Bioequivalence and Safety Assessment of 2 Formulations of Low-Dose Metformin Hydrochloride under Fasting Conditions in Healthy Chinese Participants: A Randomized Phase 1 Clinical Trial.

The incidence of type 2 diabetes is high, and the existing metformin hydrochloride (MH) tablets of 250 mg cannot meet the demands of the Chinese drug market. This study aimed to evaluate the bioequivalence and safety of generic formulations of MH tablets (test formulation [T], 250 mg/tablet) and innovative products (reference formulation [R], 250 mg/tablet) under fasting conditions. This was an open-label, single-dose, 2-period, 2-sequence crossover, single-center, randomized phase I clinical trial. T and R were considered bioequivalent if the adjusted geometric mean ratios (GMRs) and 90% confidence intervals of the area under the curve (AUC) and maximum concentration (Cmax ) were within the range of 0.8-1.25. Thirty-five participants completed the trial. The T/R adjusted GMRs (95.7% for Cmax , 98.7% for AUC0→t , 98.8% for AUC0→∞ ) were within the acceptable bioequivalence range of 80%-125%. No serious adverse events or suspected or unexpected serious adverse reactions occurred during this trial. The study findings confirmed that generic MH is a well-tolerated and bioequivalent alternative to innovative products under fasting conditions in healthy Chinese participants. (www.chinadrugtrials.org.cn; registration no. CTR20190356).

Knockdown of the SELENOK gene induces ferroptosis in cervical cancer cells.

Selenoprotein K (SELENOK) is one of the endoplasmic reticulum (ER) proteins that mainly functions in the regulation of ER stress, calcium flux, and antioxidant defense. Reactive oxygen species (ROS) is one of the key indicators of ferroptosis, and SELENOK inhibition could disrupt ROS balance, and consequently might cause ferroptosis. However, there are no previous studies about the mechanism of SELENOK in ferroptosis by regulating ROS. In this study, we report the effect of SELENOK inhibition on cell proliferation, viability, iron recycling-associated proteins, ROS, antioxidant enzymes, and lipid peroxidation of cervical cancer cells (HeLa cells). The results showed that ROS levels and iron-dependent lipid peroxidation were significantly enhanced, whereas cell viability and proliferation were significantly downregulated, and resulted in marked reductions in tumor size after SELENOK knockdown. SELENOK knockdown also caused steep decreases in glutathione peroxidase 4/glutathione levels and deterioration in ROS scavenging ability, and exacerbated ferroptosis in HeLa cells. Our findings elucidated that SELENOK knockdown could shrink tumor size by regulating ferroptosis, which might provide a theoretical basis for treating cervical cancer.

Borana rangeland of southern Ethiopia: Estimating biomass production and carrying capacity using field and remote sensing data.

Assessing rangeland productivity is critical to reduce ecological degradation and promote sustainable livestock management. Here, we estimated biomass productivity and carrying capacity dynamics in the Borana rangeland of southern Ethiopia by using field-based data and remote sensing data (i.e., normalized difference vegetation index (NDVI)). Data was collected from both rainy and dry seasons when biomass production was high and low respectively. Results of linear regression showed that both biomass production (R2 adj = 0.672) and NDVI value (R2 adj = 0.471) were significantly decreased from 1990 to 2019. Field data and NDVI values for mean annual biomass showed a significant linear relationship. The model accuracy in the annual relationship between the observed and predicted biomass values was strong (R2 adj = 0.986) but with high standard error, indicating that the observed biomass production in the rangeland area was not in good condition as compared with the predicted one. This study suggests that, using NDVI data and field-based data in combined way has high potential to estimate rangeland biomass and carrying capacity dynamics at extensively grazed arid and semi-arid rangelands. And to use for estimating stoking rates and predicting future management techniques for decision making.

Selenomethionine Improves Mitochondrial Function by Upregulating Mitochondrial Selenoprotein in a Model of Alzheimer's Disease.

Alzheimer's disease (AD), the most common neurodegenerative disease in elderly humans, is pathologically characterized by amyloid plaques and neurofibrillary tangles. Mitochondrial dysfunction that occurs in the early stages of AD, which includes dysfunction in mitochondrial generation and energy metabolism, is considered to be closely associated with AD pathology. Selenomethionine (Se-Met) has been reported to improve cognitive impairment and reduce amyloid plaques and neurofibrillary tangles in 3xTg-AD mice. Whether Se-Met can regulate mitochondrial dysfunction in an AD model during this process remains unknown.In this study, the N2a-APP695-Swedish (N2aSW) cell and 8-month-old 3xTg-AD mice were treated with Se-Met in vitro and in vivo. Our study showed that the numbers of mitochondria were increased after treatment with Se-Met. Se-Met treatment also significantly increased the levels of NRF1 and Mfn2, and decreased those of OPA1 and Drp1. In addition, the mitochondrial membrane potential was significantly increased, while the ROS levels and apoptosis rate were significantly decreased, in cells after treatment with Se-Met. The levels of ATP, complex IV, and Cyt c and the activity of complex V were all significantly increased. Furthermore, the expression level of SELENO O was increased after Se-Met treatment. Thus, Se-Met can maintain mitochondrial dynamic balance, promote mitochondrial fusion or division, restore mitochondrial membrane potential, promote mitochondrial energy metabolism, inhibit intracellular ROS generation, and reduce apoptosis. These effects are most likely mediated via upregulation of SELENO O. In summary, Se-Met improves mitochondrial function by upregulating mitochondrial selenoprotein in these AD models.

Selenoprotein K deficiency-induced apoptosis: A role for calpain and the ERS pathway.

Selenoprotein K (SELENOK), an endoplasmic reticulum (ER) resident protein, is regulated by dietary selenium and expressed at a relatively high level in neurons. SELENOK has been shown to participate in oxidation resistance, calcium (Ca2+) flux regulation, and the ER-associated degradation (ERAD) pathway in immune cells. However, its role in neurons has not been elucidated. Here, we demonstrated that SELENOK gene knockout markedly enhanced ER stress (ERS) and increased apoptosis in neurons. SELENOK gene knockout elicited intracellular Ca2+ flux and activated the m-calpain/caspase-12 cascade, thus inducing neuronal apoptosis both in vivo and in vitro. In addition, SELENOK knockout significantly reduced cognitive ability and increased anxiety in 7-month-old mice. Our findings reveal an unexpected role of SELENOK in regulating ERS-induced neuronal apoptosis.

Corrigendum: Selenomethionine Improves Mitochondrial Function by Upregulating Mitochondrial Selenoprotein in a Model of Alzheimer's Disease.

[This corrects the article DOI: 10.3389/fnagi.2021.750921.].

[Efficacy of the Sentinel Mouse Method in Monitoring Schistosoma japonicum Infection in Key #br# Water Areas of Hanchuan City].

Objective: To understand the water infectivity of schistosomes in key water areas of Hanchuan City, and explore the use of sentinel mice in surveillance and forecast of schistosomiasis. Methods: Surveillance and forecast sites were set up in North Han River, Diaocha Lake, and Miaowu Ditch in 2014. Sentinel mice （male Kunming mice, n=20 in each site） were placed there within the first ten-day period of June and September, respectively. Field detections lasted 4 h each, for a total of 2 days. The loss and death rates of mice were recorded. Humans and livestocks with activities in these sites were also examined for schistosome infection. The sentinel mice recovered were raised in laboratory for 35 days, dissected, and examined for liver granulomas and adult worm counting. The distribution of sites with positive detections and their infection status were analyzed. Emergency measures were taken in the positive sites. Results: A total of 13（5 sites in North Han River, 5 in Diaocha Lake, and 3 in Miaowu Ditch） surveillance and forecast sites were set up. No infected snail was detected in any of these sites in spring 2014. The detection rate of living snails in North Han River （18.7%, 224/1 201) was significantly higher than that in Diaocha Lake（12.8%, 852/6 644） and in Miaowu Ditch （6.4%, 202/3 147）（P<0.01）. Of the 520 mice placed, 6 were lost, and 514 were recovered, among which 4 mice died during laboratory raising. The remaining 510 sentinel mice were then dissected, revealing infection in 4 mice, with a positive rate of 0.8%. Twenty-seven Schistosoma japonicum worms were collected, and the mean worm burden of positive mice was 6.8 worms per mouse. Three sites (Sansi village, Kangjia village and Doubu village) were found to be positive sites of infection in September, with the detailed number of 2, 1 and 0 in North Han River, Diaocha Lake, and Miaowu Ditch respectively, with a positive rate of 1.5% （3/197）, 0.5% （1/195） and 0 （0/118） in sentinel mice （P>0.05）. In addition, among the 22 cattle found in the 13 sites, 2 were infected with schistosomes; and among the 62 fishermen and boatmen, 2 were infected. Emergency measures were taken in the three positive sites, and no high endemicity occurred. Conclusion: The monitoring of sentinel mice infections can improve the sensitivity of the surveillance and forecast system of schistosomiasis. The infected fishermen and cattle remain the major source of schistosomiasis transmission in Hanchuan City.

[Three-dimension temporal and spatial dynamics of soil water for the artificial vegetation in the center of Taklimakan desert under saline water drip-irrigation].

Three-dimension temporal and spatial dynamics of the soil water characteristics during four irrigating cycles of months from April to July for the artificial vegetation in the center of Taklimakan Desert under saline water drip-irrigation had been analyzed by timely measuring the soil water content in horizontal and vertical distances 60 cm and 120 cm away from the irrigating drips, respectively. Periodic spatial and temporal variations of soil water content were observed. When the precipitation effect was not considered, there were no significant differences in the characteristics of soil water among the irrigation intervals in different months, while discrepancies were obvious in the temporal and spatial changes of soil moisture content under the conditions of rainfall and non-rainfall. When it referred to the temporal changes of soil water, it was a little higher in April but a bit lower in July, and the soil water content in June was the highest among four months because some remarkable events of precipitation happened in this month. However, as a whole, the content of soil moisture was reduced as months (from April to July) went on and it took a decreasing tendency along with days (1-15 d) following a power function. Meanwhile, the characteristics of soil water content displayed three changeable stages in an irrigation interval. When it referred to the spatial distributions of soil water, the average content of soil moisture was reduced along with the horizontal distance following a linear regression function, and varied with double peaks along with the vertical distance. In addition, the spatial distribution characteristics of the soil water were not influenced by the factors of precipitation and irrigating time but the physical properties of soil.

[Effect of shifting sand burial on evaporation reduction and salt restraint under saline water irrigation in extremely arid region].

The Taklimakan Desert Highway Shelterbelt is drip-irrigated with high saline groundwater (2.58-29.70 g x L(-1)), and shifting sand burial and water-salt stress are most common and serious problems in this region. So it is of great importance to study the effect of shifting sand burial on soil moisture evaporation, salt accumulation and their distribution for water saving, salinity restraint, and suitable utilization of local land and water resources. In this study, Micro-Lysimeters (MLS) were used to investigate dynamics of soil moisture and salt under different thicknesses of sand burial (1, 2, 3, 4, and 5 cm), and field control experiments of drip-irrigation were also carried out to investigate soil moisture and salt distribution under different thicknesses of shifting sand burial (5, 10, 15, 20, 25, 30, 35, and 40 cm). The soil daily and cumulative evaporation decreased with the increase of sand burial thickness in MLS, cumulative evaporation decreased by 2.5%-13.7% compared with control. And evaporative inhibiting efficiency increased with sand burial thickness, evaporative inhibiting efficiency of 1-5 cm sand burial was 16.7%-79.0%. Final soil moisture content beneath the interface of sand burial increased with sand burial thickness, and it increased by 2.5%-13.7% than control. The topsoil EC of shifting sand in MLS decreased by 1.19-6.00 mS x cm(-1) with the increasing sand burial thickness, whereas soil salt content beneath the interface in MLS increased and amplitude of the topsoil salt content was higher than that of the subsoil. Under drip-irrigation with saline groundwater, average soil moisture beneath the interface of shifting sand burial increased by 0.4% -2.0% compare with control, and the highest value of EC was 7.77 mS x cm(-1) when the sand burial thickness was 10 cm. The trend of salt accumulation content at shifting sand surface increased firstly, and then decreased with the increasing sand burial thickness. Soil salt contents beneath the interface of shifting sand burial were much lower than that of shifting sand surface. 35 cm was the critical sand burial thickness for water-saving and salt restraint. In summary, sand burial had obvious inhibition effects on soil evaporation and salt accumulation, so maybe it could be used to save water and reduce salt accumulation in arid shifting desert areas.

[Effect of comprehensive schistosomiasis control strategy based on infection source control in Hanchuan City].

OBJECTIVE: To evaluate the effect of comprehensive schistosomiasis control measures based on infection source control in Hanchuan City (marshland and lake endemic regions). METHODS: The data of comprehensive schistosomiasis control in Hanchuan City from 2004 to 2013 were collected, and the change trends of the Oncomelania hupensis snail status and the infection situation of human and livestock were analyzed to evaluate the control effect. RESULTS: After the implementation of the comprehensive measures, the infection rates of residents and cattle decreased from 6.38% and 8.11% in 2004 to 0.16% and 0 in 2013 respectively. There were no acute schistosomiasis patients since 2007, no new infection cases since 2011, and no infected snails since 2012. Compared with 2004, the occurrence rate of frames with living snails and the average density of living snails decreased by 56.78% and 68.35%, respectively, but the snail area and susceptible area increased by 0.62% and 7.10%, respectively. In 2013, all the 367 endemic villages in 26 townships reached the criteria of transmission controlled. CONCLUSIONS: The comprehensive schistosomiasis control measures based on infection source control can control the schistosomiasis transmission effectively in marshland and lake endemic regions. When consolidating the achievement, the snail area in inner embankment should be compressed to prevent the schistosome re-infection in human and livestock.

[Variation characteristics of soil microbial activities in the Tarim Desert Highway shelter forests, Xinjiang of Northwast China].

By the methods of Biolog, fumigation extraction, and colorimetric titration, this paper determined the soil carbon sources metabolic intensities, microbial biomass, and enzyme activities in the Tarim Desert Highway shelter-forests with different plantation times, and analyzed the variation characteristics of soil microbial activities in these shelter forests. With the increasing planting years of the shelter forests, the soil microbial metabolic activities (AWCD) and microbial diversity indices enhanced obviously, but the AWCD values in different soil layers had no significant differences. The soil catalase activity among the forests had no significant difference, but the soil cellulase and sucrase activities varied significantly. The soil microbial biomass carbon and nitrogen increased with the increasing planting years of the shelter forests, having a significant difference among the forests, but the microbial biomass phosphorus had no significant difference. The AWCD values had significant correlations with soil available nutrient contents, but less correlations with soil bulk density and moisture content. It was suggested that under the present management patterns and climate conditions, the soil metabolic activities in the Tarim Desert Highway shelter forests would be improved continuously with the increasing planting years of the forests.

[Field evaluation of a novel plant molluscicide "Luo-wei" against Oncomelania hupensis snails II molluscicidal effect in the field of lake areas in Hanchuan City, Hubei Province].

OBJECTIVE: To evaluate the effect of a novel plant molluscicide "Luo-wei" (Tea-seed distilled saponins, TDS) against Oncomelania hupensis in the field of lake areas in Hanchuan City, Hubei Province. METHODS: Immersing experiment and spraying experiment were carried out in 5 ditches and a beach land respectively in Hanchuan City, Hubei Province to compare the molluscicidal effects among 4% TDS, 50% wettable powder of niclosamide ethanolamine salt (WPN), and 26% suspension concentrate of metaldehyde and niclosamide (MNSC) by different dosages and time. The chi2 test or Fish's exact test was used to examine the differences of snail death rates among them. RESULTS: After 72 h of immersing experiment, the snail death rates in the 2.5 g/m3 TDS group, 3.0 g/m3 TDS group, 2.0 g/m3 WPN group and 2.0 g/m3 MNSC group were 99.33%, 100%, 100%, and 100%, respectively, and there was no significant difference among them (P > 0.05). By the end of 15 d after the spraying experiments, the snail death rates were 91.86% in the 2.0 g/m2 MNSC group, 90.26% in the 5.0 g/m2 TDS group, 87.45% in the 2 g/m2 WPN group, and 86.10% in the 3 g/m2 TDS group. The differences between the 5.0 g/m2 TDS group and 2.0 g/m2 MNSC group, as well as the 3.0 g/m2 TDS group and the 2.0 g/m2 WPN group had no statistical significance (both P > 0.05). CONCLUSIONS: The molluscicidal effect of TDS is similar to that of WPN or MNSC. The recommended dosage of TDS is 2.5 g/m3 for immersing or 5 g/ m2 for spraying in the field.

[Effects of different prevention and control measures on schistosomiasis prevalence in different limnetic regions].

OBJECTIVE: To compare the schistosomiasis control effects of the comprehensive control measures based on infectious resources control and the conventional control measures, so as to provide the evidence for improving prevention and control strategies. METHODS: In the Hanbei River basin, the comprehensive control measures based on infectious resources control (conventional measures plus grazing prohibition in the marshland, machine instead of cattle, and marshland development, and so on) were carned out, and in the Nanzhi River basin, the conventional control measures were performed. The schistosomiasis epidemic data were collected, analyzed and compared from 2004 to 2011. RESULTS: In 2004, the infection rate of the populations and cattle in Nanzhi River basin was lower than that in the Hanbei River basin. From 2004 to 2011, the Oncomelania hupensis snail frame occurrence rate and the average density of living snails in the Nanzhi River basin was lower than that in the non-ploughing marshland and preventing wave woods of the Hanbei River basin, and there were schistosome infected snails in the Nanzhi River basin. From 2008 to 2010, there were no infected snails in the non-ploughing marshland of the Hanbei River basin. From 2007, the cattle have been eliminated in the Hanbei River basin. From 2007 to 2011, there were no infected snails in the preventing wave woods of the Hanbei River, but there were schistosome infected cattle found by stool examinations every year in the Nanzhi River basin. From 2004 to 2011, the infection rates of population presented downward trends in the two river basins, but the downward trend was more significant in the Hanbei River basin than in the Nanzhi River basin. CONCLUSION: The conventional control measures and comprehensive control measures based on infectious resources control are both effective, but the latter is more effective.

[Effects of stumping on Calligonum mongolicum shelterbelt growth and soil moisture and salt distribution along Tarim Desert Highway, Xinjiang of Northwest China].

In order to ensure the stability and sustainability of the Calligonum mongolicum shelterbelt along Tarim Desert Highway, the aged C. mongolicum was stumped to investigate its growth and soil moisture and salt distribution. After stumping twice, C. mongolicum grew rapidly in its height, crown width, maximum basal diameter, and sprout number. Three years after stumping, the average height of the sprouts exceeded the control (no stumping), and the crown width and maximum basal diameter was 92.0% and 73.0% of the control, respectively. The fresh mass of the branches and assimilating branches, their dry mass, and the total fresh mass and dry mass of the aboveground parts reached 80.0%, 115.0%, 80.0%, 116.0%, 93.5%, and 88.0% of the control, respectively. Four years after stumping, the aboveground biomass surpassed the control. Comparing with the control, stumping increased the soil moisture content significantly and decreased the soil salt concentration. It was suggested that, to stump the aged C. mongolicum repeatedly could increase the soil moisture content and decrease the soil salt concentration in root zone, and effectively promote the rejuvenation and renewing of C. mongolicum.

[Effects of thinning on Calligonum arborescens growth and soil water-salt distribution in Tarim Desert Highway shelterbelt, Xinjiang of Northwest China].

In order to understand the effects of thinning on the growth of Calligonum arborescens and the soil water-salt distribution in Tarim Desert Highway shelterbelt, a thinning experiment was conducted on an aged and declined C. arborescens woodland in a demonstration section of the shelterbelt, with the growth of C. arborescens and the soil water-salt distribution monitored. Thinning had no effects on the phenophase of C. arborescens, but after thinning, the growth of the current year plant height, crown width, ground diameter, and new branch length of reserved trees was larger than that of the control, and the increment was in the order of planting space 2 mx 1 m > 1 m x 1 m > the control, with significant differences among the treatments. The assimilation branch surface area in treatments 2 mx 1 m and 1 m x 1 m were 5.97 m2 and 5.22 m2 per plant, respectively, being significantly larger than the control (3.1 m2 per plant). The soil moisture content in 0-160 cm layer was significantly higher in treatments 2 m x 1 m and 1 mx 1 m than in the control, and increased obviously with thinning intensity. The soil salt content was in the order of control > planting space 1 m x 1 m > 2 m x 1 m, and the differences among the treatments were significant. It was suggested that the best reserved plant density after thinning was planting space 2 m x 1 m.

[Effects of the grain size and thickness of dust deposits on soil water and salt movement in the hinterland of the Taklimakan Desert].

By using mcirolysimeter, a laboratory simulation experiment was conducted to study the effects of the grain size and thickness of dust deposits on the soil water evaporation and salt movement in the hinterland of the Taklimakan Desert. Under the same initial soil water content and deposition thickness condition, finer-textured (<0.063 mm) deposits promoted soil water evaporation, deeper soil desiccation, and surface soil salt accumulation, while coarse-textured (0.063-2 mm) deposits inhibited soil water evaporation and decreased deeper soil water loss and surface soil salt accumulation. The inhibition effect of the grain size of dust deposits on soil water evaporation had an inflection point at the grain size 0.20 mm, i. e., increased with increasing grain size when the grain size was 0.063-0.20 mm but decreased with increasing grain size when the grain size was > 0.20 mm. With the increasing thickness of dust deposits, its inhibition effect on soil water evaporation increased, and there existed a logarithmic relationship between the dust deposits thickness and water evaporation. Surface soil salt accumulation had a negative correlation with dust deposits thickness. In sum, the dust deposits in study area could affect the stability of arid desert ecosystem.

[Relationships of soil microbial biomass with soil environmental factors in Tarim Desert highway shelter-forest].

By using correlation analysis, this paper studied the relationships of soil microbial quantity and biomass with soil physical and chemical factors and enzyme activities in highway shelter-forests of Tarim Desert, aimed to approach the interactions between microbes and environmental factors in aeolian sandy soil of extremely arid area. The results showed that soil microbial quantity and biomass in the shelter-forests had an increasing trend with the decrease of soil bulk density and particle size (R < -0.84) and the increase of soil moisture content and porosity (R > 0.85), with the correlation between soil microbial biomass and soil bulk density as the key. Soil microbial quantity and biomass were positively correlated with soil nutrient contents, mainly caused by the correlations of soil actinomycetes and microbial biomass C and P with soil available nutrients. Greater differences (R = 0.51-0.91) were observed in the correlations of soil enzyme activities with soil microbial quantity and biomass, which was mainly determined by the correlations of soil invertase and phosphatase activities with soil actinomycetes and microbial biomass C. The increase of soil salt content was not favorable to the accumulation of soil microbial biomass (R < -0.71), and there was a higher positive correlation (R > 0.63) between soil microbial amount and biomass. In practice, good soil condition should be established in the forestlands of arid area for the development of soil microbes and the promotion of soil matter cycling.