RESUMO
Associational effects, whereby plants influence the biotic interactions of their neighbors, are an important component of plant-insect interactions. Plant chemistry has been hypothesized to mediate these interactions. The role of chemistry in associational effects, however, has been unclear in part because the diversity of plant chemistry makes it difficult to tease apart the importance and roles of particular classes of compounds. We examined the chemical ecology of associational effects using backcross-bred plants of the Solanum pennellii introgression lines. We used eight genotypes from the introgression line system to establish 14 unique neighborhood treatments that maximized differences in acyl sugars, proteinase inhibitor, and terpene chemical diversity. We found that the chemical traits of the neighboring plant, rather than simply the number of introgression lines within a neighborhood, influenced insect abundance on focal plants. Furthermore, within-chemical class diversity had contrasting effects on herbivore and predator abundances, and depended on the frequency of neighboring plant chemotypes. Notably, we found insect mobility-flying versus crawling-played a key role in insect response to phytochemistry. We highlight that the frequency and chemical phenotype of plant neighbors underlie associational effects and suggest this may be an important mechanism in maintaining intraspecific phytochemical variation within plant populations.
RESUMO
BACKGROUND: Pulmonary hypertension leads to right ventricular failure, which is a major determinant of prognosis. Circulating biomarkers for right ventricular function are poorly explored in pulmonary hypertension. This study aimed to clarify the significance of collagen triple helix repeat-containing protein 1 (CTHRC1) as a biomarker of right ventricular failure in pulmonary hypertension. METHODS: A monocrotaline-induced pulmonary hypertension rat model was used to evaluate right ventricular CTHRC1 expression and its relationship with fibrosis. Next, human plasma CTHRC1 levels were measured in controls (n = 20), pulmonary arterial hypertension (n = 46), and patients with chronic thromboembolic pulmonary hypertension (CTEPH) (n = 64) before the first and after the final balloon pulmonary angioplasty. RESULTS: CTHRC1 expression was higher in the right ventricles of rats with monocrotaline-induced pulmonary hypertension than in those of controls. CTHRC1 was colocalized with vimentin and associated with fibrosis in the right ventricles. Plasma CTHRC1 levels were higher in human patients with pulmonary arterial hypertension (P = 0.006) and CTEPH (P = 0.011) than in controls. Plasma CTHRC levels were correlated with B-type natriuretic peptide (R = 0.355, P < 0.001), tricuspid lateral annular peak systolic velocity (R = -0.213, P = 0.029), and right ventricular fractional area change (R = -0.225, P = 0.017). Finally, plasma CTHRC1 levels were decreased after the final balloon pulmonary angioplasty (P < 0.001) in CTEPH. CONCLUSIONS: CTHRC1 can be a circulating biomarker associated with right ventricular function and fibrosis in pulmonary hypertension and might reflect the therapeutic efficacy of balloon pulmonary angioplasty in CTEPH.
Assuntos
Arabidopsis , Flavonoides , Flavonoides/metabolismo , Flavonoides/biossíntese , Arabidopsis/genética , Arabidopsis/enzimologia , Arabidopsis/metabolismo , Liases Intramoleculares/genética , Liases Intramoleculares/metabolismo , Proteínas de Arabidopsis/metabolismo , Proteínas de Arabidopsis/genéticaRESUMO
Idiopathic pulmonary arterial hypertension is a progressive and life-threatening disease with pulmonary vasculature remodeling, leading to right-sided heart failure. Epoprostenol (prostaglandin I2) is highly recommended for patients with severe pulmonary arterial hypertension (PAH) categorized by the World Health Organization as functional class III or IV. It has been reported that prostaglandin I2 analogs can cause thyroid gland swelling and abnormal thyroid function. A 34-year-old woman was diagnosed with idiopathic pulmonary arterial hypertension and started receiving continuous intravenous epoprostenol. Three years after starting epoprostenol, she began complaining of neck swelling and was diagnosed with Graves' disease. The patient's thyroid function was controlled by thiamazole and levothyroxine; nevertheless, her thyroid gland enlargement worsened as the epoprostenol dose was titrated. After 20 years, she developed respiratory failure with a giant goiter leading to airway stenosis, and she passed away. The pathological autopsy confirmed a massive goiter associated with hyperthyroidism and airway stenosis. We experienced a case of idiopathic pulmonary hypertension with a giant goiter and airway stenosis after long-term intravenous epoprostenol therapy.
RESUMO
Chronic thromboembolic pulmonary hypertension (CTEPH) is designated as an intractable disease by the Ministry of Health, Labour and Welfare of Japan, and has an extremely poor prognosis if untreated. Surgical pulmonary endarterectomy is the curative treatment for cases in which the organized thrombi are located in the central part of the pulmonary artery, but there had been no effective treatment for cases in which the thrombi are located in the peripheral part of the pulmonary artery. Recently, balloon pulmonary angioplasty (BPA), a transcatheter procedure to dilate stenotic or occluded lesions in the peripheral pulmonary artery, has been rapidly developed. Although BPA was once a globally abandoned procedure due to hemorrhagic complications, Japanese experts have improved the technique, and its safety and efficacy have been enhanced. As a result, BPA is now being reevaluated worldwide. This review describes the history and development of BPA in the treatment of CTEPH, as well as the status of this treatment in Fukushima Prefecture.
Assuntos
Angioplastia com Balão , Hipertensão Pulmonar , Embolia Pulmonar , Humanos , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/terapia , Embolia Pulmonar/complicações , Embolia Pulmonar/terapia , Doença Crônica , Angioplastia com Balão/efeitos adversos , Angioplastia com Balão/métodos , Artéria PulmonarRESUMO
OBJECTIVE: Since novel therapeutic agents for malignancies are developed rapidly mainly in the US, the interval of approval timing between the US and other countries is an important issue. Among them, drugs for hematologic malignancies tended to have a particularly long delays in Japan, but its characteristics have not been fully understood. This study assessed the approval delays in drugs for hematologic malignancies in Japan compared with that in Europe. METHODS: Using the public database of Europe, Japan and the US, we analyzed the differences in drug approval delays between Europe and the US and between Japan and US according to disease. New molecular entity drugs for hematologic malignancies that were already approved in the US and were approved from April 2010 to March 2022 in Europe or Japan were identified. RESULTS: The results showed the longer drug approval delays in Japan compared with that in Europe (29 vs. 9.4 months, median), presumably due to the lower proportion of participation in global clinical trials (37 vs. 94%). Notably, the participation rate in global clinical trials varied widely by disease in Japan, resulting in a greater difference in drug approval delays by disease. In contrast, when focusing on early phase trials, Japanese participation was uniformly very limited regardless of the disease. CONCLUSIONS: The current study provided data that can be used as a basis for discussion on how to improve drug approval delays in drugs for hematologic malignancies.
Assuntos
Aprovação de Drogas , Neoplasias Hematológicas , Humanos , Japão/epidemiologia , Fatores de Tempo , Neoplasias Hematológicas/tratamento farmacológico , Europa (Continente)/epidemiologiaRESUMO
BACKGROUND/AIM: The treatment strategy for metastatic upper tract urothelial carcinoma (mUTUC) is currently based on the evidence from metastatic urinary bladder cancer (mUBC). However, some reports have shown that the outcomes of UTUC differ from those of UBC. Therefore, we retrospectively analyzed the prognosis of patients with mUBC and mUTUC treated with first-line platinum-based chemotherapy. PATIENTS AND METHODS: Patients who underwent platinum-based chemotherapy at the Kindai University Hospital and affiliated hospitals between January 2010 and December 2021 were included in the study. There were 56 patients with mUBC and 73 with mUTUC. Kaplan-Meier curves were used to estimate progression-free (PFS) and overall (OS) survival. Multivariate analyses were performed using Cox proportional hazards model to predict prognostic factors. RESULTS: The median PFS was 4.5 and 4.0 months for the mUBC and mUTUC groups, respectively (p=0.094). The median OS was 17.0 months for both groups (p=0.821). The multivariate analysis showed no prognostic factor for PFS. The multivariate analysis for OS showed that younger age at the initiation of chemotherapy and immune checkpoint inhibitor use after first-line therapy were significantly associated with better OS. CONCLUSION: Platinum-based chemotherapy had a similar effect on patients with mUTUC and mUBC.
RESUMO
In flowering plants, pollination, pollen tube growth, and fertilization are regarded as the first hierarchical processes of producing offspring. However, their independent contributions to fruit set and development remain unclear. In this study, we examined the effect of three different types of pollen, intact pollen (IP), soft X-ray-treated pollen (XP) and dead pollen (DP), on pollen tube growth, fruit development and gene expression in "Micro-Tom" tomato. Normal germination and pollen tube growth were observed in flowers pollinated with IP; pollen tubes started to penetrate the ovary at 9 h after pollination, and full penetration was achieved after 24 h (IP24h), resulting in ~94% fruit set. At earlier time points (3 and 6 h after pollination; IP3h and IP6h, respectively), pollen tubes were still in the style, and no fruit set was observed. Flowers pollinated with XP followed by style removal after 24 h (XP24h) also demonstrated regular pollen tubes and produced parthenocarpic fruits with ~78% fruit set. As expected, DP could not germinate and failed to activate fruit formation. Histological analysis of the ovary at 2 days after anthesis (DAA) revealed that IP and XP comparably increased cell layers and cell size; however, mature fruits derived from XP were significantly smaller than those derived from IP. Furthermore, there was a high correlation between seed number and fruit size in fruit derived from IP, illustrating the crucial role of fertilization in the latter stages of fruit development. RNA-Seq analysis was carried out in ovaries derived from IP6h, IP24h, XP24h and DP24h in comparison with emasculated and unpollinated ovaries (E) at 2 DAA. The results revealed that 65 genes were differentially expressed (DE) in IP6h ovaries; these genes were closely associated with cell cycle dormancy release pathways. Conversely, 5062 and 4383 DE genes were obtained in IP24h and XP24h ovaries, respectively; top enriched terms were mostly associated with cell division and expansion in addition to the 'plant hormone signal transduction' pathway. These findings indicate that full penetration of pollen tubes can initiate fruit set and development independently of fertilization, most likely by activating the expression of genes regulating cell division and expansion.
RESUMO
Jasmonates (JAs) are plant hormones with crucial roles in development and stress resilience. They activate MYC transcription factors by mediating the proteolysis of MYC inhibitors called JAZ proteins. In the absence of JA, JAZ proteins bind and inhibit MYC through the assembly of MYC-JAZ-Novel Interactor of JAZ (NINJA)-TPL repressor complexes. However, JAZ and NINJA are predicted to be largely intrinsically unstructured, which has precluded their experimental structure determination. Through a combination of biochemical, mutational, and biophysical analyses and AlphaFold-derived ColabFold modeling, we characterized JAZ-JAZ and JAZ-NINJA interactions and generated models with detailed, high-confidence domain interfaces. We demonstrate that JAZ, NINJA, and MYC interface domains are dynamic in isolation and become stabilized in a stepwise order upon complex assembly. By contrast, most JAZ and NINJA regions outside of the interfaces remain highly dynamic and cannot be modeled in a single conformation. Our data indicate that the small JAZ Zinc finger expressed in Inflorescence Meristem (ZIM) motif mediates JAZ-JAZ and JAZ-NINJA interactions through separate surfaces, and our data further suggest that NINJA modulates JAZ dimerization. This study advances our understanding of JA signaling by providing insights into the dynamics, interactions, and structure of the JAZ-NINJA core of the JA repressor complex.
Assuntos
Proteínas de Arabidopsis , Arabidopsis , Proteínas de Arabidopsis/metabolismo , Arabidopsis/genética , Arabidopsis/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/química , Proteínas Repressoras/metabolismo , Ciclopentanos/metabolismoRESUMO
A 57-year-old male patient with relapsed/refractory diffuse large B-cell lymphoma received 4 courses of Pola-BR (polatuzumab vedotin-bendamustine-rituximab). After treatment, stem cell collection with G-CSF and plerixafor successfully yielded 4.2×106 cells/kg of CD34-positive cells. The patient underwent autologous peripheral hematopoietic stem cell transplantation. Neutrophil engraftment was achieved on day 12 and the patient was followed up without progression. In this case, stem cell mobilization with G-CSF and plerixafor was effective even in patients who had received chemotherapy including bendamustine, which is known to sometimes complicate stem cell collection. Although bendamustine should generally be avoided in cases where stem cell collection is planned, there are cases in which the decision to perform transplantation is made after chemotherapy including bendamustine. We have reported a case in which we were able to perform stem cell collection after pola-BR regimen.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Compostos Heterocíclicos , Linfoma Difuso de Grandes Células B , Masculino , Humanos , Pessoa de Meia-Idade , Rituximab , Mobilização de Células-Tronco Hematopoéticas , Cloridrato de Bendamustina/efeitos adversos , Terapia de Salvação , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante Autólogo , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Fator Estimulador de Colônias de GranulócitosAssuntos
Compostos Bicíclicos Heterocíclicos com Pontes , Neutropenia Febril , Leucemia Mieloide Aguda , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Azacitidina/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , População do Leste Asiático , Neutropenia Febril/induzido quimicamente , Leucemia Mieloide Aguda/tratamento farmacológicoRESUMO
Volatiles from herbivore-infested plants function as a chemical warning of future herbivory for neighboring plants. (Z)-3-Hexenol emitted from tomato plants infested by common cutworms is taken up by uninfested plants and converted to (Z)-3-hexenyl ß-vicianoside (HexVic). Here we show that a wild tomato species (Solanum pennellii) shows limited HexVic accumulation compared to a domesticated tomato species (Solanum lycopersicum) after (Z)-3-hexenol exposure. Common cutworms grow better on an introgression line containing an S. pennellii chromosome 11 segment that impairs HexVic accumulation, suggesting that (Z)-3-hexenol diglycosylation is involved in the defense of tomato against herbivory. We finally reveal that HexVic accumulation is genetically associated with a uridine diphosphate-glycosyltransferase (UGT) gene cluster that harbors UGT91R1 on chromosome 11. Biochemical and transgenic analyses of UGT91R1 show that it preferentially catalyzes (Z)-3-hexenyl ß-D-glucopyranoside arabinosylation to produce HexVic in planta.
Assuntos
Solanum lycopersicum , Solanum , Compostos Orgânicos Voláteis , Solanum lycopersicum/genética , Pentosiltransferases , Glicosiltransferases/genética , Compostos Orgânicos Voláteis/análise , HerbivoriaRESUMO
High mannose-type free N-glycans with a single N-acetyl-D-glucosamine (GlcNAc) residue at the reducing end (GN1-HMT-FNGs) are produced by cytosolic endo-ß-N-acetylglucosaminidase (EC:3.2.1.96) (ENGase) and are ubiquitous in differentiating and growing plant cells. To elucidate the physiological functions of HMT-FNGs in plants, we identified the ENGase gene in tomato (Solyc06g050930) and detected ENGase activity and increased production of GN1-HMT-FNGs during tomato fruit maturation. However, the precise role of GN1-HMT-FNGs in fruit maturation remains unclear. In this study, we established tomato ENGase mutants with suppressed ENGase activity via CRISPR/Cas9 genome editing technology. DNA sequencing of the Δeng mutants (T0 and T1 generations) revealed that they had the same mutations in the genomic DNA around the target sequences. Three null CRISPR/Cas9 segregant plants of the T1 generation (Δeng1-2, -22, and -26) were used to measure ENGase activity and analyze the structural features of HMT-FNGs in the leaves. The Δeng mutants did not exhibit ENGase activity and produced GN2-HMT-FNGs bearing tow GlcNAc residues at the reducing end side instead of GN1-HMT-FNGs. The Δeng mutants lack the N-terminal region of ENGase, indicating that the N-terminal region is important for full ENGase activity. The fruits of Δeng mutants (T2 generation) also showed loss of ENGase activity and similar structural features of HMT-FNGs of the T1 generation. However, there was no significant difference in fruit maturation between the T2 generation of the Δeng mutants and the wild type. The Δeng mutants rich in GN2-HMT-FNGs could be offered as a new tomato that is different from wild type containing GN1-HMT-FNGs.
Assuntos
Solanum lycopersicum , Acetilglucosamina , Acetilglucosaminidase/genética , Sistemas CRISPR-Cas/genética , Edição de Genes , Solanum lycopersicum/genética , Manose/química , Polissacarídeos/químicaRESUMO
Responses of plant cells to reactive oxygen species (ROS), e.g., reprogramming of defense genes or progression of cell death, should include the ROS signal transmission to target proteins, but the biochemistry of this process is largely unknown. Lipid peroxide-derived α,ß-unsaturated aldehydes and ketones (reactive carbonyl species; RCS), downstream products of ROS stimuli, are recently emerging endogenous agents that can mediate ROS signal to proteins via covalent modification. The involvement of RCS in certain ROS signaling in plants (oxidative injury of leaves and roots, ROS-induced programmed cell death, senescence, and abscisic acid and auxin signaling) has been verified by the determination of RCS with the use of conventional HPLC. Because distinct kinds of RCS act differently in the cell and so are metabolized, identification and quantification of each RCS in plant tissues provide central information to decipher biochemical mechanisms of plant responses to ROS. This article illustrates practical methods of plant sample preparation and extraction and analysis of RCS.
Assuntos
Arabidopsis , Células Vegetais , Ácido Abscísico/metabolismo , Arabidopsis/genética , Estresse Oxidativo , Células Vegetais/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
One of the characteristic aspects of odour sensing in humans is the activation of olfactory receptors in a slightly different manner in response to different enantiomers. Here, we focused on whether plants showed enantiomer-specific response similar to that in humans. We exposed Arabidopsis seedlings to methanol (control) and (+)- or (-)-borneol, and found that only (+)-borneol reduced the root length. Furthermore, the root-tip width was more increased upon (+)-borneol exposure than upon (-)-borneol exposure. In addition, root-hair formation was observed near the root tip in response to (+)-borneol. Auxin signalling was strongly reduced in the root tip following exposure to (+)-borneol, but was detected following exposure to (-)-borneol and methanol. Similarly, in the root tip, the activity of cyclin B1:1 was detected on exposure to (-)-borneol and methanol, but not on exposure to (+)-borneol, indicating that (+)-borneol inhibits the meristematic activity in the root. These results partially explain the (+)-borneol-specific reduction in the root length of Arabidopsis. Our results indicate the presence of a sensing system specific for (+)-borneol in Arabidopsis.
Assuntos
Proteínas de Arabidopsis , Arabidopsis , Arabidopsis/fisiologia , Proteínas de Arabidopsis/fisiologia , Canfanos , Humanos , Ácidos Indolacéticos/farmacologia , Meristema/fisiologia , Metanol , Raízes de Plantas/fisiologiaRESUMO
The pathogenesis of sepsis-induced acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) has not yet been fully elucidated. Growth arrest-specific 6 (Gas6) has marked effects on hemostasis and reduces inflammation through its interaction with receptor tyrosine kinases of the TAM family: Tyro3, Axl, and Mer. Here, we found that plasma concentrations of Gas6 and soluble Mer were greater in patients with severe sepsis or septic ALI/ARDS compared with those in normal healthy donors. To determine whether the Gas6-Mer axis was critical in the pathogenesis of ALI/ARDS, we investigated the effects of intravenous administration of the selective Mer inhibitor UNC2250 on lipopolysaccharide (LPS)-induced ALI in mouse models subjected to inhalation of LPS. UNC2250 markedly inhibited the infiltration into the lungs of neutrophils and monocytes with increased amounts of Gas6 and Mer proteins, severe lung damage, and increased amounts of reactive oxygen species (ROS) in LPS-induced ALI in mice. In human pulmonary aortic endothelial cells, LPS induced decreases in the amounts of endothelial nitric oxide synthase, thrombomodulin, and vascular endothelial-cadherin, which was blocked by treatment with UNC2250. UNC2250 also inhibited the LPS-dependent increases in cell proliferation and enhanced apoptosis in HL-60 cells, a human neutrophil-like cell line, and RAW264.7 cells, a mouse monocyte/macrophage cell line. These data provide insights into the potential multiple beneficial effects of the Mer inhibitor UNC2250 as a therapeutic reagent to treat inflammatory responses in ALI/ARDS.
Assuntos
Síndrome do Desconforto Respiratório , Sepse , Animais , Células Endoteliais/metabolismo , Humanos , Lipopolissacarídeos/farmacologia , Pulmão/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Síndrome do Desconforto Respiratório/induzido quimicamente , Síndrome do Desconforto Respiratório/tratamento farmacológico , Sepse/metabolismoRESUMO
Glandular trichomes (GTs) are epidermal structures that provide the first line of chemical defense against arthropod herbivores and other biotic threats. The most conspicuous structure on leaves of cultivated tomato (Solanum lycopersicum) is the type-VI GT (tVI-GT), which accumulates both flavonoids and volatile terpenoids. Although these classes of specialized metabolites are derived from distinct metabolic pathways, previous studies with a chalcone isomerase 1 (CHI1)-deficient mutant called anthocyanin free (af) showed that flavonoids are required for terpenoid accumulation in tVI-GTs. Here, we combined global transcriptomic and proteomic analyses of isolated trichomes as a starting point to show that the lack of CHI1 is associated with reduced levels of terpenoid biosynthetic transcripts and enzymes. The flavonoid deficiency in af trichomes also resulted in the upregulation of abiotic stress-responsive genes associated with DNA damage and repair. Several lines of biochemical and genetic evidence indicate that the terpenoid defect in af mutants is specific for the tVI-GT and is associated with the absence of bulk flavonoids rather than loss of CHI1 per se. A newly developed genome-scale model of metabolism in tomato tVI-GTs helped identify metabolic imbalances caused by the loss of flavonoid production. We provide evidence that flavonoid deficiency in this cell type leads to increased production of reactive oxygen species (ROS), which may impair terpenoid biosynthesis. Collectively, our findings support a role for flavonoids as ROS-scavenging antioxidants in GTs.