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As a common air pollutant, formaldehyde is widely present in nature, industrial production and consumer products. Endogenous formaldehyde is mainly produced through the oxidative deamination of methylamine catalysed by semicarbazide‐sensitive amine oxidase (SSAO) and is ubiquitous in human body fluids, tissues and cells. Vascular endothelial cells and smooth muscle cells are rich in this formaldehyde‐producing enzyme and are easily damaged owing to consequent cytotoxicity. Consistent with this, increasing evidence suggests that the cardiovascular system and stages of heart development are also susceptible to the harmful effects of formaldehyde. Exposure to formaldehyde from different sources can induce heart disease such as arrhythmia, myocardial infarction (MI), heart failure (HF) and atherosclerosis (AS). In particular, long‐term exposure to high concentrations of formaldehyde in pregnant women is more likely to affect embryonic development and cause heart malformations than long‐term exposure to low concentrations of formaldehyde. Specifically, the ability of mouse embryos to effect formaldehyde clearance is far lower than that of the rat embryos, more readily allowing its accumulation. Formaldehyde may also exert toxic effects on heart development by inducing oxidative stress and cardiomyocyte apoptosis. This review focuses on the current progress in understanding the influence and underlying mechanisms of formaldehyde on cardiovascular disease and heart development.

βII spectrin, the most common isoform of non-erythrocyte spectrin, is a cytoskeleton protein present in all nucleated cells. Interestingly, βII spectrin is essential for the development of various organs such as nerve, epithelium, inner ear, liver and heart. The functions of βII spectrin include not only establishing and maintaining the cell structure but also regulating a variety of cellular functions, such as cell apoptosis, cell adhesion, cell spreading and cell cycle regulation. Notably, βII spectrin dysfunction is associated with embryonic lethality and the DNA damage response. More recently, the detection of altered βII spectrin expression in tumors indicated that βII spectrin might be involved in the development and progression of cancer. Its mutations and disorders could result in developmental disabilities and various diseases. The versatile roles of βII spectrin in disease have been examined in an increasing number of studies; nonetheless, the exact mechanisms of βII spectrin are still poorly understood. Thus, we summarize the structural features and biological roles of βII spectrin and discuss its molecular mechanisms and functions in development, homeostasis, regeneration and differentiation. This review highlight the potential effects of βII spectrin dysfunction in cancer and other diseases, outstanding questions for the future investigation of therapeutic targets. The investigation of the regulatory mechanism of βII spectrin signal inactivation and recovery may bring hope for future therapy of related diseases.

Reconfiguration of the plastidial proteome in response to environmental cues is central to tailoring adaptive responses. To define the underlying mechanisms and consequences of these reconfigurations, we performed a suppressor screen, using a mutant ( ceh1 ) accumulating high levels of a plastidial retrograde signaling metabolite, MEcPP. We isolated a revertant partially suppressing the dwarf stature and high salicylic acid of ceh1 and identified the mutation in a putative plastidial metalloprotease (VIR3). Biochemical analyses showed increased VIR3 levels in ceh1 , accompanied by reduced abundance of VIR3-target enzymes, ascorbate peroxidase, and glyceraldehyde 3-phophate dehydrogenase B. These proteomic shifts elicited increased H 2 O 2 , salicylic acid, and MEcPP levels, as well as stromule formation. High light recapitulated VIR3-associated reconfiguration of plastidial metabolic and structural states. These results establish a link between a plastidial stress-inducible retrograde signaling metabolite and a putative metalloprotease and reveal how the reciprocity between the two components modulates plastidial metabolic and structural states, shaping adaptive responses.

Reconfiguration of the plastidial proteome in response to environmental inputs is central to readjustment of its metabolic and structural states. This is necessary for the functionality of this metabolic hub, and the maintenance of organismal integrity. This report establishes the role of the plastidial retrograde signaling metabolite, MEcPP, in increasing the abundance of the putative plastidial metalloprotease (VIR3), and the ensuing decline of VIR3 target enzymes, ascorbate peroxidase and glyceraldehyde 3-phophate dehydrogenase B. The decreased abundance of these enzymes is linked to increased levels of their substrates: H2O2, an elicitor of salicylic acid production and stromule formation; and G3P the substrate for MEcPP synthesis. High-light treatment of wild type plants recapitulated the VIR3-associated reconfiguration of the plastidial metabolic and structural states. These results identify a previously unrecognized link between the stress-induced plastidial retrograde signaling metabolite and a putative zinc-binding metalloprotease. Moreover, the data reveal that the reciprocity between these two components, results in the reconfiguration of the metabolic and structural states of the plastid, deemed necessary to maintain cellular integrity and to shape adaptive responses.

Circular RNAs (circRNAs) are a novel type of long non-coding RNAs that can regulate gene expression in heart development and heart disease. However, the expression pattern of circRNAs in congenital heart disease (CHD) induced by formaldehyde exposure is still unknown. We detected circRNAs expression profiles in heart tissue taken from six neonatal rat pups with formaldehyde exposure group and normal group using RNA-sequencing. Results revealed that a total of 54 circRNAs were dysregulated in the formaldehyde exposure group compared to the normal group. Among them, 31 were upregulated and 23 were downregulated (fold change = 2.0, p 0.0 5). The qRT-qPCR results showed that expressions of 12:628708|632694, 18:77477060|77520779, 5:167486001|167526275 were significantly upregulated, while that of 7:41167312|4116775 and 20:50659751|5068786 were notably downregulated; the expression pattern was consistent with the RNA sequencing data. Bioinformatics analysis shows that the pathogenesis of formaldehyde exposure-induced CHD may involve Hippo-YAP pathway、Notch signaling pathway and other pathways. A key miRNA (rno-miR-665) was identified by constructing a circRNA-miRNA-mRNA co-expression network. In summary, the study illustrated that circRNAs differentially expressed in fetal heart tissues during formaldehyde exposure has potential biological functions and may be a biomarker or therapeutic target for CHD.

Smoking is an independent risk factor for atherosclerosis. The smoke produced by tobacco burning contains more than 7000 chemicals, among which nicotine is closely related to the occurrence and development of atherosclerosis. Nicotine, a selective cholinergic agonist, accelerates the formation of atherosclerosis by stimulating nicotinic acetylcholine receptors (nAChRs) located in neuronal and non-neuronal tissues. This review introduces the pathogenesis of atherosclerosis and the mechanisms involving nicotine and its receptors. Herein, we focus on the various roles of nicotine in atherosclerosis, such as upregulation of growth factors, inflammation, and the dysfunction of endothelial cells, vascular smooth muscle cells (VSMC) as well as macrophages. In addition, nicotine can stimulate the generation of reactive oxygen species, cause abnormal lipid metabolism, and activate immune cells leading to the onset and progression of atherosclerosis. Exosomes, are currently a research hotspot, due to their important connections with macrophages and the VSMC, and may represent a novel application into future preventive treatment to promote the prevention of smoking-related atherosclerosis. In this review, we will elaborate on the regulatory mechanism of nicotine on atherosclerosis, as well as the effects of interference with nicotine receptors and the use of exosomes to prevent atherosclerosis development.

Light and gravity are two key environmental factors that control plant growth and architecture. However, the molecular basis of the coordination of light and gravity signaling in plants remains obscure. Here, we report that two classes of transcription factors, PHYTOCHROME INTERACTING FACTORS (PIFs) and ELONGATED HYPOCOTYL5 (HY5), can directly bind and activate the expression of LAZY4, a positive regulator of gravitropism in both shoots and roots in Arabidopsis. In hypocotyls, light promotes degradation of PIFs to reduce LAZY4 expression, which inhibits the negative gravitropism of hypocotyls. LAZY4 overexpression can partially rescue the negative gravitropic phenotype of pifq in the dark without affecting amyloplast development. Our identification of the PIFs-LAZY4 regulatory module suggests the presence of another role for PIF proteins in gravitropism, in addition to a previous report demonstrating that PIFs positively regulate amyloplast development to promote negative gravitropism in hypocotyls. In roots, light promotes accumulation of HY5 proteins to activate expression of LAZY4, which promotes positive gravitropism in roots. Together, our data indicate that light exerts opposite regulation of LAZY4 expression in shoots and roots by mediating the protein levels of PIFs and HY5, respectively, to inhibit the negative gravitropism of shoots and promote positive gravitropism of roots in Arabidopsis.

Photomorphogenesis is a pivotal developmental strategy used by plants to respond to environmental light levels. During emergence from the soil and the establishment of photomorphogenesis, seedlings encounter increasing levels of UV-B irradiation and develop adaptive responses accordingly. However, the molecular mechanisms that orchestrate UV-B signaling cascades remain elusive. Here, we provide biochemical and genetic evidence that the prolonged signaling circuits of UV-B-induced photomorphogenesis involve two sets of E3 ligases and a transcription factor in Arabidopsis thaliana The UV-B-inducible protein RUP1/RUP2 associates with the CUL4-DDB1 scaffold to form an E3 ligase, which represses photomorphogenesis by mediating the degradation of HY5, the hub transcription factor in the light signaling pathway. Conversely, COP1 directly targets RUP1/RUP2 for ubiquitination and degradation, leading to balanced RUP1/RUP2 accumulation, alleviation of the COP1-HY5 interaction, and stabilization of HY5 protein. Therefore, our study reveals that these two E3-substrate modules, CUL4-DDB1-RUP1/RUP2-HY5 and COP1-RUP1/RUP2, constitute the repression and derepression machinery by which plants respond to prolonged UV-B irradiation in photomorphogenic development.

Plants have evolved tightly regulated signaling networks to respond and adapt to environmental perturbations, but the nature of the signaling hub(s) involved have remained an enigma. We have previously established that methylerythritol cyclodiphosphate (MEcPP), a precursor of plastidial isoprenoids and a stress-specific retrograde signaling metabolite, enables cellular readjustments for high-order adaptive functions. Here, we specifically show that MEcPP promotes two Brassicaceae-specific traits, namely endoplasmic reticulum (ER) body formation and induction of indole glucosinolate (IGs) metabolism selectively, via transcriptional regulation of key regulators NAI1 for ER body formationand MYB51/122 for IGs biosynthesis). The specificity of MEcPP is further confirmed by the lack of induction of wound-inducible ER body genes as well as IGs by other altered methylerythritol phosphate pathway enzymes. Genetic analyses revealed MEcPP-mediated COI1-dependent induction of these traits. Moreover, MEcPP signaling integrates the biosynthesis and hydrolysis of IGs through induction of nitrile-specifier protein1 and reduction of the suppressor, ESM1, and production of simple nitriles as the bioactive end product. The findings positionthe plastidial metabolite, MEcPP, as the initiation hub, transducing signals to adjust the activity of hard-wired gene circuitry to expand phytochemical diversity and alter the associated subcellular structure required for functionality of the secondary metabolites, thereby tailoring plant stress responses.

Photomorphogenesis is a pivotal developmental strategy used by plants to respond to environmental light levels. During emergence from the soil and the establishment of photomorphogenesis, seedlings encounter increasing levels of UV-B irradiation and develop adaptive responses accordingly. However, the molecular mechanisms that orchestrate UV-B signaling cascades remain elusive. Here, we provide biochemical and genetic evidence that the prolonged signaling circuits of UV-B-induced photomorphogenesis involve two sets of E3 ligases and a transcription factor in

Among T-DNA insertion mutants of various cullin4-RING ubiquitin E3 ligase (CRL4) substrate receptors, one mutant that exhibits enhanced sensitivity in response to ultraviolet-B (UV-B) illumination has been isolated and its corresponding gene has been named DWD HYPERSENSITIVE TO UV-B 1 (DHU1) in Arabidopsis. dhu1 lines showed much shorter hypocotyls than those in wild type under low doses of UV-B. Other light did not alter hypocotyl growth patterns in dhu1, indicating the hypersensitivity of dhu1 is restricted to UV-B. DHU1 was upregulated by more than two times in response to UV-B application of 1.5 μmol m(-2) s(-1), implying its possible involvement in UV-B signaling. DHU1 is able to bind to DDB1, an adaptor of CRL4; accordingly, DHU1 is thought to act as a substrate receptor of CRL4. Microarray data generated from wild-type and dhu1 under low doses of UV-B revealed that 209 or 124 genes were upregulated or downregulated by more than two times in dhu1 relative to wild type, respectively. About 23.4 % of the total upregulated genes in dhu1 were upregulated by more than five times in response to UV-B based on the AtGenExpress Visualization Tool data, while only about 1.4 % were downregulated to the same degree by UV-B, indicating that loss of DHU1 led to the overall enhancement of the upregulation of UV-B inducible genes. dhu1 also showed altered responsiveness under high doses of UV-B. Taken together, these findings indicate that DHU1 is a potent CRL4 substrate receptor that may function as a negative regulator of UV-B response in Arabidopsis.

Long-wavelength and low-fluence UV-B light is an informational signal known to induce photomorphogenic development in plants. Using the model plant Arabidopsis thaliana, a variety of factors involved in UV-B-specific signaling have been experimentally characterized over the past decade, including the UV-B light receptor UV resistance locus 8; the positive regulators constitutive photomorphogenesis 1 and elongated hypocotyl 5; and the negative regulators cullin4, repressor of UV-B photomorphogenesis 1 (RUP1), and RUP2. Individual genetic and molecular studies have revealed that these proteins function in either positive or negative regulatory capacities for the sufficient and balanced transduction of photomorphogenic UV-B signal. Less is known, however, regarding how these signaling events are systematically linked. In our study, we use a systems biology approach to investigate the dynamic behaviors and correlations of multiple signaling components involved in Arabidopsis UV-B-induced photomorphogenesis. We define a mathematical representation of photomorphogenic UV-B signaling at a temporal scale. Supplemented with experimental validation, our computational modeling demonstrates the functional interaction that occurs among different protein complexes in early and prolonged response to photomorphogenic UV-B.

As sessile organisms, higher plants have evolved the capacity to sense and interpret diverse light signals to modulate their development. In Arabidopsis thaliana, low-intensity and long-wavelength UV-B light is perceived as an informational signal to mediate UV-B-induced photomorphogenesis. Here, we report that the multifunctional E3 ubiquitin ligase, CONSTITUTIVE PHOTOMORPHOGENESIS1 (COP1), a known key player in UV-B photomorphogenic responses, is also a UV-B-inducible gene. Two transcription factors, FAR-RED ELONGATED HYPOCOTYL3 (FHY3) and ELONGATED HYPOCOTYL5 (HY5), directly bind to distinct regulatory elements within the COP1 promoter, which are essential for the induction of the COP1 gene mediated by photomorphogenic UV-B signaling. Absence of FHY3 results in impaired UV-B-induced hypocotyl growth and reduced tolerance against damaging UV-B. Thus, FHY3 positively regulates UV-B-induced photomorphogenesis by directly activating COP1 transcription, while HY5 promotes COP1 expression via a positive feedback loop. Furthermore, FHY3 and HY5 physically interact with each other, and this interaction is diminished by UV-B. Together, our findings reveal that COP1 gene expression in response to photomorphogenic UV-B is controlled by a combinatorial regulation of FHY3 and HY5, and this UV-B-specific working mode of FHY3 and HY5 is distinct from that in far-red light and circadian conditions.

Highlight 2-C-Methyl-D-erythritol cyclopyrophosphate is an isoprenoid intermediate and a dynamic plastidial stress-specific signal that calibrates salicylic acid–jasmonic acid crosstalk and induces jasmonic acid-responsive genes in the presence of high salicylic acid in a manner dependent on the F-box protein COI1., The exquisite harmony between hormones and their corresponding signaling pathways is central to prioritizing plant responses to simultaneous and/or successive environmental trepidations. The crosstalk between jasmonic acid (JA) and salicylic acid (SA) is an established effective mechanism that optimizes and tailors plant adaptive responses. However, the underlying regulatory modules of this crosstalk are largely unknown. Global transcriptomic analyses of mutant plants (ceh1) with elevated levels of the stress-induced plastidial retrograde signaling metabolite 2-C-methyl-D-erythritol cyclopyrophosphate (MEcPP) revealed robustly induced JA marker genes, expected to be suppressed by the presence of constitutively high SA levels in the mutant background. Analyses of a range of genotypes with varying SA and MEcPP levels established the selective role of MEcPP-mediated signal(s) in induction of JA-responsive genes in the presence of elevated SA. Metabolic profiling revealed the presence of high levels of the JA precursor 12-oxo-phytodienoic acid (OPDA), but near wild type levels of JA in the ceh1 mutant plants. Analyses of coronatine-insensitive 1 (coi1)/ceh1 double mutant plants confirmed that the MEcPP-mediated induction is JA receptor COI1 dependent, potentially through elevated OPDA. These findings identify MEcPP as a previously unrecognized central regulatory module that induces JA-responsive genes in the presence of high SA, thereby staging a multifaceted plant response within the environmental context.

In Arabidopsis, ultraviolet (UV)-B-induced photomorphogenesis is initiated by a unique photoreceptor UV RESISTANCE LOCUS 8 (UVR8) which utilizes its tryptophan residues as internal chromophore to sense UV-B. As a result of UV-B light perception, the UVR8 homodimer shaped by its arginine residues undergoes a conformational switch of monomerization. Then UVR8 associates with the CONSTITUTIVELY PHOTOMORPHOGENIC 1-SUPPRESSOR OF PHYA (COP1-SPA) core complex(es) that is released from the CULLIN 4-DAMAGED DNA BINDING PROTEIN 1 (CUL4-DDB1) E3 apparatus. This association, in turn, causes COP1 to convert from a repressor to a promoter of photomorphogenesis. It is not fully understood, however, regarding the biological significance of light-absorbing and dimer-stabilizing residues for UVR8 activity in photomorphogenic UV-B signaling. Here, we take advantage of transgenic UVR8 variants to demonstrate that two light-absorbing tryptophans, W233 and W285, and two dimer-stabilizing arginines, R286 and R338, play pivotal roles in UV-B-induced photomorphogenesis. Mutation of each residue results in alterations in UV-B light perception, UVR8 monomerization and UVR8-COP1 association in response to photomorphogenic UV-B. We also identify and functionally characterize two constitutively active UVR8 variants, UVR8W285A and UVR8R338A, whose photobiological activities are enhanced by the repression of CUL4, a negative regulator in this pathway. Based on our molecular and biochemical evidence, we propose that the UVR8-COP1 affinity in plants critically determines the photomorphogenic UV-B signal transduction coupling with UVR8-mediated UV-B light perception., Author Summary Higher plants are able to sense and interpret diverse light signals to modulate their growth. In response to long-wavelength and low-intensity ultraviolet-B (UV-B) light, plants establish photomorphogenic development and stress acclimation. UV RESISTANCE LOCUS 8 (UVR8) is a unique UV-B photoreceptor that triggers photomorphogenesis in Arabidopsis thaliana. However, the signaling process following UV-B light perception by plants is not fully understood. In this study, by generating transgenic UVR8 variants in Arabidopsis, we have extensively analyzed the biological significance of key residues in UVR8 for UV-B-induced photomorphogenesis. Furthermore, by engineering and characterizing two constitutively active UVR8 variants, we have provided the biochemical insight that the in vivo association between UVR8 and CONSTITUTIVELY PHOTOMORPHOGENIC 1 (COP1) critically determines the photomorphogenic UV-B signaling output.

The evolutionarily conserved CONSTITUTIVE PHOTOMORPHOGENESIS 1 (COP1) is a RING and WD40 protein that functions as a substrate receptor of CULLIN4–DAMAGED DNA BINDING PROTEIN 1 (CUL4–DDB1)–based E3 ubiquitin ligases in both plants and animals. In Arabidopsis, COP1 is a central repressor of photomorphogenesis in the form of COP1–SUPPRESSOR OF PHYA (SPA) complex(es). CUL4–DDB1–COP1–SPA suppresses the photomorphogenic program by targeting the transcription factor ELONGATED HYPOCOTYL 5 for degradation. Intriguingly, under photomorphogenic UV-B light, COP1 reverses its repressive role and promotes photomorphogenesis. However, the mechanism by which COP1 is functionally switched is still obscure. Here, we demonstrate that UV-B triggers the physical and functional disassociation of the COP1–SPA core complex(es) from CUL4–DDB1 and the formation of a unique complex(es) containing the UV-B receptor UV RESISTANCE LOCUS 8 (UVR8). The establishment of this UV-B–dependent COP1 complex(es) is associated with its positive modulation of ELONGATED HYPOCOTYL 5 stability and activity, which sheds light on the mechanism of COP1’s promotive action in UV-B–induced photomorphogenesis.