in Lake Taihu, undisturbed sediment cores were collected from Meiliang Bay, Gonghu Bay, Zhushan Bay, Dapukou Bay, Xukou Bay, and the center of Lake Taihu in the spring and summer of 2020. The results showed that the spatial distribution of the denitrification and ANAMMOX rates varied greatly in different areas of Lake Taihu in spring. The denitrification and ANAMMOX rates were (27.74±8.45)-(142.43±35.54) µmol·(m2·h)-1 and (2.35±1.06)-(17.95±8.66) µmol·(m2·h)-1, respectively. The contribution of ANAMMOX to nitrogen removal was relatively low, ranging from (7.82±1.71)% to (11.20±1.53)%. In summer, the denitrification and ANAMMOX rates were (165.68±62.14) µmol·(m2·h)-1 and (33.56±10.66) µmol·(m2·h)-1, respectively. The nitrogen removal rates were relatively low in other areas where the denitrification and ANAMMOX rates were (25.47±10.46)-(42.50±16.46) µmol·(m2·h)-1 and (2.65±0.94)-(5.95±2.65) µmol·(m2·h)-1, respectively. The contribution of ANAMMOX to nitrogen removal was (13.62±1.95)%-(7.24±1.78)%. The denitrification rate in summer was generally lower than that in spring, while the ANAMMOX rate did not decrease significantly compared with that in spring. The statistical analysis showed that the denitrification and ANAMMOX rates were significantly correlated with the substrate nitrogen concentration (P<0.01), which indicated that the nitrogen concentration was the main factor causing the difference in the nitrogen removal rates in different lake regions. In addition, there was a significant positive correlation between the contribution rate of ANAMMOX and the concentration of chlorophyll-a (P<0.05), thereby indicating that cyanobacteria blooms have a great influence on the change in the contribution of ANAMMOX to nitrogen removal.

Polysulfide-mediated sulfhydration of SIRT1 prevents diabetic nephropathy by suppressing phosphorylation and acetylation of p65 NF-κB and STAT3.

Diabetic kidney disease is known as a major cause of chronic kidney disease and end stage renal disease. Polysulfides, a class of chemical agents with a chain of sulfur atoms, are found to confer renal protective effects in acute kidney injury. However, whether a polysulfide donor, sodium tetrasulfide (Na2S4), confers protective effects against diabetic nephropathy remains unclear. Our results showed that Na2S4 treatment ameliorated renal dysfunctional and histological damage in diabetic kidneys through inhibiting the overproduction of inflammation cytokine and reactive oxygen species (ROS), as well as attenuating renal fibrosis and renal cell apoptosis. Additionally, the upregulated phosphorylation and acetylation levels of p65 nuclear factor κB (p65 NF-κB) and signal transducer and activator of transcription 3 (STAT3) in diabetic nephropathy were abrogated by Na2S4 in a sirtuin-1 (SIRT1)-dependent manner. In renal tubular epithelial cells, Na2S4 directly sulfhydrated SIRT1 at two conserved CXXC domains (Cys371/374; Cys395/398), then induced dephosphorylation and deacetylation of its targeted proteins including p65 NF-κB and STAT3, thereby reducing high glucose (HG)-caused oxidative stress, cell apoptosis, inflammation response and epithelial-to-mesenchymal transition (EMT) progression. Most importantly, inactivation of SIRT1 by a specific inhibitor EX-527, small interfering RNA (siRNA), a de-sulfhydration reagent dithiothreitol (DTT), or mutation of Cys371/374 and Cys395/398 sites at SIRT1 abolished the protective effects of Na2S4 on diabetic kidney insulting. These results reveal that polysulfides may attenuate diabetic renal lesions via inactivation of p65 NF-κB and STAT3 phosphorylation/acetylation through sulfhydrating SIRT1.

[Effect of Heavy Rainfall on Nitrogen and Phosphorus Concentrations in Rivers at River-net Plain].

To understand the quantitative effect of heavy rain on nitrogen and phosphorus pollution in river-net plain, daily observations of nutrient concentrations in two rivers, flowing into Lake Taihu, were conducted from 1st September, 2017 to 31st August, 2019. The daily rainfall was recorded by auto-recording meteorological stations located on the two rivers and the Taihu Laboratory for Lake Ecosystem Research. Intensive sampling in different sections of the two rivers during Super Typhoon Lekima was also conducted in August 2019. Using these datasets, the influence of heavy rainfall on various forms of nitrogen and phosphorus concentrations in the rivers, and its environmental effects, were analyzed. The results showed that 16 heavy rainfall events (19 d) were observed in two years, 50% of which occurred in the summer season. In addition, heavy rainfall accounted for as much as 41.33% of the total rainfall over the entire year. After the period of heavy rainfall, the concentrations of various forms of nitrogen and phosphorus increased, and the particulate P generally exhibited the fastest response, usually peaking on the day of heavy rainfall. In contrast, the peaks of N were delayed for 2-5 days with the occurrence of heavy rain. In general, the duration of the increase in the concentration of nutrients in the study river caused by heavy rainfall was short (usually 1-2 days), and sometimes was lower than the concentration before the rains. The Dapu River exhibited a slower response to heavy rains than the Yincun River because it has a larger and longer catchment area than the Dapu River. In addition, the effect of heavy rain on N and P concentrations was also strongly influenced by the land-use situation around the river basin. The increase of nitrogen in the reach, affected by agricultural non-point sources, was dominated by granular nitrogen, and the increase of nitrogen in the reach affected by urban non-point sources was dominated by dissolved nitrogen. The increase of phosphorus was dominated by granular phosphorus in the entire process. The conclusions of this study are as follows:In the plain river network area, the fluctuations of nitrogen and phosphorus concentrations in the river water body caused by heavy rainfall are small, and the response of various forms of nitrogen and phosphorus are significantly affected by the local environmental background. Therefore, the water quality generally exhibited limited variation. Due to the large proportion of water entering the lake during heavy rainfall events, a high level of the nutrient loading was also observed, and the occurrence of heavy rainfall was occasional. The short-term effect of heavy rainfall on the nitrogen and phosphorus loading entering the lake in the river channel in the plain river network area is therefore, also significant, and requires further investigation.

DR-region of Na+/K+-ATPase is a target to ameliorate hepatic insulin resistance in obese diabetic mice.

Reduced hepatic Na+/K+-ATPase (NKA) activity and NKAα1 expression are engaged in the pathologies of metabolism diseases. The present study was designed to investigate the potential roles of NKAα1 in hepatic gluconeogenesis and glycogenesis in both hepatocytes and obese diabetic mice. Methods: Insulin resistance was mimicked by glucosamine (GlcN) in either human hepatocellular carcinoma (HepG2) cells or primary mouse primary hepatocytes. Obese diabetic mice were induced by high-fat diet (HFD) feeding for 12 weeks. Results: We found that both NKA activity and NKAα1 protein level were downregulated in GlcN-treated hepatocytes and in the livers of obese diabetic mice. Pharmacological inhibition of NKA with ouabain worsened, while activation of NKAα1 with an antibody against an extracellular DR region of NKAα1 subunit (DR-Ab) prevented GlcN-induced increase in gluconeogenesis and decrease in glycogenesis. Likewise, the above results were also corroborated by the opposite effects of genetic knockout/overexpression of NKAα1 on both gluconeogenesis and glycogenesis. In obese diabetic mice, hepatic activation or overexpression of NKAα1 stimulated the PI3K/Akt pathway to suppress hyperglycemia and improve insulin resistance. More importantly, loss of NKA activities in NKAα1+/- mice was associated with more susceptibility to insulin resistance following HFD feeding. Conclusions: Our findings suggest that NKAα1 is a physiological regulator of glucose homoeostasis and its DR-region is a novel target to treat hepatic insulin resistance.