Telo boxes within the AGAMOUS second intron recruit histone 3 lysine 27 methylation to increase petal number in rose (Rosa chinensis) in response to low temperatures.

The petals of rose (Rosa sp.) flowers determine the ornamental and industrial worth of this species. The number of petals in roses was previously shown to be subject to fluctuations in ambient temperature. However, the mechanisms by which rose detects and responds to temperature changes are not entirely understood. In this study, we identified short interstitial telomere motifs (telo boxes) in the second intron of AGAMOUS (RcAG) from China rose (Rosa chinensis) that play an essential role in precise temperature perception. The second intron of RcAG harbors two telo boxes that recruit telomere repeat binding factors (RcTRBs), which interact with CURLY LEAF (RcCLF) to compose a repressor complex. We show that this complex suppresses RcAG expression when plants are subjected to low temperatures via depositing H3K27me3 marks (trimethylation of lysine 27 on histone H3) over the RcAG gene body. This regulatory mechanism explains the low-temperature-dependent decrease in RcAG transcript levels, leading to the production of more petals under these conditions. Our results underscore an interesting intron-mediated regulatory mechanism governing RcAG expression, enabling rose plants to perceive temperature cues and establish petal numbers.

RcOST1L phosphorylates RcPIF4 for proteasomal degradation to promote flowering in rose.

Flowering is a vital agronomic trait that determines the economic value of most ornamental plants. The flowering time of rose (Rosa spp.) is photoperiod insensitive and is thought to be tightly controlled by light intensity, although the detailed molecular mechanism remains unclear. Here, we showed that rose plants flower later under low-light (LL) intensity than under high-light (HL) intensity, which is mainly related to the stability of PHYTOCHROME-INTERACTING FACTORs (RcPIFs) mediated by OPEN STOMATA 1-Like (RcOST1L) under different light intensity regimes. We determined that HL conditions trigger the rapid phosphorylation of RcPIFs before their degradation. A yeast two-hybrid screen identified the kinase RcOST1L as interacting with RcPIF4. Moreover, RcOST1L positively regulated rose flowering and directly phosphorylated RcPIF4 on serine 198 to promote its degradation under HL conditions. Additionally, phytochrome B (RcphyB) enhanced RcOST1L-mediated phosphorylation of RcPIF4 via interacting with the active phyB-binding motif. RcphyB was activated upon HL and recruited RcOST1L to facilitate its nuclear accumulation, in turn leading to decreased stability of RcPIF4 and flowering acceleration. Our findings illustrate how RcPIF abundance safeguards proper rose flowering under different light intensities, thus uncovering the essential role of RcOST1L in the RcphyB-RcPIF4 module in flowering.

A Bibliometric Analysis of the Spatial Transcriptomics Literature from 2006 to 2023.

In recent years, spatial transcriptomics (ST) research has become a popular field of study and has shown great potential in medicine. However, there are few bibliometric analyses in this field. Thus, in this study, we aimed to find and analyze the frontiers and trends of this medical research field based on the available literature. A computerized search was applied to the WoSCC (Web of Science Core Collection) Database for literature published from 2006 to 2023. Complete records of all literature and cited references were extracted and screened. The bibliometric analysis and visualization were performed using CiteSpace, VOSviewer, Bibliometrix R Package software, and Scimago Graphica. A total of 1467 papers and reviews were included. The analysis revealed that the ST publication and citation results have shown a rapid upward trend over the last 3 years. Nature Communications and Nature were the most productive and most co-cited journals, respectively. In the comprehensive global collaborative network, the United States is the country with the most organizations and publications, followed closely by China and the United Kingdom. The author Joakim Lundeberg published the most cited paper, while Patrik L. Ståhl ranked first among co-cited authors. The hot topics in ST are tissue recognition, cancer, heterogeneity, immunotherapy, differentiation, and models. ST technologies have greatly contributed to in-depth research in medical fields such as oncology and neuroscience, opening up new possibilities for the diagnosis and treatment of diseases. Moreover, artificial intelligence and big data drive additional development in ST fields.

Efficacy and Safety of Lomitapide in Homozygous Familial Hypercholesterolaemia: A Systematic Review.

Background: Homozygous familial hypercholesterolaemia (HoFH) patients have little or no low-density lipoprotein receptor (LDLR) function. HMG-CoA (3-hydroxy-3-methyl glutaryl coenzyme A) reductase inhibitors (statins) and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have limited lipid-lowering effects, therefore, there is an urgent need to develop new HoFH treatments. In 2012, the US Food and Drug Administration (FDA) approved the administration of lomitapide for lowering low-density lipoprotein cholesterol (LDL-C) levels. However, lomitapide is associated with various gastrointestinal disorders, elevated hepatic alanine aminotransferase (ALT) levels and other adverse reactions, thus, its long-term efficacy and safety in pediatrics and adults should be evaluated. A systematic review conducted in 2017 reported the efficacy and safety of lomitapide in Family hypercholesterolaemia (FH) patients. In this systematic review, we elucidate on the efficacy and safety of lomitapide in HoFH patients. Methods: A search was conducted in PubMed, Embase, Web of Science and Cochrane library databases to identify valid studies involving lomitapide-treated HoFH patients published before 11th August 2021. Results: A total of 18 clinical studies involving 120 lomitapide-treated HoFH patients were identified. Lomitapide significantly suppressed LDL-C levels in HoFH patients. Clinical manifestations for lomitapide in children were comparable to those in adults. The most common adverse events were gastrointestinal disturbances and elevated ALT levels. However, most patients tolerated the treatment-associated adverse reactions. Low-fat diets and drug dose adjustments were appropriate measures for controlling the treatment-associated adverse reactions. Conclusions: In pediatric and adult HoFH patients, lomitapide significantly suppresses LDL-C levels, therefore, it is an important option for HoFH treatment. The most common adverse events of lomitapide treatment include gastrointestinal disorders and elevated hepatic ALT levels. Despite the limitations, lomitapide is feasible for long-term treatment of HoFH patients, with dietary and safety monitoring. Registration Number in PROSPERO: CRD42021284425.

Bedside echocardiography for diagnosis of intracardiac cement embolism after percutaneous vertebroplasty: A case report.

This case report is to demonstrate that a female patient had suddenly become unconscious 14 hours after percutaneous vertebroplasty. Bedside echocardiogram showed that the patient had a strong echo in the right heart with a small amount of pericardial effusion. CT showed high density in the distal branches of both pulmonary arteries and a high density in the right heart. With the help of that, the doctor made the diagnosis of intracardiac cement embolism in a very short time. The bone cement in the heart was removed under emergency cardiopulmonary bypass, then the patient was discharged smoothly.

Characterization and functional analysis of serpin-28 gene from silkworm, Bombyx mori.

Serine protease inhibitors (Serpins) are a broadly distributed superfamily of proteins with a SERPIN domain and participate in several immune responses. In this study, a serpin-28 gene was identified in B. mori and its role in immune regulation was investigated. This gene has an open reading frame of 1065 bp that encodes a 354-amino acid residue polypeptide containing one SERPIN domain with a predicted molecular weight of 40.3 kDa. Recombinant Bmserpin-28 protein was expressed in Escherichia coli and used to raise rabbit anti-Bmserpin-28 polyclonal antibodies. Quantitative real-time PCR analysis revealed that Bmserpin-28 was expressed in all examined tissues, with maximum expression in the fat body and silk gland. Expression pattern of different developmental stages showed that the highest expression level was in the pupae, while the lowest expression level was recorded at the egg stage. After challenge with four different microorganisms (Escherichia coli, Beauveria bassiana, Micrococcus luteus and B. mori nuclear polyhedrosis virus), the expression pattern of Bmserpin-28 was investigated in fat body and haemocyte samples. A substantial upregulation of Bmserpin-28 expression level was recorded following pathogen challenge in both the tested tissues. Furthermore, RNA interference of Bmserpin-28 resulted in significant upregulation of antimicrobial peptide genes. In summary, our results indicated that Bmserpin-28 may be involved in the innate immunity of B. mori.

Bibliometric analysis of atrial fibrillation and ion channels.

Atrial fibrillation (AF) is a common clinical malignant arrhythmia with an increasing global incidence. Ion channel dysfunction is an important mechanism in the development of AF. In this study, we used bibliometrics to analyze the studies of ion channels and AF, aiming to provide inspiration and reference for researchers. A total of 3179 literature citations were obtained from Web of Science core databases. Analysis software included Excel 2019, VOSviewer 1.6.16, and CiteSpace 5.7.R2. This field of research has been growing since 1985. The most active country is the United States. The University of Montreal is the most important research institution. The journal Cardiovascular Research has published the largest number of articles in this field. Stanley Nattel and Dobromir Dobrev are the most frequently cited authors. The most cited literature was published in Nature and Science. Cardiac electrophysiology, gene expression, pathogenesis of AF, and AF prevention and treatment are the hot topics for this field research. Cardiac fibrillation and catheter ablation may be future research hotspots in this field.

Knowledge Domain and Emerging Trends of Glucagon-Like Peptide 1 Receptor Agonists in Cardiovascular Research: A Bibliometric Analysis.

Patients with type 2 diabetes (T2DM) are more likely to have cardiovascular disease (CVD). Glucose-lowering drugs with cardiovascular benefits represented by Glucagon-like peptide 1 receptor agonists (GLP1RAs) were discovered and gained more and more attention. Data from 1985 to the 2021 were downloaded in the Web of Science Core Collection (WoSCC) database. CiteSpaceV was used for bibliometric analysis to find research hotspots and frontiers. The 2088 papers were published by 74 countries (regions), 876 institutions, and 2203 authors. The annual publications increased over time from 2005 to 2020. DIABETES OBESITY METABOLISM published the most papers. The USA and China were the top 2 productive nations. The leading institution was the University of Copenhagen, and the most productive researcher was John B Buse. The most cited paper is "Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes" (by Marso SP, 2016). The research hotspots include the effects of GLP1RA on cardiovascular outcomes, efficacy, complicated metabolic abnormalities, protective mechanisms, and other novel anti-diabetic drugs for cardiovascular protection. Research frontiers include cardiovascular studies on semaglutide, as well as the most prominent research approach in the field-placebo-controlled trial. Numerous countries, institutions, and authors have focused on GLP1RA in cardiovascular research and a great deal of literature has been published. Five research hotspots and two frontiers illustrate the current status and emerging trends of GLP1RA in cardiovascular research. The cardiovascular effects and clinical efficacy of GLP1RA are a current hot topic that is rapidly evolving and of high research value.

The Role of VEGF Family in Lipid Metabolism.

The vascular endothelial growth factor (VEGF) family plays a major role in tumors and ophthalmic diseases. However, increasingly more data reported its potential in regulating lipids. With its biological functions mainly expressed in lymphatic vessels, some factors in the families, like VEGF-A and VEGF-C, have been proved to regulate intestinal absorption of lipids by affecting chylous ducts. Other effects, including regulating lipoprotein lipase (LPL), endothelial lipase (EL), and recombinant syndecan 1 (SDC1), have also been confirmed. However, given the scant-related studies, further research should be conducted to examine the concrete mechanisms and provide pragmatic ways to apply them in the clinic. The VEGF family may treat dyslipidemia in specific ways that are different from common methods and concurrently contribute to the treatment of other metabolic diseases, like diabetes and obesity.

A Bibliometric Analysis of Familial Hypercholesterolemia From 2011 to 2021.

Familial Hypercholesterolemia (FH), an autosomal dominant genetic disease, is increasingly emerging as a global threat. To learn more about the development of FH, 1 617 papers about FH and related research were retrieved in the Web of Science Core Collection from 2011 to 2021. Then, these publications were scientometrically analyzed based on CiteSpace and VOSviewer in terms of spatiotemporal distribution, author distribution, subject categories, topic distribution, and references. The results showed that research on FH is at a stable stage. More FH research has been conducted in developed countries, implying the necessity for strengthening international cooperation and exchanges. We have obtained scholars, institutions, relevant journals, and representative literatures that play an important role in FH. The research direction of FH is on the mechanisms of FH and its complications, diagnosis, statin therapy, and new lipid-lowering drug therapy. Care is the research frontier in FH, and it is in an explosive period.

Heart Transplantation: A Bibliometric Review From 1990-2021.

As the rapidly aging population and the rising incidence of end-stage heart failure, extensive research has been conducted on heart transplantation (HTx). Bibliometrics harbors the function for describing the relationships of knowledge structures in different research fields and predicting the growth trend. The publications were searched and filtered based on the Web of Science core database. The target literature was visualized and analyzed by CiteSpace or VOSviewer. In total, 19,998 published papers were obtained. There is a wave-like growth in HTx development. Most advanced research results are concentrated in a few developed countries, while the interactions with developing countries are still in infancy. The United States occupies a strong dominant position among active countries on HTx. Early research hotpots mostly focused on primary disease, survival risk factors, and complications. In recent years, the research frontiers have shifted steadily to clinical evaluation of immunosuppressants and diagnosis of acute rejection, cardiac re-injury with coronavirus disease 2019, innovations in ventricular assist devices, and donation allocation strategies. The research directions of HTx are gradually shifting from observational studies to intervention research.

Knowledge domain and emerging trends in Takotsubo cardiomyopathy: a scientometric review based on CiteSpace analysis.

Takotsubo cardiomyopathy (TTC) is often acute with a high mortality rate and is subject to relapse. Meanwhile, its complex pathogenesis has attracted increasing attention. To learn more about TTC, CiteSpace V.5.7 R5W was used in this study to analyze the research status, hot spots, and trends in TTC before 2020. The keywords, co-citation references, as well as country and institution distribution were explored. A total of 2,349 papers were reviewed. The United States, Italy, and Germany were the main countries studying TTC and had good cooperation relationships. The Mayo Clinic topped the institution list, but the rate of inter-institutional cooperation was not high. Research hotspots include disease features, auxiliary diagnostic methods, epidemiology, and pathophysiological mechanisms, and the latest ones are complications related to prognosis, such as cardiovascular abnormalities caused by myocardial infarction and normal or non-obstructive coronary arteries (MINOCA), atrial fibrillation, stroke, cancer, and COVID-19. In conclusion, the research of TTC is in a hot development period. Our research will help clinicians and researchers to better understand TTC and its research status by providing a foundation for research objectives. In doing this, our research will help to provide better scientific management, diagnosis, and treatment for patients with TTC, which will in turn improve the prognosis of this condition.

Network Pharmacology and Molecular Docking Analysis on Molecular Mechanism of Qingzi Zhitong Decoction in the Treatment of Ulcerative Colitis.

Ulcerative colitis (UC) is a disease with complex pathological mechanisms. We explored the potential molecular mechanisms behind the therapeutic functions of Qingzi Zhitong decoction (QZZTD) in the treatment of UC by network pharmacology and molecular docking. QZZTD is a formula of Chinese traditional medicine consisting of 10 herbs. The potential active ingredients of QZZTD and their target genes were obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform database, and UC-related target genes were obtained from GeneCards and OMIM databases. A total of 138 co-identified target genes were obtained by plotting the intersection target Venn diagram, and then the STRING database and Cytoscape software were used to establish protein-protein interaction networks and herb-ingredient-target networks. Four key active compounds and nine key proteins were identified. Then, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses showed that the biological functions of potential target genes were associated with DNA transcription, signaling receptor and ligand activity, cytokine activity, cellular autophagy, and antioxidant pathways, with related pathways involving the phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway, advanced glycosylation end product (AGE)-RAGE signaling pathway, tumor necrosis factor (TNF) signaling pathway, and IL-17 signaling pathway. Moreover, the binding activities of key target genes and essential active compounds of Chinese herbal medicines in QZZTD were further validated by molecular docking. This demonstrated that quercetin, luteolin, hyndarin, and beta-sitosterol had good binding to eight key proteins, and Akt1 was the target protein with the best binding activity, suggesting that Akt1 could be the essential mediator responsible for signaling transduction after QZZTD administration. The rat experiment verified that QZZTD inhibited PI3K-Akt pathway activation and reduced inflammation in UC. In conclusion, our study suggested four potential key active components, including quercetin, were identified in QZZTD, which could interact with Akt1 and modulate the activation of the PI3K-Akt pathway. The other three pathways may also be involved in the signaling transduction induced by QZZTD in the treatment of UC.

Characterization and functional analysis of LoUDT1, a bHLH transcription factor related to anther development in the lily oriental hybrid Siberia (Lilium spp.).

Lily (Lilium spp.), with its beautiful flower, is an important horticultural crop and a popular ornamental plant, but because the abundant pollen pollutes the flowers and surroundings, its use is restricted. To solve this problem, the mechanism of pollen development in lily needs to be analyzed. However, the complex and delicate process of anther development in lily remains largely unknown. In this study, LoUDT1, a bHLH transcription factor (TF), was isolated and identified in lily. LoUDT1 was closely related to OsUDT1 of Oryza sativa and AtDYT1 of Arabidopsis. It was localized in the cytoplasm and nucleus and showed no transcriptional activation in yeast cells. LoUDT1 interacted with another bHLH TF, LoAMS, and the interaction depended on their BIF domains. LoUDT1 and LoAMS were both expressed in the anthers but showed different expression patterns. LoUDT1 was continuously expressed during the entire development of anthers, whereas LoAMS was only highly expressed early in anther development. With overexpression of LoUDT1 in Arabidopsis, normal anther development was affected and defective pollens were produced, which caused partial male sterility of transgenic plants. These defects depended on the level of LoUDT1 accumulation. By contrast, with the appropriate expression of LoUDT1 in a dyt1-3 mutant, normal pollen grains were produced, showing partial fertility. Thus, LoUDT1 might be a key regulator of anther development in lily. By further increasing the understanding of anther development, the results of this study can provide a theoretical basis for the molecular breeding of pollen-free lilies.

The Role of the VEGF Family in Coronary Heart Disease.

The vascular endothelial growth factor (VEGF) family, the regulator of blood and lymphatic vessels, is mostly investigated in the tumor and ophthalmic field. However, the functions it enjoys can also interfere with the development of atherosclerosis (AS) and further diseases like coronary heart disease (CHD). The source, regulating mechanisms including upregulation and downregulation, target cells/tissues, and known functions about VEGF-A, VEGF-B, VEGF-C, and VEGF-D are covered in the review. VEGF-A can regulate angiogenesis, vascular permeability, and inflammation by binding with VEGFR-1 and VEGFR-2. VEGF-B can regulate angiogenesis, redox, and apoptosis by binding with VEGFR-1. VEGF-C can regulate inflammation, lymphangiogenesis, angiogenesis, apoptosis, and fibrogenesis by binding with VEGFR-2 and VEGFR-3. VEGF-D can regulate lymphangiogenesis, angiogenesis, fibrogenesis, and apoptosis by binding with VEGFR-2 and VEGFR-3. These functions present great potential of applying the VEGF family for treating CHD. For instance, angiogenesis can compensate for hypoxia and ischemia by growing novel blood vessels. Lymphangiogenesis can degrade inflammation by providing exits for accumulated inflammatory cytokines. Anti-apoptosis can protect myocardium from impairment after myocardial infarction (MI). Fibrogenesis can promote myocardial fibrosis after MI to benefit cardiac recovery. In addition, all these factors have been confirmed to keep a link with lipid metabolism, the research about which is still in the early stage and exact mechanisms are relatively obscure. Because few reviews have been published about the summarized role of the VEGF family for treating CHD, the aim of this review article is to present an overview of the available evidence supporting it and give hints for further research.

A Novel R2R3-MYB Gene LoMYB33 From Lily Is Specifically Expressed in Anthers and Plays a Role in Pollen Development.

Lily (Lilium spp.) is an important commercial flower crop, but its market popularity and applications are adversely affected by severe pollen pollution. Many studies have examined pollen development in model plants, but few studies have been conducted on flower crops such as lily. GAMYBs are a class of R2R3-MYB transcription factors and play important roles in plant development and biotic resistance; their functions vary in different pathways, and many of them are involved in anther development. However, their function and regulatory role in lily remain unclear. Here, the GAMYB homolog LoMYB33 was isolated and identified from lily. The open reading frame of LoMYB33 was 1620 bp and encoded a protein with 539 amino acids localized in the nucleus and cytoplasm. Protein sequence alignment showed that LoMYB33 contained a conserved R2R3 domain and three BOX motifs (BOX1, BOX2, and BOX3), which were unique to the GAMYB family. LoMYB33 had transcriptional activation activity, and its transactivation domain was located within 90 amino acids of the C-terminal. LoMYB33 was highly expressed during the late stages of anther development, especially in pollen. Analysis of the promoter activity of LoMYB33 in transgenic Arabidopsis revealed that the LoMYB33 promoter was highly activated in the pollen of stage 12 to 13 flowers. Overexpression of LoMYB33 in Arabidopsis significantly retarded growth; the excess accumulation of LoMYB33 also negatively affected normal anther development, which generated fewer pollen grains and resulted in partial male sterility in transgenic plants. Silencing of LoMYB33 in lily also greatly decreased the amount of pollen. Overall, our results suggested that LoMYB33 might play an important role in the anther development and pollen formation of lily.

Causal Association Between Heart Failure and Alzheimer's Disease: A Two-Sample Bidirectional Mendelian Randomization Study.

Background: Traditional observational studies have demonstrated an association between heart failure and Alzheimer's disease. The strengths of observational studies lie in their speed of implementation, cost, and applicability to rare diseases. However, observational studies have several limitations, such as uncontrollable confounders. Therefore, we employed Mendelian randomization of genetic variants to evaluate the causal relationships existing between AD and HF, which can avoid these limitations. Materials and Methods: A two-sample bidirectional MR analysis was employed. All datasets were results from the UK's Medical Research Council Integrative Epidemiology Unit genome-wide association study database, and we conducted a series of control steps to select the most suitable single-nucleotide polymorphisms for MR analysis, for which five primary methods are offered. We reversed the functions of exposure and outcomes to explore the causal direction of HF and AD. Sensitivity analysis was used to conduct several tests to avoid heterogeneity and pleiotropic bias in the MR results. Results: Our MR studies did not support a meaningful causal relationship between AD on HF (MR-Egger, p = 0.634 > 0.05; weighted median (WM), p = 0.337 > 0.05; inverse variance weighted (IVW), p = 0.471 > 0.05; simple mode, p = 0.454 > 0.05; weighted mode, p = 0.401 > 0.05). At the same time, we did not find a significant causal relationship between HF and AD with four of the methods (MR-Egger, p = 0.195 > 0.05; IVW, p = 0.0879 > 0.05; simple mode, p = 0.170 > 0.05; weighted mode, p = 0.110 > 0.05), but the WM method indicated a significant effect of HF on AD (p = 0.025 < 0.05). Because the statistical powers of IVW and MR-Egger are more than that of WM, we think that there is no causal effect of HF on AD. Sensitivity analysis and horizontal pleiotropy were not detected in the MR analysis. Conclusion: Our results did not provide significant evidence indicating any causal relationships between HF and AD in the European population. Therefore, more large-scale datasets or datasets related to similar factors are expected for further MR analysis.

Cardiac Rehabilitation: A Bibliometric Review From 2001 to 2020.

Cardiovascular disease (CVD) is a serious threat to global public health due to its high prevalence and disability rate. Meanwhile, cardiac rehabilitation (CR) has attracted increasing attention for its positive effects on the cardiovascular system. There is overwhelming evidence that CR for patients with CVD is effective in reducing cardiovascular morbidity and mortality. To learn more about the development of CR, 5,567 papers about CR and related research were retrieved in the Web of Science Core Collection from 2001 to 2020. Then, these publications were scientometrically analyzed based on CiteSpace in terms of spatiotemporal distribution, author distribution, subject categories, topic distribution, and references. The results can be elaborated from three aspects. Firstly, the number of annual publications related to CR has increased year by year in general over the past two decades. Secondly, a co-occurrence analysis of the output countries and authors shows that a few developed countries such as the United States, Canada, and the UK are the most active in carrying out CR and where regional academic communities represented by Sherry Grace and Ross Arena were formed. Thirdly, an analysis of the subject categories and topic distribution of the papers reveals that CR is a typical interdiscipline with a wide range of disciplines involved, including clinical medicine, basic medicine, public health management, and sports science. The research topics cover the participants and implementers, components, and the objectives and requirements of CR. The current research hotspots are the three core modalities of CR, namely patient education, exercise training and mental support, as well as mobile health (mHealth) dependent on computer science. In conclusion, this work has provided some useful information for acquiring knowledge about CR, including identifying potential collaborators for researchers interested in CR, and discovering research trends and hot topics in CR, which can offer some guidance for more extensive and in-depth CR-related studies in the future.

Use of Network Pharmacology to Explore the Mechanism of Gegen (Puerariae lobatae Radix) in the Treatment of Type 2 Diabetes Mellitus Associated with Hyperlipidemia.

Rapid increases in metabolic disorders, such as type 2 diabetes mellitus (T2DM) and hyperlipidemia, are becoming a substantial challenge to worldwide public health. Traditional Chinese medicine has a long history and abundant experience in the treatment of diabetes and hyperlipidemia, and Puerariae lobatae Radix (known as Gegen in Chinese) is one of the most prevalent Chinese herbs applied to treat these diseases. The underlying mechanism by which Gegen simultaneously treats diabetes and hyperlipidemia, however, has not been clearly elucidated to date. Therefore, we systematically explored the potential mechanism of Gegen in the treatment of T2DM complicated with hyperlipidemia based on network pharmacology. We screened the potential targets of Gegen, T2DM, and hyperlipidemia in several online databases. Then, the hub targets were analyzed by performing protein-protein interaction, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment assays, and finally, the complicated connections among compounds, targets, and pathways were visualized in Cytoscape. We found that isoflavones, including daidzein, genistein, and puerarin, as well as ß-sitosterol, are the key active ingredients of Gegen responsible for its antidiabetic and antihyperlipidemia effects, which mainly target AKR1B1, EGFR, ESR, TNF, NOS3, MAPK3, PPAR, CYP19A1, INS, IL6, and SORD and multiple pathways, such as the PI3K-Akt signaling pathway; the AGE-RAGE signaling pathway in diabetic complications, fluid shear stress, and atherosclerosis; the PPAR signaling pathway; insulin resistance; the HIF-1 signaling pathway; the TNF signaling pathway; and others. These active ingredients also target multiple biological processes, including the regulation of glucose and lipid metabolism, the maintenance of metabolic homeostasis, and anti-inflammatory and antioxidant pathways. In conclusion, Gegen is a promising therapeutic phytomedicine for T2DM with hyperlipidemia that targets multiple proteins, biological processes, and pathways.

LlWRKY39 is involved in thermotolerance by activating LlMBF1c and interacting with LlCaM3 in lily (Lilium longiflorum).

WRKY transcription factors (TFs) are of great importance in plant responses to different abiotic stresses. However, research on their roles in the regulation of thermotolerance remains limited. Here, we investigated the function of LlWRKY39 in the thermotolerance of lily (Lilium longiflorum 'white heaven'). According to multiple alignment analyses, LlWRKY39 is in the WRKY IId subclass and contains a potential calmodulin (CaM)-binding domain. Further analysis has shown that LlCaM3 interacts with LlWRKY39 by binding to its CaM-binding domain, and this interaction depends on Ca2+. LlWRKY39 was induced by heat stress (HS), and the LlWRKY39-GFP fusion protein was detected in the nucleus. The thermotolerance of lily and Arabidopsis was increased with the ectopic overexpression of LlWRKY39. The expression of heat-related genes AtHSFA1, AtHSFA2, AtMBF1c, AtGolS1, AtDREB2A, AtWRKY39, and AtHSP101 was significantly elevated in transgenic Arabidopsis lines, which might have promoted an increase in thermotolerance. Then, the promoter of LlMBF1c was isolated from lily, and LlWRKY39 was found to bind to the conserved W-box element in its promoter to activate its activity, suggesting that LlWRKY39 is an upstream regulator of LlMBF1c. In addition, a dual-luciferase reporter assay showed that via protein interaction, LlCaM3 negatively affected LlWRKY39 in the transcriptional activation of LlMBF1c, which might be an important feedback regulation pathway to balance the LlWRKY39-mediated heat stress response (HSR). Collectively, these results imply that LlWRKY39 might participate in the HSR as an important regulator through Ca2+-CaM and multiprotein bridging factor pathways.