Flowering repressor CmSVP recruits the TOPLESS corepressor to control flowering in chrysanthemum.

Plant flowering time is induced by environmental and endogenous signals perceived by the plant. The MCM1-AGAMOUSDEFICIENS-Serum Response Factor-box (MADS-box) protein SHORT VEGETATIVE PHASE (SVP) is a pivotal repressor that negatively regulates the floral transition during the vegetative phase; however, the transcriptional regulatory mechanism remains poorly understood. Here, we report that CmSVP, a chrysanthemum (Chrysanthemum morifolium Ramat.) homolog of SVP, can repress the expression of a key flowering gene, a chrysanthemum FLOWERING LOCUS T-like gene (CmFTL3), by binding its promoter CArG element to delay flowering in the ambient temperature pathway in chrysanthemum. Protein-protein interaction assays identified an interaction between CmSVP and CmTPL1-2, a chrysanthemum homologue of TOPLESS (TPL) that plays critical roles as transcriptional corepressor in many aspects of plant life. Genetic analyses revealed the CmSVP-CmTPL1-2 transcriptional complex is a prerequisite for CmSVP to act as a floral repressor. Furthermore, overexpression of CmSVP rescued the phenotype of the svp-31 mutant in Arabidopsis (Arabidopsis thaliana), overexpression of AtSVP or CmSVP in the Arabidopsis dominant-negative mutation tpl-1 led to ineffective late flowering, and AtSVP interacted with AtTPL, confirming the conserved function of SVP in chrysanthemum and Arabidopsis. We have validated a conserved machinery wherein SVP partially relies on TPL to inhibit flowering via a thermosensory pathway.

Safflower yellow for injection enhances anti-coagulation of warfarin in rats: implications in pharmacodynamics and pharmacokinetics.

This study investigated whether Safflower Yellow for injection (SYI) would affect the anticoagulation of warfarin in rats.Wistar male rats were divided into six groups randomly and administered with SYI (9 mg/kg, intraperitoneal injection) in single-dose and steady-dose warfarin (0.2 mg/kg, oral gavage), respectively. The pharmacodynamic parameters of PT and APTT were measured by a coagulation analyser. R/S-warfarin concentration was measured by UHPLC-MS/MS, and pharmacokinetic parameters calculated using DAS 2.0 software.The single-dose study demonstrated that SYI, alone or co-administered with warfarin, could significantly increase PT, INR, and APTT values (p < 0.01). R-warfarin Cmax, AUC, and t1/2 values increased by 9.25% (p > 0.05), 25.96% (p < 0.01), and 26.17% (p < 0.01), respectively, whereas the CL/F value reduced by 22.22% (p < 0.01) in the presence of SYI. Meanwhile, S-warfarin Cmax, AUC, and t1/2 values increased by 37.41%, 32.11%, and 31.73% (all p < 0.01), respectively, whereas the CL/F value reduced by 33.33% (p < 0.01). The steady-dose study showed that PT, INR, APTT, and the concentrations of R/S-warfarin increased significantly when SYI was co-administered with warfarin (p < 0.01).SYI can enhance warfarin's anticoagulation intensity and decelerate its metabolism in rats.

Composite water value: A way forward to balance the development and protection of transboundary lakes.

Transboundary lakes are shared by multiple administrative regions. The key to balance the development and protection of transboundary lakes is to properly measure the value of water resources. Most of previous studies on the measurement of lake water resources value have not fully considered the ecosystem service function. This paper proposes a new concept "composite water value" to measure the value of transboundary lakes by integrating the external runoff value and the internal runoff value of water resources. The study constructs a composite water value measurement system for transboundary lakes, further analyzes its influencing factors,and applies the system to the case of Nansi Lake, a representative transboundary lake in eastern China. The results show that: (1) The composite water value of lakes is influenced by various factors, including industrial structure, water withdrawal, and water use methods, which impact the external runoff water value; meanwhile, the composite water quality and fluctuations in lake level are closely associated with the internal runoff water value. From 2008 to 2021, the average annual composite water value of Nansi Lake was 39.628 billion yuan, exhibiting a "rising-falling-fluctuating rising" trend due to pollution control policies, reduced precipitation, and enhanced water-saving technologies successively. (2) From a long-term perspective, it is necessary to focus on the internal runoff water use value of lakes. The internal runoff water value of Nansi Lake has been over 75% of the composite water value, and flood storage and water conservation are important manifestations of its ecosystem service value. (3) The external runoff water value of lake is closely related to the internal runoff water value, and relevant departments need to consider the balance between the water withdrawal of multiple cities along the lake and the retained water volume of the lake to achieve the maximum benefit of composite water value.

Solvent-Induced Umpolung Reaction from Dioxygenation to C-S Coupling in Bis(2-phenylquinoline) Iridium(III) Thiolate Complexes.

The construction of C-S bonds is of great importance in the field of synthetic and medicinal chemistry. Herein, solvent-induced umpolung reactions from dioxygenation to interligand C-S cross-coupling in bis(cyclometalated) Ir(III) thiolate complexes are reported in good to excellent yields at room temperature. Specifically, the reaction of rac-[Ir(pq)2(aet)] (where pq is 2-phenylquinoline and aet is 2-aminoethanethiolate) can be selectively switched to dioxygenation in acetonitrile solution in the presence of O2, resulting in the formation of a sulfinato complex rac-[Ir(pq)2(aes)] (where aes is 2-aminoethanesulfinato). Alternatively, the reaction in trifluoroethanol solution leads to interligand C-S cross-coupling, affording a rac-[Ir(pq)(pqaet)](PF6) [where pqaet is 2-((2-phenylquinolin-8-yl)thio)ethan-1-amine] complex, which generates a new tetradentate ligand in situ. Mechanistically, the formation of electrophilic metal thiyl radicals is proposed as a key intermediate in the interligand C-S coupling reaction. Furthermore, the sequential oxidation of a thioether complex into a sulfoxide complex is also observed at room temperature using H2O2 as an oxidant. Additionally, a new approach for the synthesis of a hexadentate ligand is developed through sequential C-S and C-N interligand coupling of metal thiolate complexes in situ under visible light irradiation in the presence of O2.

A study on dynamic simulation and improvement strategies of flood resilience for urban road system.

As one of the most important and directly affected infrastructure by flood disasters in urban areas, the road system plays a crucial role in maintaining the order of human production and life, as well as providing a foundation for the implementation of emergency response work in disaster scenarios. The existing flood resilience quantification methods based on maximum inundation depths of each individual road unit neglects the influences on flood resilience caused by the connectivity of road system. Therefore, this paper focuses on the road system, simulates the flood resilience of the road system in multiple disaster scenarios based on the functionality curve of road system under rainfall-inundation processes, then quantifies the improvement effect of Low Impact Development (LID) measures on flood resilience. A case study is conducted in Yunmen community, Jingdezhen city in China. The results indicate that: (1) The flood resilience of the road system decreases with the increase of rainfall intensity under different scenarios, and the magnitude of the decrease reduces. (2) The road system exhibits strong adaptability during the early stages of rainfall; The duration of functionality loss increases with increasing of rainfall intensity in different scenarios. (3) Implementation of LID measures can significantly improve system robustness by enhancing the reliability of the roads around critical nodes, thereby effectively enhancing flood resilience. The conclusions can provide a theoretical basis for decision-makers to develop urban flood mitigation engineering plans and resilience strategies tailored to local conditions.

China Medicinal Plants of the Ampelopsis grossedentata-A Review of Their Botanical Characteristics, Use, Phytochemistry, Active Pharmacological Components, and Toxicology.

Ampelopsis grossedentata (AG) is mainly distributed in Chinese provinces and areas south of the Yangtze River Basin. It is mostly concentrated or scattered in mountainous bushes or woods with high humidity. Approximately 57 chemical components of AG have been identified, including flavonoids, phenols, steroids and terpenoids, volatile components, and other chemical components. In vitro studies have shown that the flavone of AG has therapeutic properties such as anti-bacteria, anti-inflammation, anti-oxidation, enhancing immunity, regulating glucose and lipid metabolism, being hepatoprotective, and being anti-tumor with no toxicity. Through searching and combing the related literature, this paper comprehensively and systematically summarizes the research progress of AG, including morphology, traditional and modern uses, chemical composition and structure, and pharmacological and toxicological effects, with a view to providing references for AG-related research.

Change of motifs in C. elegans reveals developmental principle of neural network.

Revealing the organizing principles of developing neural networks is a difficult but significant task in neuroscience. As a creature with a rather compact and well-studied neural network, C. elegans is an ideal subject for neuroscience study. However, the researches on its developing neural network remain challenging. The changes in specific properties of neural network across development may uncover part of its principles. Motif is a typical structure property that can be well applied to various complex networks. Here, we study the motif changes in C. elegans neural network across development. By counting the occurrence number of all three-node subgraph motif structures in its neural network at different stages of C. elegans development, along with those in corresponding random networks, we determine which of these structures are motifs for C. elegans, finding out the regular changes of motifs during its development. Combined with the potential function of these subgraph motifs and synaptic information, we gain insight into the organizing principle of neural network during development, which may increase our understanding of neuroscience and inspire the construction of artificial neural network.

Melatonin biosynthesis and signal transduction in plants in response to environmental conditions.

Melatonin, the most widely distributed hormone in nature, plays important roles in plants. Many physiological processes in plants are linked to melatonin, including seed germination, anisotropic cell growth, and senescence. Compared with animals, different plants possess diverse melatonin biosynthetic pathways and regulatory networks. Whereas melatonin biosynthesis in animals is known to be regulated by ambient signals, little is known about how melatonin biosynthesis in plants responds to environmental signals. Plants are affected by numerous environmental factors, such as light, temperature, moisture, carbon dioxide, soil conditions, and nutrient availability at all stages of development and in different tissues. Melatonin content exhibits dynamic changes that affect plant growth and development. Melatonin plays various species-specific roles in plant responses to different environmental conditions. However, much remains to be learned, as not all environmental factors have been studied, and little is known about the mechanisms by which these factors influence melatonin biosynthesis. In this review, we provide a detailed, systematic description of melatonin biosynthesis and signaling and of the roles of melatonin in plant responses to different environmental factors, providing a reference for in-depth research on this important issue.

Sex differences in the pharmacokinetics and tissue residues of Macleaya cordata extracts in rats.

Macleaya cordata extracts (MCE) are listed as feed additives in animal production by the European Food Authority. The core components of MCE are mainly sanguinarine (SA) and chelerythrine (CHE). This study aims to investigate sex differences in the pharmacokinetics and tissue residues of MCE in rats.Male and female rates were intragastrically administered MCE (1.25 mg·kg-1 body weight and 12.5 mg·kg-1 body weight dose for 28 days). SA and CHE concentrations were determined using high-performance liquid chromatography/tandem mass spectrometry.The peak plasma concentration (Cmax) and area under the curve (AUC) of both CHE and SA were higher in female than in male rats (12.5 mg·kg-1 body weight group), whereas their half-life (T1/2) and apparent volume of distribution (Vd) was lower (p < 0.05). Tissue rfesidue analysis indicated that SA and CHE were more distributed in male than in female rats and were highly distributed in the caecum and liver. SA and CHE were completely eliminated from the liver, kidney, lung, heart, spleen, leg muscle, and caecum after 120 h, indicating they did not accumulate in rats for a long time.Overall, we found that the pharmacokinetics and tissue residues of SA and CHE of male and female rats showed sex differences.

Pharmacokinetics and Pharmacodynamics of Linezolid in Patients With Sepsis Receiving Continuous Venovenous Hemofiltration and Extended Daily Hemofiltration.

BACKGROUND: This prospective study compared pharmacokinetics (PK) and pharmacodynamics (PD) of linezolid in patients with sepsis receiving continuous venovenous hemofiltration (CVVH) with patients receiving extended daily hemofiltration (EDH). METHODS: Patients with sepsis treated with linezolid and CVVH or EDH were included. Serial blood samples were collected and linezolid concentrations measured. PKs were analyzed using Pmetrics. Monte Carlo simulations were used to evaluate PD target achievement. RESULTS: From 20 patients, 320 blood samples were collected for PK and PD analysis. PK profiles of linezolid were best described by a 2-compartment model. PK parameters were not significantly different between EDH and CVVH groups and were associated with body weight, renal replacement therapy (RRT) duration, and sequential organ failure assessment score. Monte Carlo simulations showed poor fractional target attainment for a minimum inhibitory concentration (MIC) of 2 mg/L with standard 600 mg intravenous administration every 12 hours. CONCLUSIONS: Patients with sepsis receiving RRT exhibited variability in PK/PD parameters for linezolid. PK parameters were not significantly different between CVVH- and EDH-treated patients. Higher probability of target attainment would be achievable at a MIC of 2 mg/L in EDH patients. Higher linezolid doses should be considered for patients on RRT to achieve adequate blood levels.

Subcomponent Self-Assembly of Covalent Metallacycles Templated by Catalytically Active Seven-Coordinate Transition Metal Centers.

Coordination geometries of transition metals play vital roles in the self-assembly process of supramolecular coordination complexes. Herein, seven-coordinate 3d metal ions were applied as templates and catalytically active sites for subcomponent self-assembly that resulted in a new category of covalent metallacycles. Single-crystal structures showed that the sizes, configurations, and functionalization of covalent metallacycles could be tuned by the selection of rigid dihydrazide, transition metal ions, and prefunctionalized subcomponents, respectively. Moreover, metallacycles decorated with carboxylic groups could be employed as precursors to prepare aerogels through hierarchical self-assembly, which also exhibited high catalytic activity for cycloaddition of CO2 into cyclic carbonates.

Effects of sulfotanshinone sodium injection on the pharmacokinetics and pharmacodynamics of warfarin in rats in vivo.

This study was to explore the effects of sulfotanshinone sodium injection (SSI) on the pharmacokinetics and pharmacodynamics of warfarin in rats.The studies of single dose and multiple dose of warfarin were designed to assess the interaction between warfarin and SSI. Rats were divided into different groups randomly and administered with warfarin in the absence or presence of SSI. Prothrombin time (PT) and activated partial thromboplastin time (APTT) values were detected by blood coagulation analyzer, and international normalized ratio (INR) values were calculated. Plasma concentrations of warfarin enantiomers were determined by UPLC-MS/MS method, pharmacokinetic parameters were calculated.The single-dose study demonstrated that the repeated doses of SSI alone had no effect on PT, APTT and INR values, but had a significant effect on PT and INR values produced by a single dose of warfarin, APTT values were unaffected. The Cmax, AUC of R-warfarin and S-warfarin were reduced, t1/2 were shortened. The multiple-dose study showed that PT, APTT, INR values, and the Cmax and AUC of R-warfarin and S-warfarin decreased significantly after administration of SSI.The finding implied that SSI could accelerate warfarin metabolism and weaken its anticoagulation. However, human SSI-warfarin interaction studies need to be conducted to confirm this finding.

Effects of shuanghuanglian injection on the activities of CYP1A2, 2C11, 2D1 and 3A1/2 in rats in vivo and in vitro.

Shuanghuanglian Injection (SHLI), one of the most popular herbal prescription in China, has been commonly used to treat pneumonia, tonsillitis, and other respiratory diseases caused by bacterium and virus. This study is to investigate the effects of SHLI on the activities of Cytochrome P450 (CYP) 1A2, 2C11, 2D1 and 3A1/2 in rats. Sixteen rats were randomly divided into two groups (SHLI-treated and blank control). They were administered SHLI or physiological saline for consecutive seven days. On day eight, 16 animals were administrated cocktail drugs as probe substrates of the four CYP in vivo. In addition, other four probe drugs were added, respectively, into incubation systems of rat liver microsomes (RLM) to assess the effects of SHLI on the four CYP isoforms in vitro. SHLI exhibited an inductive effect on CYP2C11 in vivo by decreasing Cmax, t1/2 and AUC0-∞ of tolbutamide, while the main pharmacokinetic parameters of caffeine, metoprolol and dapsone have no significant changes. In vitro study, SHLI showed no significant effects on the activities of CYP1A2, 2D1 and 3A1/2, but increasing the metabolism of tolbutamide in RLM. SHLI induced the activities of CYP2C11, but had no significant effects on the activities of CYP1A2, CYP2D1 and CYP3A1/2 in rats.

Effects of safflower injection on the pharmacodynamics and pharmacokinetics of warfarin in rats.

1. Safflower injection (SI) is extracted from Chinese herbal medicine safflower that comprises many active components. Warfarin is a common anticoagulant and has exhibited drug interactions with several herbal products. This study aimed to investigate the effects of SI on pharmacodynamics and pharmacokinetics of warfarin in rats. 2. Wistar rats were randomly divided into blank control group, SI group, warfarin control group and SI + warfarin group, respectively. In SI and SI + warfarin groups, rats were injected with SI (1.6 mL/kg/d, i.p.) for 14 days. Warfarin (0.2 mg/kg) was given orally on the eighth day. Saline was given as control. The blood samples were collected at various time points. Prothrombin time (PT) and activated partial thromboplastin time (APTT) were measured. UPLC-MS/MS was used to determine the plasma concentrations of S(R)-warfarin, and the pharmacokinetic parameters were calculated. 3. PT, APTT in SI and SI + warfarin rats increased significantly compared with corresponding control rats. The pharmacokinetic parameters including Cmax, t1/2, AUC0-t and AUC0-∞ of S-warfarin and R-warfarin in SI + warfarin rats were higher than those in warfarin control rats. 4. These findings suggest that SI significantly increases the anticoagulant effect of warfarin by affecting its pharmacodynamic and pharmacokinetic parameters.

The DNA Methylome and Association of Differentially Methylated Regions with Differential Gene Expression during Heat Stress in Brassica rapa.

Cytosine DNA methylation is a critical epigenetic mechanism in the silencing of transposable elements, imprinting and regulating gene expression. However, little is known about the potential role of mC in response to heat stress. To determine and explore the functions of the dynamic DNA methylome during heat stress, we characterized single-base resolution methylome maps of Brassica rapa and assessed the dynamic changes of mC under heat stress using whole genome bisulfite sequencing. On average, the DNA methylation levels of CG, CHG and CHH are 39.3%, 15.38% and 5.24% in non-heading Chinese cabbage (NHCC), respectively. We found that the patterns of methylation are similar to other eudicot plants, but with higher CHH methylation levels. Further comparative analysis revealed varying patterns for three sequence contexts (mCG, mCHG and mCHH) under heat stress indicating context- and position-dependent methylation regulation. DNA methylation near the TSS and TES may be closely associated with methylation-dependent transcriptional silencing. Association analysis of differential methylation and differential gene expression revealed a different set of methDEGs involved at early and late stages under heat stress. The systemic characterization of the dynamic DNA methylome during heat stress will improve our understanding of the mechanism of epigenetic regulation under heat stress.

Effects of phillyrin and forsythoside A on rat cytochrome P450 activities in vivo and in vitro.

1. Phillyrin and forsythoside A are two important active ingredients in Forsythia suspensa. However, the effects of phillyrin and forsythoside A on the activities of cytochrome P450 (CYP450) remain unclear. 2. This study aimed to investigate the effects of phillyrin and forsythoside A on the activities of CYP1A2, CYP2C11, CYP2D1 and CYP3A1/2 by cocktail probe drugs in rats both in vivo and in vitro. 3. Many pharmacokinetic parameters of caffeine and metoprolol in phillyrin pretreatment group, caffeine and tolbutamide in forsythoside A pretreatment group were affected significantly. In rat liver microsomal incubation system, the concentrations of acetaminophen and dextrophan in the phillyrin pretreatment group are higher than blank control group by 207.69% and 125.00%, however, the concentrations of 4-hydroxytolbutamide and 6ß-hydroxytestosterone were not significantly altered. The concentrations of acetaminophen and 4-hydroxytolbutamide in the forsythoside A pretreatment group are higher than blank control group by 223.07% and 154.16%, whereas the concentrations of dextrophan and 6ß-hydroxytestosterone were not significantly altered. 4. These results indicated that Phillyrin had potential inductive effects on rat CYP1A2 and CYP2D1 activities, without affecting CYP2C11 and CYP3A1/2 activities. Moreover, forsythoside A had inductive effects on the activities of CYP1A2 and CYP2C11, without affecting CYP2D1 and CYP3A1/2 activities.

[Effect of Shuxuetong injection on anticoagulant effect of warfarin in rats].

To explore the effect of Shuxuetong injection on the pharmacodynamics and pharmacokinetics of warfarin in rats, and to provide reference for rational drug use. In studies on the single dose of warfarin, Wistar rats were randomly divided into four groups： blank control group(group A), Shuxuetong injection group(group B), warfarin control group(group C), and warfarin+Shuxuetong injection group(group D). In studies on the steady state of warfarin, Wistar rats were randomly divided into warfarin control group(group E) and warfarin+Shuxuetong injection group(group F). To investigate the pharmacodynamic effect of Shuxuetong injection on warfarin, prothrombin time(PT) and activated partial thromboplastin time(APTT) were measured by coagulation analyzer, and international normalized ratio(INR) was calculated. To investigate the pharmacokinetic effect of Shuxuetong injection on warfarin, the blood concentrations of S-warfarin and R-warfarin were determined by UPLC-MS/MS combined with technology of chiral chromatographic column, and the related pharmacokinetic parameters were calculated accordingly. The results on the single dose of warfarin showed that Shuxuetong injection markedly increased PT, INR(P<0.01), and APTT(P<0.05). Meanwhile, when Shuxuetong injection was co-administrated with warfarin, it significantly increased PT, INR(P<0.01), and APTT(P<0.05) as compared with warfarin control group. In addition, increased pharmacokinetic parameters including Cmax, AUC0-t and AUC0-∞, prolonged t1/2, and decreased CL/F were observed for S-warfarin and R-warfarin. The results of the steady state of warfarin suggested that Shuxuetong injection significantly increased PT and INR of warfarin(P<0.01), and elevated the plasma concentrations of S-warfarin and R-warfarin when co-administrated with warfarin. These findings indicated that Shuxuetong injection had anticoagulant effect, and would produce pharmacodynamics synergistic action when it was co-administrated with warfarin. Shuxuetong injection also decelerated the metabolism of warfarin, and resulted in pharmacokinetics interaction. Therefore, Shuxuetong injection could significantly increase anticoagulant effect of warfarin, indicating that the combination use of these two drugs should be refrained in order to avoid the risk of bleeding in clinical application. If they need to be used in combination, special attention should be paid to ensure the safety of patients.

Janusarene: A Homoditopic Molecular Host.

A homoditopic molecular host, janusarene, is presented that has two back-to-back compactly arranged nanocavities for guest complexation. The unique two-face structural feature of janusarene allows it to bind and align various guest compounds concurrently, which include spherical pristine fullerene C60 and planar polycyclic aromatic hydrocarbons (PAHs), such as pyrene, perylene, and 9,10-dimethylanthracene. The host-guest interactions were characterized by single-crystal X-ray diffraction. A pairwise encapsulation of the PAH guests by janusarene enables PAH dimers to be obtained that deliver spectroscopic properties distinct from those of PAHs dissolved in solution, or in the bulk state. A monotopic control host was also synthesized and used to characterize the host-guest complexing behavior in solution.

Temperature expression patterns of genes and their coexpression with LncRNAs revealed by RNA-Seq in non-heading Chinese cabbage.

BACKGROUND: Non-heading Chinese cabbage (NHCC, Brassica rapa ssp. chinensis) is an important leaf vegetable grown worldwide. However, little is known about the molecular mechanisms underlying tolerance for extreme temperature in NHCC. The limited availability of NHCC genomic information has greatly hindered functional analysis and molecular breeding. RESULTS: Here, we conduct comprehensive analyses of cold and heat treatments in NHCC using RNA-seq. Approximately 790 million paired-end reads representing 136,189 unigenes with N50 length of 1705 bp were obtained. Totally, 14,329 differentially expressed genes (DEGs) were detected. Among which, 10 DEGs were detected in all treatments, including 7 up-regulated and 3 down-regulated. The enrichment analyses showed 25 and 33 genes were enriched under cold and heat treatments, respectively. Additionally, 10,001 LncRNAs were identified, and 9,687 belonged to novel LncRNAs. The expression of miRNAs were more than that of pri-miRNAs and LncRNAs. Furthermore, we constructed a coexpression network for LncRNAs and miRNAs. It showed 67 and 192 genes were regulated by LncRNAs under cold and heat treatments, respectively. We constructed the flowchart for identifying LncRNAs of NHCC using transcriptome. Except conducting the de novo transcriptome analyses, we also compared these unigenes with the Chinese cabbage proteins. We identified several most important genes, and discussed their regulatory networks and crosstalk in cold and heat stresses. CONCLUSIONS: We presented the first comprehensive characterization for NHCC crops and constructed the flowchart for identifying LncRNAs using transcriptome. Therefore, this study represents a fully characterized NHCC transcriptome, and provides a valuable resource for genetic and genomic studies under abiotic stress.

Mobilization and removing of cadmium from kidney by GMDTC utilizing renal glucose reabsorption pathway.

Chronic exposure to cadmium compounds (Cd(2+)) is one of the major public health problems facing humans in the 21st century. Cd(2+) in the human body accumulates primarily in the kidneys which leads to renal dysfunction and other adverse health effects. Efforts to find a safe and effective drug for removing Cd(2+) from the kidneys have largely failed. We developed and synthesized a new chemical, sodium (S)-2-(dithiocarboxylato((2S,3R,4R,5R)-2,3,4,5,6 pentahydroxyhexyl)amino)-4-(methylthio) butanoate (GMDTC). Here we report that GMDTC has a very low toxicity with an acute lethal dose (LD50) of more than 10,000mg/kg or 5000mg/kg body weight, respectively, via oral or intraperitoneal injection in mice and rats. In in vivo settings, up to 94% of Cd(2+) deposited in the kidneys of Cd(2+)-laden rabbits was removed and excreted via urine following a safe dose of GMDTC treatment for four weeks, and renal Cd(2+) level was reduced from 12.9µg/g to 1.3µg/g kidney weight. We observed similar results in the mouse and rat studies. Further, we demonstrated both in in vitro and in animal studies that the mechanism of transporting GMDTC and GMDTC-Cd complex into and out of renal tubular cells is likely assisted by two glucose transporters, sodium glucose cotransporter 2 (SGLT2) and glucose transporter 2 (GLUT2). Collectively, our study reports that GMDTC is safe and highly efficient in removing deposited Cd(2+) from kidneys assisted by renal glucose reabsorption system, suggesting that GMDTC may be the long-pursued agent used for preventive and therapeutic purposes for both acute and chronic Cd(2+) exposure.