Anthracycline­induced delayed­onset cardiac toxicity: A case report and literature review.

Anthracyclic (ANT) drugs are widely used for patients with malignant tumors and can markedly prolong the disease-free survival rate of patients. As its clinical application becomes more common, information regarding serious cardiotoxicity as a result of ANT treatment is becoming understood. However, to the best of our knowledge, delayed-onset cardiotoxicity due to ANT use has not been studied sufficiently. The present report describes a 36-year-old male patient who presented to Guiqian International General Hospital (Guiyang, China) with a complaint of dyspnea in the last 10 days. Substantially elevated B-type natriuretic peptide levels and echocardiography showing enlargement of the entire heart, of the patient suggested that severe heart failure was the cause of his symptoms. However, the cause of this potential heart failure was not apparent until the patient was questioned about his cancer treatment history. Following consultation to evaluate the assessment of end-stage heart failure, currently only anti-heart failure treatment and symptomatic treatment can be provided. The present report describes this case and reviews the existing literature to provide a basis for the diagnosis and treatment of patients with delayed-onset heart failure following ANT treatment.

Nitrogen-Regulated Theanine and Flavonoid Biosynthesis in Tea Plant Roots: Protein-Level Regulation Revealed by Multiomics Analyses.

Theanine and flavonoids (especially proanthocyanidins) are the most important and abundant secondary metabolites synthesized in the roots of tea plants. Nitrogen promotes theanine and represses flavonoid biosynthesis in tea plant roots, but the underlying mechanism is still elusive. Here, we analyzed theanine and flavonoid metabolism in tea plant roots under nitrogen deficiency and explored the regulatory mechanism using proteome and ubiquitylome profiling together with transcriptome data. Differentially expressed proteins responsive to nitrogen deficiency were identified and found to be enriched in flavonoid, nitrogen, and amino acid metabolism pathways. The proteins responding to nitrogen deficiency at the transcriptional level, translational level, and both transcriptional and translational levels were classified. Nitrogen-deficiency-responsive and ubiquitinated proteins were further identified. Our results showed that most genes encoding enzymes in the theanine synthesis pathway, such as CsAlaDC, CsGDH, and CsGOGATs, were repressed by nitrogen deficiency at transcriptional and/or protein level(s). While a large number of enzymes in flavonoid metabolism were upregulated at the transcriptional and/or translational level(s). Importantly, the ubiquitylomic analysis identified important proteins, especially the hub enzymes in theanine and flavonoid biosynthesis, such as CsAlaDC, CsTSI, CsGS, CsPAL, and CsCHS, modified by ubiquitination. This study provided novel insights into the regulation of theanine and flavonoid biosynthesis and will contribute to future studies on the post-translational regulation of secondary metabolism in tea plants.

Shading Promoted Theanine Biosynthesis in the Roots and Allocation in the Shoots of the Tea Plant (Camellia sinensis L.) Cultivar Shuchazao.

Shading was thought as an effective approach to increase theanine in harvested tea shoots. Previous studies offered conflicting findings, perhaps since the integration of theanine metabolism and transport in different tissues was not considered. Theanine is synthesized primarily in the roots and is then transported, via the vascular system, to new vegetative tissues. Here, we found that theanine increased in the stem, was reduced in the leaf, and remained stable in the roots, under shading conditions. Notably, in tea roots, shading significantly increased ethylamine and activated the theanine biosynthesis pathway and theanine transporter genes. Furthermore, shading significantly increased the expression of theanine transporter genes, CsAAP2/4/5/8, in the stem, while decreasing the expression of CsAAP1/2/4/5/6 in the leaf, in accordance with shading effects on theanine levels in these tissues. These findings reveal that shading of tea plants promotes theanine biosynthesis and allocation in different tissues, processes which appear to involve the theanine biosynthesis pathway enzymes and AAP family of theanine transporters.

HAK/KUP/KT family potassium transporter genes are involved in potassium deficiency and stress responses in tea plants (Camellia sinensis L.): expression and functional analysis.

BACKGROUND: Tea plant is one of the most important non-alcoholic beverage crops worldwide. While potassium (K+) is an essential macronutrient and greatly affects the growth and development of plants, the molecular mechanism underlying K+ uptake and transport in tea plant root, especially under limited-K+ conditions, is still poorly understood. In plants, HAK/KUP/KT family members play a crucial role in K+ acquisition and translocation, growth and development, and response to stresses. Nevertheless, the biological functions of these genes in tea plant are still in mystery, especially their roles in K+ uptake and stress responses. RESULTS: In this study, a total of 21 non-redundant HAK/KUP/KT genes (designated as CsHAKs) were identified in tea plant. Phylogenetic and structural analysis classified the CsHAKs into four clusters (I, II, III, IV), containing 4, 8, 4 and 5 genes, respectively. Three major categories of cis-acting elements were found in the promoter regions of CsHAKs. Tissue-specific expression analysis indicated extremely low expression levels in various tissues of cluster I CsHAKs with the exception of a high root expression of CsHAK4 and CsHAK5, a constitutive expression of clusters II and III CsHAKs, and a moderate cluster IV CsHAKs expression. Remarkably, the transcript levels of CsHAKs in roots were significantly induced or suppressed after exposure to K+ deficiency, salt and drought stresses, and phytohormones treatments. Also notably, CsHAK7 was highly expressed in all tissues and was further induced under various stress conditions. Therefore, functional characterization of CsHAK7 was performed, and the results demostrated that CsHAK7 locates on plasma membrane and plays a key role in K+ transport in yeast. Taken together, the results provide promising candidate CsHAKs for further functional studies and contribute to the molecular breeding for new tea plants varieties with highly efficient utilization of K+. CONCLUSION: This study demonstrated the first genome-wide analysis of CsHAK family genes of tea plant and provides a foundation for understanding the classification and functions of the CsHAKs in tea plants.

Transcriptome analysis provides insights into the molecular bases in response to different nitrogen forms-induced oxidative stress in tea plant roots (Camellia sinensis).

Previous studies have suggested that the maintenance of redox homeostasis is essential for plant growth. Here we investigated how redox homeostasis and signalling is modulated in response to different nitrogen (N) forms in tea plant roots. Our results showed that both N deficiency and nitrate (NO3-) can trigger the production of hydrogen peroxide and lipid peroxidation in roots. In contrast, these responses were not altered by NH4+. Further, N deficiency and NO3--triggered redox imbalance was re-established by increased of proanthocyanidins (PAs) and glutathione (GSH), as well as upregulation of representative antioxidant enzyme activities and genes. To further explore the molecular bases of these responses, comparative transcriptome analysis was performed, and redox homeostasis-associated differentially expressed genes (DEGs) were selected for bioinformatics analysis. Most of these genes were involved in the flavonoid biosynthesis, GSH metabolism and the antioxidant system, which was specifically altered by N deficiency or NO3-. Moreover, the interplay between H2O2 (generated by RBOH and Ndufab1) and hormones (including abscisic acid, auxin, cytokinin and ethylene) in response to different N forms was suggested. Collectively, the above findings contribute to an understanding of the underlying molecular mechanisms of redox homeostasis and signalling in alleviating oxidative stress in tea plant roots.

Transcriptional regulation of amino acid metabolism in response to nitrogen deficiency and nitrogen forms in tea plant root (Camellia sinensis L.).

Free amino acids, including theanine, glutamine and glutamate, contribute greatly to the pleasant taste and multiple health benefits of tea. Amino acids in tea plants are mainly synthesized in roots and transported to new shoots, which are significantly affected by nitrogen (N) level and forms. However, the regulatory amino acid metabolism genes have not been systemically identified in tea plants. Here, we investigated the dynamic changes of free amino acid contents in response to N deficiency and forms in tea plant roots, and systemically identified the genes associated amino acid contents in individual metabolism pathways. Our results showed that glutamate-derived amino acids are the most dynamic in response to various forms of N and N deficiency. We then performed transcriptomic analyses of roots treated with N deficiency and various forms of N, and differentially expressed amino acid metabolic genes in each pathway were identified. The analyses on expression patterns and transcriptional responses of metabolic genes to N treatments provided novel insights for the molecular basis of high accumulation of theanine in tea plant root. These analyses also identified potential regulatory genes in dynamic amino acid metabolism in tea plant root. Furthermore, our findings indicated that the dynamic expression levels of CsGDH, CsAlaDC, CsAspAT, CsSDH, CsPAL, CsSHMT were highly correlated with changes of amino acid contents in their corresponding pathways. Herein, this study provides comprehensive insights into transcriptional regulation of amino acid metabolism in response to nitrogen deficiency and nitrogen forms in tea plant root.

Influence of phenotype conversion of epicardial adipocytes on the coronary atherosclerosis and its potential molecular mechanism.

OBJECTIVE: To investigate the phenotype conversion of epicardial adipocytes and its potential molecular mechanism during the occurrence and development of coronary atherosclerosis. METHODS: A total of 30 health male New Zealand white rabbits were used. In experiment group (n=15), rabbits were fed with high fat food to establish atherosclerosis animal model; rabbits in control group (n=15) were fed with normal food. RESULTS: At week 0, UCP-1 and PPARγ mRNA expressions in EAT and sBAT were significantly higher than in eWAT, and leptin mRNA expression lower than (P<0.05). In experiment group, the mRNA expressions of UCP-1 and PPARγ reduced gradually, but leptin mRNA increased progressively in EAT (P<0.05). UCP-1 expression reduced gradually, the newly generated blood vessels reduced significantly, but leptin and RAM11 increased gradually (P<0.05). The adipocyte volume in EAT increased gradually, but the adipocyte number reduced progressively (P<0.05). The number of mitochondria with multiple crests reduced gradually in EAT; IL-6 reduced the mRNA expressions of UCP-1 and PPARγ in adipocytes of BAT in a dose dependent manner, but it increased the mRNA expressions of leptin and STAT3 (P<0.05). In the presence of IL-6, JSI-124 increased the mRNA expressions of UCP-1 and PPAR-γ in adipocytes of BAT in a dose dependent manner, but it reduced the mRNA expressions of leptin and STAT3 (P<0.05). CONCLUSION: During the progression of atherosclerosis, there is a phenotype conversion of EAT from BAT to WAT, which further promotes the focal occurrence and development of atherosclerosis; IL-6 may activate JAK-STAT3 pathway to induce this conversion.

Associations of C1q/TNF-Related Protein-9 Levels in Serum and Epicardial Adipose Tissue with Coronary Atherosclerosis in Humans.

OBJECTIVE: To investigate the correlation of CTRP9 with coronary atherosclerosis. METHODS: Coronary angiography confirmed CAD in 241 patients (62 received CABG) and non-CAD in 121 (55 received valve replacement). RESULTS: Serum levels of LDL-C, CRP, TNF-α, IL-6, and leptin in CAD patients were significantly higher than those in non-CAD patients (P < 0.05), but APN and CTRP9 were lower (P < 0.05). Serum levels of CTRP9 and APN were negatively related to BMI, HOMA-IR, TNF-α, IL-6, and leptin but positively to HDL-C (P < 0.05) in CAD patients. After adjustment of APN, CTRP9 was still related to the above parameters. Serum CTRP9 was a protective factor of CAD (P < 0.05). When compared with non-CAD patients, leptin mRNA expression increased dramatically, while CTRP9 mRNA expression reduced markedly in epicardial adipose tissue of CAD patients (P < 0.05). The leptin expression and macrophage count in CAD group were significantly higher than in non-CAD group, but CAD patients had a markedly lower CTRP9 expression (P < 0.05). CONCLUSIONS: Circulating and coronary CTRP9 plays an important role in the inflammation and coronary atherosclerosis of CAD patients. Serum CTRP9 is an independent protective factor of CAD.

Acute myocardial infarction caused by tumor-associated thrombotic thrombocytopenic purpura: case report.

OBJECTIVE: To describe a case with acute myocardial infarction caused by gastric carcinoma-associated thrombotic thrombocytopenic purpura. CLINICAL PRESENTATION AND INTERVENTION: A 79-year-old man was admitted with abdominal pain and pyrexia. He later developed cardiac complications and microangiopathy that indicated worsening progression. Manifold evidence confirmed the diagnosis of myocardial infarction caused by thrombotic thrombocytopenic purpura. The patient was treated mainly with plasma transfusion incorporated with steroids. CONCLUSION: This case should remind physicians to consider microangiopathy as a differential diagnosis in patients with unexplained cardiac symptoms or atypical presentation. Early diagnosis and treatment are helpful in decreasing the sequelae of this syndrome.

[Membrane testosterone receptors in cultured vascular smooth muscle cells].

OBJECTIVE: To determine the presence of membrane testosterone receptors in cultured vascular smooth muscle cells (VSMC), and investigate their relationship with classical intracellular androgen receptors (iAR). METHODS: VSMCs were cultured from the thoracic aorta of male Sprague-Dawley rats by the explant method. Subconfluent VSMCs were incubated with serum-free medium for 24 h to obtain quiescent non-dividing cells, and then treated with the indicated agents. The aliquots of VSMCs were labeled with testosterone-BSA-FITC (T-BSA-FITC) and analyzed by flow cytometry. Classical iARs in intact- and permeabilized-cells were detected with anti-iAR antibodies and FITC-labeled secondary antibodies by immunofluorescence, followed by flow cytometry analysis. RESULTS: Incubation of VSMCs with T-BSA-FITC obviously increased their relative fluorescence intensity at 10 sec as compared with the untreated controls (P < 0.01), and so did it at 10 min in comparison with the treatment with BSA-FITC alone or together with free testosterone (P < 0.01). Pretreatment with iAR antagonist flutamide exhibited no significant influence on the relative fluorescence intensity of VSMCs (P = 0.318). Traditional iARs were not detectable on the surface of intact VSMCs, although permeabilized cells contained iARs. CONCLUSION: VSMCs contain testosterone receptors in the plasma membrane, and these membrane receptors are not identical to classical iARs.

[Testosterone at physiological level inhibits PGF2alpha-induced increase in intracellular Ca2+ in cultured vascular smooth muscle cells].

OBJECTIVE: To explore the acute effects of testosterone at the physiological level on PGF2alpha-induced increase in intracellular Ca2+ in cultured vascular smooth muscle cells (VSMCs). METHODS: VSMCs from the thoracic aorta of male Sprague-Dawley rats were cultured using the explant method. The subconfluent VSMCs were incubated with serum-free medium for 24 hours to obtain quiescent non-dividing cells and then treated with the indicated agents. For the measurement of [Ca2+]i, the VSMCs were loaded with fura-2. Changes of [Ca2+]i were determined ratiometrically with a Nikon TE-2000E system. RESULTS: The resting level of [Ca2+]i was around 100 nmol/L in the VSMCs. Exposing cells to perfusate containing 10 micromol/L PGF2alpha triggered an immediate and transient peak in [Ca2+]i, which gradually decreased afterwards. Interference at the peak with the physiological concentration (40 nmol/L) of testosterone significantly decreased the peak-to-baseline time of [Ca2+]i, compared with ethanol vehicle (104.9 +/- 27.0 s vs 153.5 +/- 40.4 s, P < 0.01). Pretreatment with testosterone at 40 nmol/L for 2 minutes also reduced the peak-to-baseline time of [Ca2+]i significantly in comparison with the ethanol control (120.6 +/- 32.0 s vs 151.4 +/- 27.4 s, P < 0.01), but it had no significant effect on the peak level of PGF2alpha-induced intracellular Ca2+ (390.0 +/- 126.0 nmol/L vs 403.4 +/- 160.7 nmol/L, P > 0.05). CONCLUSION: Testosterone at physiological concentration inhibits PGF2alpha-induced Ca2+ fluxes, probably via receptor-operated calcium channels by a non-genomic mechanism in VSMCs, which may be involved in the vasodilatory effect of testosterone.