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PubMed2026

Integrated Metabolomic and Transcriptomic Analysis Reveals Tissue-Specific Secondary Metabolic Differentiation and Indole Alkaloid Accumulation in Evodia rutaecarpa.

Evodia rutaecarpa is a valuable medicinal plant, yet its non-medicinal tissues remain largely underexplored. Here, we integrated ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS)-based widely targeted metabolomics and RNA sequencing (RNA-seq) transcriptomics to systematically profile the metabolic and transcriptional landscapes of roots, stems, leaves, and flowers of Evodia rutaecarpa (Juss.) Benth. Our aim was to characterize tissue-specific metabolic differentiation and its underlying transcriptional regulatory mechanisms. Metabolomic analysis, employing principal component analysis (PCA) and orthogonal partial least squares-discriminant analysis (OPLS-DA) with robust model parameters (R2Y > 0.9, Q2 > 0.5), identified 3090 differential metabolite features (variable importance in projection, VIP > 1.0; p < 0.05) across the four tissues, which exhibited distinct tissue-specific clustering patterns. Integrated Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis and weighted gene co-expression network analysis (WGCNA) revealed that roots specifically accumulated quinolone alkaloids and flavonoid glycosides, accompanied by the coordinated upregulation of genes involved in flavonoid and phenylpropanoid biosynthetic pathways. In contrast, stems, leaves, and flowers were enriched in indole alkaloids (evodiamine and rutaecarpine) and volatile oil precursors, with concurrent upregulation of genes involved in tryptophan metabolism and indole alkaloid biosynthesis (e.g., tryptophan decarboxylase, TDC; s N-methyltransferase, NMT). Notably, leaves and flowers displayed particularly high accumulation levels of these bioactive alkaloids, suggesting their potential as alternative sources for industrial and pharmaceutical applications. WGCNA further identified multiple transcription factors and structural gene modules tightly correlated with evodiamine accumulation, offering promising candidate regulators for future biosynthetic pathway engineering. Collectively, this multi-omics integration study systematically elucidates the tissue-partitioned secondary metabolism of Evodia rutaecarpa (Juss.) Benth. and provides a solid scientific foundation for full-plant resource utilization, targeted development of non-medicinal tissues, and future metabolic engineering of indole alkaloid production.

Evodia rutaecarpa↗

PubMed2001

VR1 protein expression increases in undamaged DRG neurons after partial nerve injury.

Changes in phenotype or connectivity of primary afferent neurons following peripheral nerve injury may contribute to the hyperalgesia and allodynia associated with neuropathic pain conditions. Although earlier studies using partial nerve injury models have focused on the role of damaged fibres in the generation of ectopic discharges and pain, it is now thought that remaining undamaged fibres may be equally important. We have examined the expression of the sensory neuron-specific cation channel Vanilloid Receptor 1 (VR1), an important transducer of noxious stimuli, in three models of nerve injury in the rat, using anatomical separation or fluorescent retrograde tracers to identify damaged or undamaged sensory neurons. After total or partial sciatic nerve transection, or spinal nerve ligation, VR1-immunoreactivity (IR) was significantly reduced in the somata of all damaged dorsal root ganglion (DRG) neuronal profiles, compared to controls. However, after partial transection or spinal nerve ligation, VR1 expression was greater in the undamaged DRG somata than in controls. Unexpectedly, after L5 spinal nerve ligation, VR1-IR of the A-fibre somata increased approximately 3-fold in the uninjured L4 DRG compared to controls; a much greater increase than seen in the somata with C-fibres. Furthermore, we found that VR1-IR persisted in the transected sciatic nerve proximal to the lesion, despite its down-regulation in the damaged neuronal somata. This persistence in the nerve proximal to the lesion after nerve section, together with increased VR1 in DRG neurons left undamaged after partial nerve injury, may be crucial to the development or maintenance of neuropathic pain.

Animals↗

PubMed2004

A molecular modeling and QSAR study of suppressors of the growth of Trypanosoma cruzi epimastigotes.

In this work, we have used molecular modeling and QSAR tools to study 18 dithiocarbamate suppressors of the growth of Trypanosoma cruzi epimastigotes, which have been reported in the literature as superoxide dismutase (SOD) inhibitors. The principal component analysis (PCA) showed that the descriptors superficial area, heat of formation, logarithm of the partition coefficient, charge of the nitrogen atom from the dithiocarbamate group and Charges of the two carbon atoms adjacent to that nitrogen are responsible for the classification between the higher and lower trypanomicid activity. Using multiple linear regression (MLR) and docking methods it was possible to identify the probable bioactive isomers that suppress of the growth of T. cruzi epimastigotes. Our best partial least square (PLS) model obtained with these six descriptors yields a good correlation between experimental and predicted biological activities and compares two different SODs as possible target for interaction with the dithiocarbamates.

Amino Acid Sequence↗

PubMed2005

Risk factors for visual loss in an Italian population-based cohort of patients with giant cell arteritis.

OBJECTIVE: To evaluate the frequency of visual manifestations at presentation in an Italian population-based cohort of patients with biopsy-proven giant cell arteritis (GCA), and to investigate predictors for the development of permanent visual loss. METHODS: We identified 136 Reggio Emilia (Italy) residents with biopsy-proven GCA diagnosed between 1986 and 2002. Medical records of these 136 patients were reviewed, and demographic, clinical, and laboratory data were collected.Multivariate analysis with multiple logistic regression models was performed to identify the best predictors of visual loss. RESULTS: Visual manifestations developed in 41 patients (30.1%). Partial or total visual loss was observed in 26 patients (19.1%). Anterior ischemic optic neuropathy was seen in 24 patients, and 2 patients had central retinal artery occlusion. Unilateral vision loss occurred in 19 patients, and bilateral visual loss in 7. In 25 patients, visual loss developed before glucocorticoid therapy for GCA was started. The age at disease onset was significantly higher in patients with permanent visual loss compared with those without it. The frequency of systemic signs/symptoms and erythrocyte sedimentation rate (ESR) and C-reactive protein values at diagnosis were significantly lower in patients with permanent visual loss. By multivariate logistic regression, the only statistically significant predictor for the development of permanent visual loss was the absence of high levels of ESR at diagnosis (tertile 2: Odds ratio [OR] 0.08; tertile 3: OR 0.11). Other predictors included in the model were the absence of systemic manifestations (OR 0.24), an older age at disease diagnosis (quintile 5: OR 5.60), and the presence of an elevated platelet count at diagnosis (OR 4.99), however they were only of borderline statistical significance. CONCLUSION: The proportion of Italian patients with GCA that developed visual loss was similar to that reported from other countries. The patients with low inflammatory response had a higher risk of visual loss.

Age of Onset↗

PubMed2000

Nerve injury-associated kinase: a sterile 20-like protein kinase up-regulated in dorsal root ganglia in a rat model of neuropathic pain.

Partial injury of the rat sciatic nerve elicits a variety of characteristic chemical, electrophysical and anatomical changes in primary sensory neurons and constitutes a physiologically relevant model of neuropathic pain. To elucidate molecular mechanisms that underlie the physiology of neuropathic pain, we have used messenger RNA differential display to identify genes that exhibit increased ipsilateral expression in L4/5 dorsal root ganglia, following unilateral partial ligation of the rat sciatic nerve. One set of partial complementary DNA clones identified in this screen was found to encode a protein kinase, nerve injury-associated kinase. Cloning of the full-length human nerve injury-associated kinase complementary DNA, together with recombinant expression analysis, reveal nerve injury-associated kinase to be a functional member of a subgroup of sterile 20-like protein kinases characterised by the presence of a putative carboxy terminal autoregulatory domain. Induction of nerve injury-associated kinase expression in dorsal root ganglia in the rat neuropathic pain model was confirmed by quantitative reverse transcription-polymerase chain reaction, and RNA in situ hybridization analysis revealed enhanced levels of nerve injury-associated kinase within neurons.Together, our data implicate nerve injury-associated kinase as a novel upstream component of an intracellular signalling cascade that is up-regulated in dorsal root ganglia neurons in response to sciatic nerve injury.

Amino Acid Sequence↗

PubMed2004

Mass spectrometry and partial least-squares regression: a tool for identification of wheat variety and end-use quality.

Rapid methods for the identification of wheat varieties and their end-use quality have been developed. The methods combine the analysis of wheat protein extracts by mass spectrometry with partial least-squares regression in order to predict the variety or end-use quality of unknown wheat samples. The whole process takes approximately 30 min. Extracts of alcohol-soluble storage proteins (gliadins) from wheat were analysed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Partial least-squares regression was subsequently applied using these mass spectra for making models that could predict the wheat variety or end-use quality. Previously, an artificial neural network was used to identify wheat varieties based on their protein mass spectra profiles. The present study showed that partial least-squares regression is at least as useful as neural networks for this identification. Furthermore, it was demonstrated that partial least-squares regression could be used to predict wheat end-use quality, which has not been possible using neural networks.

Denmark↗

PubMed2005

Immunization with myelin oligodendrocyte glycoprotein and complete Freund adjuvant partially protects dopaminergic neurons from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced damage in mouse model of Parkinson's disease.

The concept of neuroprotective immunity identifies a new role of autoimmune cells in the CNS pathology. Specifically, immune cells infiltrating the CNS during an injury may help in a regeneration process and prevent the secondary degeneration of neurons. The objectives of our study were to determine the role of autoimmune and peripheral immune enhancement in neurodegeneration process, and to compare the results between young adult and aging animals. C57Bl mice were immunized with either myelin oligodendrocyte glycoprotein (MOG) 35-55 combined with complete Freund adjuvant (CFA), or CFA alone. Following 6 days, the animals were injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine to produce a damage of the nigrostriatal dopaminergic system. Although immunization with MOG 35-55 combined with CFA resulted in autoimmune encephalomyelosis, it substantially enhanced neuronal survival after the toxic insult. The immunization with CFA alone was also effective in preventing neuronal cell death, but the magnitude of the neuroprotective effect was smaller. Interestingly, the neuroprotective effect of MOG 35-55 and CFA was more pronounced in aging (i.e. 10-month-old) compared with young (i.e. 2-month-old) mice. Our results indicate that an increased immune activation may be beneficial for neurodegenerative processes following the CNS injury, but the mechanisms of such immune neuroprotection and of age differences need further investigation.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed2005

Identification of epistasis through a partial advanced intercross reveals three arthritis loci within the Cia5 QTL in mice.

Identification of genes controlling complex diseases has proven to be difficult; however, animal models may pave the way to determine how low penetrant genes interact to promote disease development. We have dissected the Cia5/Eae3 susceptibility locus on mouse chromosome 3 previously identified to control disease in experimental models of multiple sclerosis and rheumatoid arthritis. Congenic strains showed significant but small effects on severity of both diseases. To improve the penetrance, we have now used a new strategy that defines the genetic interactions. The QTL interacted with another locus on chromosome 15 and a partial advanced intercross breeding of the two congenic strains for eight generations accumulated enough statistical power to identify interactions with several loci on chromosome 15. Thereby, three separate loci within the original QTL could be identified; Cia5 affected the onset of arthritis by an additive interaction with Cia31 on chromosome 15, whereas the Cia21 and Cia22 affected severity during the chronic phase of the disease through an epistatic interaction with Cia32 on chromosome 15. The definition of genetic interactions was a prerequisite to dissect the Cia5 QTL and we suggest the partial advanced intercross strategy to be helpful also for dissecting other QTL controlling complex phenotypes.

Animals↗

PubMed2006

Teaching molecular genetics: chapter 2-Transgenesis and gene targeting: mouse models to study gene function and expression.

Many human diseases result from the (partial) loss of gene function. Once a disease-causing gene has been identified, a wide variety of techniques can be used to study its function, structure and expression. Many clues can be obtained from the comparison of RNA or proteins in tissues, cell extracts or cell lines at different physiological or developmental stages. Since the mouse genome is very similar to the human genome, expression data from mice are extremely valuable. Recently developed techniques to add genes to the mouse genome or to modify or inactivate genes form powerful tools to analyze gene function and expression. For a variety of human diseases these genetically modified mice are very informative model systems.

Animals↗

PubMed2003

Tissue microenvironments within functional cortical subdivisions adjacent to focal stroke.

Stroke produces a region of complete cell death and areas of partial damage, injury, and gliosis. The spatial relationship of these regions of damage to the infarct core and within spared neuronal circuits has not been identified. A model of cortical stroke was developed within functional subsets of the somatosensory cortex. Infarct size, regions of apoptosis, oxidative DNA damage, heat shock protein induction, and subtypes of reactive gliosis were precisely mapped with the somatosensory body map, quantified, and interrelated. Three tissue microenvironments were recognized: zones of partial ischemic damage, heat shock protein induction, and distributed gliosis. These three zones involved progressively more distant cortical regions, each larger than the infarct core. The zone of partial ischemic damage represents an overlap region of apoptotic cell death, oxidative DNA damage, loss of synaptic connections, and local reactive gliosis. The zone of distributed gliosis occupies distinct functional areas of the somatosensory cortex. The tissue reorganization induced by stroke is much larger than the stroke site itself. Adjacent tissue microenvironments are sites of distinct reactive cellular signaling and may serve as a link between the processes of acute cell death and delayed neuronal plasticity after focal stroke.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed2000

A novel rat osteoarthrosis model to assess apoptosis and matrix degradation.

Matrix degradation and apoptosis are two crucial features of osteoarthrosis (OA), but the relationship between them needs to be clarified. We developed a novel OA model in partial meniscectomisized rats for the assessment in situ of these processes. The surgical procedure used permitted us to identify and remove 30-50% of the meniscus. Furthermore, the inclusion of high impact exercise enhanced the cartilage damage in a short period of time. OA cartilage displayed a rough and eroded surface, fibrosis and even complete loss; we also found hypertrophy, chondrocyte clusters and a disrupted extracellular matrix. As evidence of matrix degradation we found a diminution of the extracellular components such as chondroitin sulfate-4, 6 (CS-4, 6) and proteoglycans (PGs), and an overall increased activity of the PGs-degrading enzyme, stromelysin-1 (SLN-1). Moreover, the frequency of apoptotic chondrocytes increased according to the severity of the matrix degradation, as detected by TUNEL technique and by morphology. All these changes were enhanced in OA rats with high-impact exercise. Trained rats showed a statistically highly significant difference in histological changes compared to untrained animals. We demonstrate that our model can be evaluated according to Mankin's histologically graded parameters. Also, it is an effective method to assess, in situ, apoptosis in an experimentally induced OA. Our results suggest that apoptosis could be involved in matrix degradation and that TUNEL might be a good method for spotting early apoptotic changes which, combined with careful morphological examinations, provide substantial help in improving apoptosis detection.

Animals↗

PubMed2006

Time delay and partial coherence analyses to identify cortical connectivities.

Recently it has been demonstrated by Albo that partial coherence analysis is sensitive to signal to noise ratio (SNR) and that it will always identify the signal with the highest SNR among the three signals as the main (driving) influence. We propose to use time delay analysis in parallel to partial coherence analysis to identify the connectivities between the multivariate time series. Both are applied to a theoretical model (used by Albo) to analyse the connections introduced in the model. Time delay analysis identifies the connections correctly. We also apply these analyses to the electroencephalogram (EEG) and electromyogram of essential tremor patients and EEG of normal subjects while bimanually tapping their index fingers. Biologically plausible cortico-muscular and cortico-cortical connections are identified by these methods.

Algorithms↗

PubMed2003

Purification and primary structure determination of Tf4, the first bioactive peptide isolated from the venom of the Brazilian scorpion Tityus fasciolatus.

In the present study Tityus fasciolatus crude venom toxicity was evaluated and we also report the purification and characterization of a 6.6 kDa neurotoxin isolated from T. fasciolatus venom. This new toxin, named Tf4, has a molecular mass of 6614Da and its primary structure is homologous to TbIT-I from T. bahiensis and TsTX-VI and TsNTxP from T. serrulatus. Tf4 delays frog sodium channel inactivation reversibly, but it is non-toxic to mammals or crustaceans. An attempt to identify the residues responsible for the partial loss of toxicity in Tf4 was carried out based on homology modeling and sequence comparison.

Action Potentials↗

PubMedDate not supplied

Molecular characterization of surface topology in protein tertiary structures by amino-acylation and mass spectrometric peptide mapping.

Amino-acetylation and -succinylation reactions in combination with mass spectrometric peptide mapping of tryptic peptide mixtures have been employed for surface topology-probing of lysine residues in bovine ribonuclease A, lysozyme, and horse heart myoglobin as model proteins of different surface structures. Direct molecular weight determinations identifying the precise number of acyl groups in partially modified proteins were obtained by electrospray and 252Cf-plasma desorption mass spectrometry. Electrospray mass spectra of multiply protonated molecular ions and deuterium exchange experiments provided a relative conformational characterization of protein derivatives and enabled the direct determinations of intact, partially acylated heme-myoglobin derivatives. Tryptic peptide mapping analysis, using plasma desorption and fast atom bombardment mass spectrometry, ascertained by mass spectrometric characterization of HPLC-separated modified peptides, yielded the exact identification of acylation sites. Relative reactivities of the amino acylation were derived from the peptide mapping data and from quantitative estimations of modified peptides upon acetylation/trideuteroacetylation and provided direct correlations with the relative surface accessibilities of lysine-epsilon-amino groups taken from X-ray crystallographic structure data of the proteins. The reactive lysine-41 residue in ribonuclease A which is part of the substrate binding site was directly identified from the mass spectrometric data. These results indicate tertiary structure-selective acylation combined with mass spectrometric peptide mapping as an efficient approach for the molecular characterization of surface topology and reactive fundamental lysine residues in proteins.

Acylation↗

PubMed1991

Conformational studies of a peptide corresponding to a region of the C-terminus of ribonuclease A: implications as a potential chain-folding initiation site.

Conformational properties of the OT-16 peptide, the C-terminal 20 amino acids of RNase A, were examined by nonradiative energy transfer. A modified OT-16 peptide was prepared by solid-phase synthesis with the inclusion of diaminobutyric acid (DABA) at the C-terminus. The OT-16-DABA peptide was labeled with a fluorescent 1,5-dimethylaminonaphthalene sulfonyl (dansyl, DNS) acceptor at the N-terminal amine and a fluorescent naphthoxyacetic acid (NAA) donor at the gamma-amine of the DABA located at the C-terminus of the peptide by using an orthogonal protection scheme. Energy transfer was monitored in DNS-OT-16-DABA-NAA by using both fluorescence intensity (sensitized emission) and lifetime (donor quenching) experiments. The lifetime data indicate that the peptide system is a dynamic, flexible one. A detailed analysis, based on a dynamic model that includes a skewed Gaussian function to model the equilibrium distribution of interprobe distances and a mutual diffusion coefficient between the two probes to model conformational dynamics in the peptide [Beechem & Haas (1989) Biophys. J. 55, 1225.], identified the existence of a partially ordered structure (relatively narrow distribution of interprobe distances) at temperatures greater than or equal to 20 degrees C in the absence of denaturant. The width and the position of the average of the distributions decrease with increasing temperature, in this range; this suggests that the structure is stabilized by hydrophobic interactions. In addition, the peptide undergoes cold denaturation at around 1.5 degrees C as indicated by broadening of the distance distribution. The addition of 6 M guanidine hydrochloride (Gdn-HCl) also broadens the distance distribution significantly, presumably by eliminating the hydrophobic interactions and unfolding the peptide. The results of the analysis of the distance distribution demonstrate that (1) nonradiative energy transfer can be used to study the conformational dynamics of peptides on the nanosecond time scale, (2) a partially ordered structure of OT-16-DABA exists in solution under typical refolding conditions, and (3) structural constraints (presumably hydrophobic interactions) necessary for the formation of a chain-folding initiation site in RNase A are also present in the OT-16-DABA peptide in the absence of denaturant and are disrupted by Gdn-HCl.

Amino Acid Sequence↗

PubMed2000

Host cell-mediated responses to infection with Cryptosporidium.

The coccidian Cryptosporidium infects epithelial cells of a variety of vertebrate hosts and is the causative agent of cryptosporidiosis. In mammals, including humans and domestic animals, C. parvum infects the gastrointestinal tract producing an acute watery diarrhoea and weight loss. CD4+ T-cell-deficient hosts have increased susceptibility to infection with the parasite and may develop severe life-threatening complications. The host responses which induce protective immunity and contribute to pathogenesis are poorly understood. In the immunological control of infection, recent studies with murine infection models suggest that IFN-gamma plays a key role in a partially protective innate immunity against infection identified in immunocompromised mice and also in the elimination of infection mediated by CD4+ T-cells. At the mucosal level, CD4+ intraepithelial lymphocytes are involved in the control of cryptosporidial infection, acting at least in part through production of IFN-gamma which has a direct inhibitory effect on parasite development in enterocytes. Primary infection of ruminants induces an intestinal inflammatory response in which increased numbers of various T-cell subpopulations appear in the villi. In addition, infection results in increased intestinal expression of pro-inflammatory cytokines such as IL-12, IFN-gamma and TNF-alpha. Because these cytokines appear to be important in the aetiology of inflammatory bowel disease, it is possible that they are involved in the mucosal pathogenesis of cryptosporidiosis.

Animals↗

PubMed2001

Disrupted signaling and inhibited regeneration in obese mice with fatty livers: implications for nonalcoholic fatty liver disease pathophysiology.

The impaired regenerative capacity of fatty livers might promote the progression of nonalcoholic fatty liver disease (NAFLD). To identify mechanisms involved, regenerative responses were compared in normal mice and ob/ob mice (a model for NAFLD) after partial hepatectomy (PH). We hypothesized that the usual PH activation of oxidant-sensitive, growth-regulatory kinase cascades would be abnormal in fatty hepatocytes, which have adapted to chronic oxidant stress, and expected that this might interfere with the induction of proliferative- and stress-related genes. The normal coordinated induction of Jun N-terminal kinases (Jnks) and extracellular regulated kinases (Erks) does not occur after PH in ob/ob mice, which cannot activate Jnks but can superinduce Erks. Jnk inhibition is associated with enhanced activation of Akt, which inhibits phosphoenolpyruvate carboxykinase (PEPCK) induction, causing severe hypoglycemia and increased lethality in the ob/ob group. Activation of nuclear factor kappaB (NF-kappaB) is also inhibited, but liver damage is increased only modestly, perhaps because Akt-regulated survival factors are protective. Despite enhanced Erk activity, induction of cyclin D-1, an NF-kappaB target gene, is abolished and this, together with hyperphosphorylated signal transducer and activator of transcription-3 (Stat-3) and reduced adenosine triphosphate (ATP) levels, arrests fatty hepatocytes in G(1). Thus, in mice with NAFLD that have adapted hepatocyte signaling mechanisms to survive chronic oxidative stress, the cellular response to an acute regenerative stimulus is altered. This contributes to NAFLD pathophysiology by inhibiting proliferation, increasing injury, and limiting function in fatty livers.

Adenosine Triphosphate↗

PubMed1992

Isolation of dominant negative mutants and inhibitory antisense RNA sequences by expression selection of random DNA fragments.

Selective inhibition of specific genes can be accomplished using genetic suppressor elements (GSEs) that encode antisense RNA, dominant negative mutant proteins, or other regulatory products. GSEs may correspond to partial sequences of target genes, usually identified by trial and error. We have used bacteriophage lambda as a model system to test a concept that biologically active GSEs may be generated by random DNA fragmentation and identified by expression selection. Fragments from eleven different regions of lambda genome, encoding specific peptides or antisense RNA sequences, rendered E. coli resistant to the phage. Analysis of these GSEs revealed some previously unknown functions of phage lambda, including suppression of the cellular lambda receptor by an 'accessory' gene of the phage. The random fragment selection strategy provides a general approach to the generation of efficient GSEs and elucidation of novel gene functions.

Bacterial Outer Membrane Proteins↗