Rutaecarpine targets hERG channels and participates in regulating electrophysiological properties leading to ventricular arrhythmia.

Drug-mediated or medical condition-mediated disruption of hERG function accounts for the main cause of acquired long-QT syndrome (acLQTs), which predisposes affected individuals to ventricular arrhythmias (VA) and sudden death. Many Chinese herbal medicines, especially alkaloids, have risks of arrhythmia in clinical application. The characterized mechanisms behind this adverse effect are frequently associated with inhibition of cardiac hERG channels. The present study aimed to assess the potent effect of Rutaecarpine (Rut) on hERG channels. hERG-HEK293 cell was applied for evaluating the effect of Rut on hERG channels and the underlying mechanism. hERG current (IhERG ) was measured by patch-clamp technique. Protein levels were analysed by Western blot, and the phosphorylation of Sp1 was determined by immunoprecipitation. Optical mapping and programmed electrical stimulation were used to evaluate cardiac electrophysiological activities, such as APD, QT/QTc, occurrence of arrhythmia, phase singularities (PSs), and dominant frequency (DF). Our results demonstrated that Rut reduced the IhERG by binding to F656 and Y652 amino acid residues of hERG channel instantaneously, subsequently accelerating the channel inactivation, and being trapped in the channel. The level of hERG channels was reduced by incubating with Rut for 24 hours, and Sp1 in nucleus was inhibited simultaneously. Mechanismly, Rut reduced threonine (Thr)/ tyrosine (Tyr) phosphorylation of Sp1 through PI3K/Akt pathway to regulate hERG channels expression. Cell-based model unables to fully reveal the pathological process of arrhythmia. In vivo study, we found that Rut prolonged QT/QTc intervals and increased induction rate of ventricular fibrillation (VF) in guinea pig heart after being dosed Rut for 2 weeks. The critical reasons led to increased incidence of arrhythmias eventually were prolonged APD90 and APD50 and the increase of DF, numbers of PSs, incidence of early after-depolarizations (EADs). Collectively, the results of this study suggest that Rut could reduce the IhERG by binding to hERG channels through F656 and Y652 instantaneously. While, the PI3K/Akt/Sp1 axis may play an essential role in the regulation of hERG channels, from the perspective of the long-term effects of Rut (incubating for 24 hours). Importantly, the changes of electrophysiological properties by Rut were the main cause of VA.

Fine-scale phylogenetic structure and major events in the history of the current wild soybean (Glycine soja) and taxonomic assignment of semi-wild type (Glycine gracilis Skvortz.) within the Chinese subgenus Soja.

Wild and cultivated species of soybeans have coexisted for 5000 years in China. Despite this long history, there is very little information on the genetic relationship of Glycine soja and G. max. To gain insight into the major events in the history of the subgenus Soja, we examined 20 simple sequence repeat (SSR) markers of a large number of accessions (910). The results showed no significant differences between wild and semi-wild soybeans in genetic diversity but significant differences between G. soja and G. max. Ancestry and cluster analyses revealed that semi-wild soybeans should belong to the wild category and not to G. max. Our results also showed that differentiation had occurred not only among G. soja, G. gracilis, and G. max but also within G. soja and within G. gracilis. Glycine soja had 3 clear genetic categories: typical small-seeded (≤2.0 g 100-seed weight), dual-origin middle-seeded (2.0-2.5 g), and large-seeded plants (2.51-3.0 g). These last were genetically close to G. gracilis, their defining some traits having been acquired mainly by introgression from soybeans. Small-seeded G. gracilis (3.01-3.5 g) were genetically different from larger seeded ones (from 3.51 to 4.0 to over 10 g). Seed size predominated over seed coat color in evolutionary degree. Typical and large-seeded G. soja were found to have 0.7% and 12% introgressive cultivar genes, respectively. The genetic boundary of G. gracilis was at the range of 2.51-3.0 g of G. soja. In the great majority of wild accessions, traits such as white flowers, gray pubescences, no-seed bloom, and colored seed coats were likely introgressive from domesticated soybeans.

The effect of chronoradiotherapy on cervical cancer patients: A multicenter randomized controlled study.

Objectives: To investigate the short-term efficacy and radiotoxicity 3.543of chronoradiotherapy in patients with cervical cancer. We also examined the overall symptom score and quality of life (QOL) of patients who underwent morning radiotherapy and evening radiotherapy. Methods: We conducted a multicenter randomized controlled trial to compare the effects of morning radiotherapy (9:00-11:00 AM) with evening radiotherapy (7:00-9:00 PM) in cervical cancer patients receiving radiotherapy. From November 2021 to June 2022, 114 cervical cancer patients admitted to eight cancer center hospitals in Tianjin, Chongqing, Hubei, Shanxi, Shandong, Shaanxi, Hebei, and Cangzhou were randomly divided into the morning radiotherapy group (MG; N = 61) and the evening radiotherapy group (EG; N = 53). The short-term efficacy of radiotherapy on cervical cancer patients at different time points and the occurrence of radiotoxicity were explored after patients had undergone radiotherapy. Results: The total effective response (partial remission [PR] + complete remission [CR]) rate was similar across the two groups (93.5% vs. 96.3%, p > 0.05). However, the incidence of bone marrow suppression and intestinal reaction in the two groups were significantly different (p < 0.05). The patients in the MG had significantly higher Anderson symptom scores than patients in the EG (21.64 ± 7.916 vs. 18.53 ± 4.098, p < 0.05). In terms of physical activity, functional status, and overall QOL, the MG had significantly lower scores than the EG (p < 0.05). No other measures showed a significant difference between the groups. Conclusion: The radiotherapy effect of the MG was consistent with that of the EG. The incidence of radiation enteritis and radiation diarrhea in the MG was significantly higher than that in the EG; however, bone marrow suppression and blood toxicity in the EG were more serious than in the MG. Because of the small sample size of the study, we only examined the short-term efficacy of radiotherapy. Therefore, further clinical trials are needed to verify the efficacy and side effects of chronoradiotherapy. Clinical Trial Registration: http://www.chictr.org.cn/searchproj.aspx, Registration Number: ChiCTR2100047140.

Grape Seed Proanthocyanidin Extract Ameliorates Streptozotocin-induced Cognitive and Synaptic Plasticity Deficits by Inhibiting Oxidative Stress and Preserving AKT and ERK Activities.

Progressive memory loss and cognitive impairment are the main clinical manifestations of Alzheimer's disease (AD). Currently, there is no effective drug available for the treatment of AD. Previous studies have demonstrated that the cognitive impairment of AD is associated with oxidative stress and the inhibition of AKT and ERK phosphorylation. Grape seed proanthocyanidin extract (GSPE) has been shown to have strong antioxidant effect and can protect the nervous system from oxidative stress damage. This study aimed to investigate the protective effect of GSPE on the cognitive and synaptic impairments of AD using a sporadic AD rat model induced by intracerebroventricular (ICV) injection of streptozotocin (STZ) (ICV-STZ). Rats were treated with GSPE (50, 100, or 200 mg/kg every day) by intragastrical (ig.) administration for continuous 7 weeks, and ICV-STZ (3 mg/kg) was performed on the first day and third day of week 5. Learning and memory abilities were assessed by the Morris water maze (MWM) test at week 8. After behavioral test, hippocampal long-term potentiation (LTP) was recorded, and the levels of malondialdehyde (MDA), superoxide dismutases (SOD), glutathione (GSH) and the protein expression of AKT and ERK were measured in the hippocampus and cerebral cortex of rats. Our study revealed that ICV-STZ significantly impaired the working learning ability and hippocampal LTP of rats, significantly increased the levels of MDA, and decreased the activity of SOD and GSH in the hippocampus and cerebral cortex. In contrast, GSPE treatment prevented the impairment of cognitive function and hippocampal LTP induced by ICV-STZ, decreased the level of MDA, and increased the level of SOD and GSH. Furthermore, Western blot results showed that GSPE treatment could prevent the loss of AKT and ERK activities in the hippocampus and cerebral cortex induced by ICV-STZ. Our findings demonstrate that GSPE treatment could ameliorate the impairment of cognitive ability and hippocampal synaptic plasticity in a rat model of sporadic AD by inhibiting oxidative stress and preserving AKT and ERK activities. Therefore, GSPE may be an effective agent for the treatment of cognitive deficits associated with sporadic AD.

Effects of wuwei dilong decoction on inflammatory cells and cytokines in asthma model guinea pigs.

OBJECTIVE: To explore the effects and the mechanism of Wuwei Dilong Decoction (Schisandra Fruit and Earthworm Decoction) for treatment of asthma. METHODS: The asthma guinea pig model was established with spray of ovalbumin (OVA). Fifteen days later, the guinea pigs were administered by intra-gastric perfusion of Wuwei Dilong Decoction once a day for 8 consecutive days. Blood samples were taken for testing the total leucocytes, eosinophil (EOS), lymphocytes, interferon-gamma (IFN-gamma) and leukotriene B4 (LTB4). RESULTS: In the asthma model group, the total leucocytes, EOS and lymphocytes were all increased, with significant differences as compared with the different dosage Wuwei Dilong Decoction groups (P < 0.01 or P < 0.05). The serum LTB4 in the asthma model group was significantly increased and IFN-gamma decreased. After administration of Wuwei Dilong Decoction of the large, medium and small dosages, LTB4 decreased, while IFN-gamma increased (P < 0.05 or P < 0.01). CONCLUSION: Wuwei Dilong Decoction can inhibit infiltration and diffusion of the inflammatory cells in the asthma model guinea pigs, and regulate LTB4 and IFN-gamma, which is probably one of the important mechanisms of Wuwei Dilong Decoction for relieving asthma.

[Effect of earthworm decoction on airway inflammation of bronchial asthma in guinea pigs].

OBJECTIVE: To investigate the effect of Earthworm decoction on the airway inflammation of experimental bronchial asthma in guinea pigs and inquire into the mechanism in the decoction. METHOD: Forty-eight guinea pigs were randomly divided into six groups: the control group, the model group, the dexamethasone group, the Xiaoqinglong decoction group, the earthworm decoction large dosage group and the Earthworm decoction low dosage group, 8 guinea pigs in each group. Except the control group, the other groups were sensitized with ovalbumin (OVA) by a combination of intraperitional injection and repeated intranasal challenges to establish the guinea pigs asthma model. However, in the control group, normal saline was used. The morphological changes of bronchial tube, the lung tectology and the inflammation germ cell quantity of eosinophils (Eos), lymphocytes (Ly), neutrophils (Neu) and total blood cells in the blood and bronchoalveolar lavaga fluid (BALF) were examinated in each group respectively. RESULT: The levels of Eos, Ly, Neu and total cell quantity in the blood and BALF after the earthworm decoction treatment in the large dosage group were significantly lower than those in the model group (P <0.01), and in the low dosage group were lower too (P <0.05). The Earthworm decoction large dosage could obviously improve the bronchial tube epidermis damage, the mucous membrane gland proliferation and hydrops, asthma pathology change and basilar membrane accumulation. Eos apoptosis was obsered in the bronchoalveolar, blood and BALF. The Earthworm decoction small dosage had a similar effect but slightly to the large dosage. CONCLUSION: The Earthworm decoction can lighten the airway inflammation in asthmatic guinea pigs, its mechanism is related with the inhibition of Eos infiltration, acceleration of Eos apoptosis and improvement of the bronchial tube and the lung tectology changes. The effect of the decoction is dose-dependent.

Characterization of the genetic basis for yield and its component traits of rice revealed by doubled haploid population.

Main-effect QTL, epistatic effects and their interactions with environment are important genetic components of quantitative traits. In this study, we analyzed the QTLs, epistatic effects and QTL by environment interactions (QE) underlying nine traits of yield and yield-component, using a doubled-haploid (DH) population consisted of 190 lines from the cross between an indica parent Zhenshan 97 and a japonica parent WYJ 2, and tested in two-year replicated field trials. A genetic linkage map with 179 SSR (simple sequence repeat) marker loci was constructed. A mixed linear model approach was applied to detect QTLs, digenic interactions and QEs for the nine traits. In total, 57 QTLs of main effects, 41 digenic interactions, eight QEs and seven interactions of epistasis by environment were detected. Each of the main-effect QTLs individually explained 1.3 % to 25.8% of the phenotypic variations. And they collectively explained 11.5% to 66.8% of the phenotypic variations for these traits. Most of the traits (except seed setting) had the QTLs simultaneously detected in two years. Many of the traits shared same QTLs with each other, which is consistent with their significant phenotypic correlations. The pleiotropism or tight linkage of QTLs for different traits might be the important genetic base for trait correlations. The environmental influences on the stability of the trait performance were also discussed.

OsELF3 is involved in circadian clock regulation for promoting flowering under long-day conditions in rice.

Heading date is a critical trait that determines cropping seasons and regional adaptability in rice (Oryza sativa). Research efforts during the last decade have identified some important photoperiod pathway genes that are conserved between Arabidopsis and rice. In this study, we identified a novel gene, Oryza sativa ELF3 (OsELF3), which is a putative homolog of the ELF3 gene in Arabidopsis thaliana. OsELF3 was required for the control of heading date under long-day conditions. Its Tos17-tagging mutants exhibited a delayed heading date phenotype only under long-day, but not short-day, conditions. OsELF3 was highly expressed in leaf blades, and the OsELF3 protein was localized in the nucleolus. An obvious diurnal rhythm of OsELF3 transcript level was observed, with a trough in the early day and a peak in the late night in wild-type plants. However, this expression pattern was disrupted in oself3 mutants. Further investigations showed that the expression of OsGI and Ghd7 was up-regulated in the oself3 mutant, indicating that OsELF3 acts as a negative regulator upstream of OsGI and Ghd7 in the flowering-time control under long-day conditions. The rhythmic expression of circadian clock-related genes, including some OsPRR members, was obviously affected in oself3 mutants. Our results indicated that OsELF3 acts as a floral activator in the long-day photoperiodic pathway via its crosstalk with the circadian clock in rice.

Ortholog alleles at Xa3/Xa26 locus confer conserved race-specific resistance against Xanthomonas oryzae in rice.

The rice disease resistance (R) gene Xa3/Xa26 (having also been named Xa3 and Xa26) against Xanthomonas oryzae pv. oryzae (Xoo), which causes bacterial blight disease, belongs to a multiple gene family clustered in chromosome 11 and is from an AA genome rice cultivar (Oryza sativa L.). This family encodes leucine-rich repeat (LRR) receptor kinase-type proteins. Here, we show that the orthologs (alleles) of Xa3/Xa26, Xa3/Xa26-2, and Xa3/Xa26-3, from wild Oryza species O. officinalis (CC genome) and O. minuta (BBCC genome), respectively, were also R genes against Xoo. Xa3/Xa26-2 and Xa3/Xa26-3 conferred resistance to 16 of the 18 Xoo strains examined. Comparative sequence analysis of the Xa3/Xa26 families in the two wild Oryza species showed that Xa3/Xa26-3 appeared to have originated from the CC genome of O. minuta. The predicted proteins encoded by Xa3/Xa26, Xa3/Xa26-2, and Xa3/Xa26-3 share 91-99% sequence identity and 94-99% sequence similarity. Transgenic plants carrying a single copy of Xa3/Xa26, Xa3/Xa26-2, or Xa3/Xa26-3, in the same genetic background, showed a similar resistance spectrum to a set of Xoo strains, although plants carrying Xa3/Xa26-2 or Xa3/Xa26-3 showed lower resistance levels than the plants carrying Xa3/Xa26. These results suggest that the Xa3/Xa26 locus predates the speciation of A and C genome, which is approximately 7.5 million years ago. Thus, the resistance specificity of this locus has been conserved for a long time.

Isolation and manipulation of quantitative trait loci for disease resistance in rice using a candidate gene approach.

Bacterial blight caused by Xanthomonas oryzae pv. oryzae and fungal blast caused by Magnaporthe grisea result in heavy production losses in rice, a main staple food for approximately 50% of the world's population. Application of host resistance to these pathogens is the most economical and environment-friendly approach to solve this problem. Quantitative trait loci (QTLs) controlling quantitative resistance are valuable sources for broad-spectrum and durable disease resistance. Although large numbers of QTLs for bacterial blight and blast resistance have been identified, these sources have not been used effectively in rice improvement because of the complex genetic control of quantitative resistance and because the genes underlying resistance QTLs are unknown. To isolate disease resistance QTLs, we established a candidate gene strategy that integrates linkage map, expression profile, and functional complementation analyses. This strategy has proven to be applicable for identifying the genes underlying minor resistance QTLs in rice-Xoo and rice-M. grisea systems and it may also help to shed light on disease resistance QTLs of other cereals. Our results also suggest that a single minor QTL can be used in rice improvement by modulating the expression of the gene underlying the QTL. Pyramiding two or three minor QTL genes, whose expression can be managed and that function in different defense signal transduction pathways, may allow the breeding of rice cultivars that are highly resistant to bacterial blight and blast.

Structure-based drug design of a novel family of chalcones as PPARalpha agonists: virtual screening, synthesis, and biological activities in vitro.

AIM: To design and synthesize a novel class of peroxisome proliferator-activated receptors (PPAR)alpha agonists, which is obtained by the combination of the classical fibrate "head group", a linker with appropriate length and a chalcone. METHODS: Thirty seven compounds were designed and identified employing the virtual screening approach. Six compounds were then selected for synthesis and bioassay according to the virtual screening results, structural similarity, and synthetic complexity. RESULTS: Six new compounds (4b and 4d-h) were synthesized and bioassayed. All were found to be potent PPARalpha agonists, compound 4 h being the most prominent with a 50% effective concentration value of 0.06 micromol/L. CONCLUSION: This study provides a promising novel family of chalcones with a potential hypolipidemic effect.

[Importation of wind-driven drift of mat-like algae bloom into Meiliang Bay of Taihu Lake in 2004 summer].

Driven by the prevailing south wind in summer, floating mat-like algal blooms in the open area of Taihu Lake would drift into Meiliang Bay located in the northern part of Taihu Lake. An exponential relationship between wind speed and algal drift velocity was found through controlled flume experiments and field observations. Then the relationship was applied to compute drift importation into Meiliang Bay in six dates when mat-like algal blooms were happening. During the six dates, except on 2004-07-31 the algal boom drifted outwards from Meiliang Bay with slight amounts of 0.05 km2; for the rest of dates, the importations were inwards positive, the maximum importation occurred on 2004-06-11, being 17.4 km2, and the minimum importation on 2004-07-30, being 4.8 km2; The results indicated importation of wind-driven algae drift during 24 hours accounts for 3.7% - 13.3% of the area of Meiliang Bay.