Homovanillic Research Articles

Lethal versus surviving sepsis phenotypes displayed a partly differential regional expression of neurotransmitters and inflammation and did not modify the blood–brain barrier permeability in female CLP mice

BackgroundSeptic encephalopathy is frequent but its pathophysiology is enigmatic. We studied expression of neurotransmitters, inflammation and integrity of the blood–brain barrier (BBB) in several brain regions during abdominal sepsis. We compared mice with either lethal or surviving phenotype in the first 4 sepsis days. Mature CD-1 females underwent cecal ligation and puncture (CLP). Body temperature (BT) was measured daily and predicted-to-die (within 24 h) mice (for P-DIE; BT < 28 °C) were sacrificed together (1:1 ratio) with mice predicted-to-survive (P-SUR; BT > 35 °C), and healthy controls (CON). Brains were dissected into neocortex, cerebellum, midbrain, medulla, striatum, hypothalamus and hippocampus.ResultsCLP mice showed an up to threefold rise of serotonin in the hippocampus, 5-hydroxyindoleacetic and homovanillic acid (HVA) in nearly all regions vs. CON. Compared to P-SUR, P-DIE mice showed a 1.7 to twofold rise of HVA (386 ng/g of tissue), dopamine (265 ng/g) and 3,4-Dihydroxyphenylacetic acid (DOPAC; 140 ng/g) in the hippocampus, hypothalamus and medulla (174, 156, 82 ng/g of tissue, respectively). CLP increased expression of TNFα, IL-1β and IL-6 mRNA by several folds in the midbrain, cerebellum and hippocampus versus CON. The same cytokines were further elevated in P-DIE vs P-SUR in the midbrain and cerebellum. Activation of astrocytes and microglia was robust across regions but remained typically phenotype independent. There was a similar influx of sodium fluorescein across the BBB in both P-DIE and P-SUR mice.ConclusionsCompared to survivors, the lethal phenotype induced a stronger deregulation of amine metabolism and cytokine expression in selected brain regions, but the BBB permeability remained similar regardless of the predicted outcome.

Point-of-Care Sensor Using Modified Nickel-doped Zinc Oxide Nanoparticle Carbon Paste Electrode for Homovanillic Acid Cancer Biomarker Detection in Urine

The prevalence of cancer worldwide has prompted efforts to develop and produce a range of electrochemical biosensors for cancer diagnosis. Efficient cancer diagnosis can be enhanced by the sensitive detection of biomarkers, which can also lower the cost of medical diagnostics. Neuroblastoma is an embryonic cancer arising from neural crest stem cells and is considered the most common malignancy in infants and the extracranial solid tumor in children. In this paper, we describe the construction of a nanoparticle-modified electrochemical sensor for detecting and quantifying homovanillic acid (HVA), a biomarker for neuroblastoma. The electrooxidation of HVA was studied at a carbon paste electrode (CPE) modified with nickel-doped zinc oxide nanoparticles (Ni-ZnO NPs). The use of these nanoparticles enhanced electrochemical sensitivity and the electrocatalytic activity. The differential pulse voltammetric response of HVA was found to be linear in the concentration range of (3.96 × 10−6 to 3.83 × 10−5 M) with a lower detection limit of 1.01 × 10−6 M. The electrode demonstrated good stability in the HVA determination process, with a minor decrease in response after 10 weeks. The proposed sensor was successfully applied to determine HVA in a urine sample with a good detection result and a worthwhile biological impact.

The participation of monoamines in the realization of vasopressin analgesic effects during electrical stimulation of paws in rats

BACKGROUND: Arginine vasopressin has been implicated in the modulation of stress and pain. The influence of a synthetic analogue of arginine vasopressin, 1-deamino-8-D-arginine-vasopressin, оn pain sensitivity, stress reactivity, levels of monoamines and brain neurotrophic factor in a model of paw electrical stimulation in rats has not been studied. AIM: The aim was to evaluate the effect of a synthetic vasopressin analog, 1-deamino-8-D-arginine-vasopressin, on pain sensitivity and the content of norepinephrine, serotonin, dopamine, brain neurotrophic factor in the parietal cortex and spinal cord in electrocutaneous paw stimulation test in rats. MATERIALS AND METHODS: The study was conducted on male Wistar rats who were injected with 1-deamino-8-D-arginine-vasopressin intranasally once a day for 5 days in small (single 20 ng, course 100 ng) and large doses (single 2 ug, course 10 ug). The content of brain neurotrophic factor in the parietal cortex and spinal cord, and corticosterone in blood serum were determined using enzyme immunoassay. The levels of norepinephrine, serotonin, dopamine and their metabolites in the brain were evaluated using high-performance liquid chromatography. RESULTS: 1-Deamino-8-D-arginine-vasopressin in different doses reduced pain sensitivity in rats, more pronounced when administered in large doses. The peptide in small doses in the parietal cortex increased the content of dopamine and reduced the levels of 5-hydroxyindolacetic acid, a metabolite of serotonin; in the spinal cord, it reduced the content of 5-hydroxyindolacetic acid. 1-Deamino-8-D-arginine-vasopressin in high doses in the parietal cortex increased the content of dopamine and reduced the levels of 5-hydroxyindolacetic acid; in the spinal cord ― reduced the content of serotonin and 3,4-dihydroxyphenylacetic acid, a metabolite of dopamine; increased the levels of norepinephrine and homovanilic acid, a metabolite of dopamine. The peptide had no effect on corticosterone levels in the blood and brain neurotrophic factor levels in the brain in rats. CONCLUSIONS: The analgesic effects of 1-deamino-8-D-arginine-vasopressin were revealed with intranasal administration in different subendocrine doses. Regardless of the administered doses, dopamine and serotonin at the supraspinal level were involved in peptide-induced anesthesia; serotonin at the spinal cord level. More pronounced analgesia with the administration of 1-deamino-8-D-arginine-vasopressin in high doses was due to the additional involvement of dopamine and norepinephrine at the spinal cord level.

The Application of Untargeted Metabolomic Approaches for the Search of Common Bioavailable Metabolites in Human Plasma Samples from Lippia citriodora and Olea europaea Extracts.

Lippia citriodora and Olea europaea are known for their shared common bioactivities. Although both matrices are rich in similar families of bioactive compounds, their specific phytochemical compounds are mostly different. Since these compounds can be metabolized in the organism, this study hypothesized that common bioavailable metabolites may contribute to their similar bioactive effects. To test this, an acute double-blind intervention study in humans was conducted with blood samples collected at multiple time points. Using an untargeted metabolomic approach based on HPLC-ESI-QTOF-MS, 66 circulating metabolites were detected, including 9 common to both extracts, such as homovanillic acid sulfate and glucuronide derivates, hydroxytyrosol sulfate, etc. These common metabolites displayed significantly different Tmax values depending on the source, suggesting distinct metabolization pathways for each extract. The study highlights how shared bioavailable metabolites may underlie similar bioactivities observed between these two plant sources.

Neurotransmitter Metabolism in Arsenic Exposure-Induced Cognitive Impairment: Emerging Insights and Predictive Implications.

Scholars have long been interested in the association between arsenic (As) exposure and neurological disorders; however, existing systematic epidemiological investigations are insufficient and lack the inclusion of diagnostic or predictive biological markers. This study sought to evaluate the association between As exposure and cognitive impairment and identify potential biomarkers by developing predictive models. Here, we found that logarithm (Ln)-transformed urinary As concentrations were negatively linearly related to the mini-mental state examination (MMSE) score exposure-response curves. Subsequently, we identified a unique plasma neurometabolite profile in subjects exposed to As compared with the reference group. Further analyses showed that tryptophan, tyrosine, dopamine, epinephrine, and homovanillic acid were all significantly associated with both urinary As concentrations and MMSE scores. Notably, the association between As exposure and MMSE scores was partly mediated by tryptophan, tyrosine, dopamine, and epinephrine. Importantly, an unprecedented prediction model utilizing neurotransmitters was established to assess the risk of cognitive impairment due to As exposure. A 91.1% consistency rate was found between the predicted and the actual probabilities. Additionally, machine learning models also produced highly accurate predictions. Overall, this study revealed a dose-dependent cognitive decline in As-exposed adults accompanied by a disturbance in the signature of neurotransmitter metabolites, offering new predictive insights.

7204 An Unexpected Cause of Ga-68 Dotatate PET/CT Somatostatin Receptor Avidity in a Pediatric Patient with Hereditary Paraganglioma-Pheochromocytoma Syndrome due to an SDHA Mutation

Abstract Disclosure: K. Leopold: None. S. Polites: None. L. Binkovitz: None. L. Casas: None. A.N. Lteif: None. Title: An Unexpected Cause of Ga-68 Dotatate PET/CT Somatostatin Receptor Avidity in a Pediatric Patient with Hereditary Paraganglioma-Pheochromocytoma Syndrome due to an SDHA Mutation. Introduction: Individuals with Succinate Dehydrogenase (SDHx) gene mutations have an increased risk of paragangliomas and pheochromocytomas beginning in childhood.Clinical Case: A 9 year old male with Cornelia de Lange syndrome and a paternally inherited SDHA pathogenic gene variant (c1534C&amp;gt;T) presented with worsening migraine headaches and skin pallor with activity. 24 hour urine fractionated metanephrines were mildly elevated, with metanephrine 122 mcg/24h (29-92 mcg/24 h), normetanephrine 187 mcg/24 h (34-169 mcg/24 h), and total metanephrine 309 mcg/24 h (47-223 mcg/24 h). Ga-68 DOTATATE PET/CT showed a focus of moderately increased radiotracer activity in the anterior aspect of the distal gastric antrum with a max SUV 8.2 corresponding to a 9x7 mm nodule on CT in the same area, suggestive of underlying somatostatin receptor positive lesion such as a paraganglioma. MRI with contrast completed to further characterize the lesion showed no visible mass corresponding to the focal area of radiotracer uptake on DOTATATE PET/CT. Repeat 24 h urine metanephrines continued to show mild elevation of metanephrine (138 mcg/24h), normetanephrine (200 mcg/24h), and total metanephrines (338 mcg/24h). 24 hour urine catecholamines, 5-Hydroxyindoleacetic acid, and homovanillic acid were normal. An upper endoscopic ultrasound was completed which confirmed the presence of a lesion near the stomach but not arising from the stomach wall and not consistent with a gastrointestinal stromal tumor. CT enterography with IV contrast showed a 6x6 mm enhancing mass within the distal right lateral gastric wall. Due to ongoing symptoms, mild elevations in urine fractionated metanephrines, and a clear mass on US and CT, the patient underwent laparoscopic abdominal exploration where a 14x14x13 mm mass with surrounding gastric and duodenal serosa was excised with primary closure of the bowel. Pathology showed ectopic pancreatic tissue in the wall of the small bowel and stomach. Repeat Ga-68 DOTATATE PET/CT 5 months following surgery showed resolution of the distal gastric somatostatin receptor avidity. Clinical Lesson: This is the first case of ectopic pancreatic tissue mimicking a paraganglioma in a pediatric patient with hereditary paraganglioma-pheochromocytoma syndrome. False positive imaging should be considered in patients with SDHx mutations when the uptake is atypical in location and when the elevation in urine metanephrines is mild. Presentation: 6/3/2024

Primary Aortic Malignant Peripheral Nerve Sheath Tumor.

A 74year-old woman suffering 1month persisting lumbago was referred with diagnosis of thoracic aortic aneurysm. Blood examinations indicated slightly or moderately elevated noradrenaline, dopamine, and homovanillic acid with normal-range vanillylmandelic acid. Contrast-enhanced CT scans revealed a tumor, protruding both intra- and extra-luminally, in the wall of the distal descending thoracic aorta without any primary focuses in the whole body. Primary aortic sarcoma or periaortic catecholamine-producing paraganglioma infiltrating the aorta was suspected. The tumor with the normal proximal and distal aorta 2-3cm apart from it was completely resected under femoro-femoral partial cardiopulmonary bypass. Macroscopically, the tumor was originated from the aortic wall and protruded both intra- and extra-luminally. Immunohistochemically, positive S-100 and vimentin; Ki67 levels of 40%; and negative CD34, CK AE1/AE3, and SMA were identified. The aforementioned findings definitively diagnosed primary aortic malignant peripheral nerve sheath tumor, which has been never reported in the literature.

Cerebrospinal Fluid Homovanillic and 5-Hydroxyindoleacetic Acids in a Large Pediatric Population; Establishment of Reference Intervals and Impact of Disease and Medication.

Cerebrospinal fluid (CSF) homovanillic (HVA), and 5-hydroxyindoleacetic acids (5-HIAA) are biomarkers of neurological diseases affecting the dopaminergic and serotoninergic pathways. Establishing reference intervals for these metabolites faces the challenges of a lack of healthy controls and a negative correlation with age, making stratified intervals unrealistic. We propose a pipeline to determine continuous reference intervals for HVA and 5-HIAA using an indirect method. We also studied the confounding effects of different variables and explored the impact of antiepileptic and neuroleptic treatments on HVA and 5-HIAA values. The study used least squares regression to fit age-concentration curves from a cohort of pediatric patients (n = 1533), where the residuals represent metabolite values excluding age effect. Presuming that HVA and 5-HIAA primary deficiencies characterize a distinct subpopulation, we fitted a two-component finite mixture model in age-normalized data and set reference intervals at the central 95% of the nondeficient population. Patients with primary genetic deficiencies of HVA and/or 5-HIAA consistently fall outside the proposed continuous reference intervals. Using the new continuous reference intervals reduces the number of secondary deficiencies detected compared with using stratified values. No correlations were observed between CSF HVA and 5-HIAA values across the studied drug categories (antiseizure and neuroleptic medications). In addition, biopterin values positively influenced both metabolite concentrations. The proposed continuous reference intervals caused a substantial reduction in the number of secondary deficiencies detected, most of which demonstrated no conclusive correlations between the diseases and altered HVA and 5-HIAA values.

Campylobacter infection of young children in Colombia and its impact on the gastrointestinal environment.

Campylobacter infections are a leading cause of bacterial-derived gastroenteritis worldwide with particularly profound impacts on pediatric patients in low- and middle-income countries. It remains unclear how Campylobacter impacts these hosts, though it is becoming increasingly evident that it is a multifactorial process that depends on the host immune response, the gastrointestinal microbiota, various bacterial factors, and host nutritional status. Since these factors likely vary between adult and pediatric patients in different regions of the world, it is important that studies define these attributes in well-characterized clinical cohorts in diverse settings. In this study, we analyzed the fecal microbiota and the metabolomic and micronutrient profiles of asymptomatic and symptomatic pediatric patients in Colombia who were either infected or uninfected with Campylobacter during a case-controlled study on acute diarrheal disease. Here, we report that the microbiome of Campylobacter-infected children only changed in their abundance of Campylobacter spp. despite the inclusion of children with or without diarrhea. In addition to increased Campylobacter, computational models were used to identify fecal metabolites that were associated with Campylobacter infection and found that glucose-6-phosphate and homovanillic acid were the strongest predictors of infection in these pediatric patients, which suggests that colonocyte metabolism is impacted during infection. Despite changes to the fecal metabolome, the concentrations of intestinal minerals and trace elements were not significantly impacted by Campylobacter infection but were elevated in uninfected children with diarrhea.IMPORTANCEGastrointestinal infection with pathogenic Campylobacter species has long been recognized as a significant cause of human morbidity. Recently, it has been observed that pediatric populations in low- and middle-income countries are uniquely impacted by these organisms in that infected children can be persistently colonized, develop enteric dysfunction, and exhibit reduced development and growth. While the association of Campylobacter species with these long-term effects continues to emerge, the impact of infection on the gastrointestinal environment of these children remains uncharacterized. To address this knowledge gap, our group leveraged clinical samples collected during a previous study on gastrointestinal infections in pediatric patients to examine the fecal microbiota, metabolome, and micronutrient profiles of those infected with Campylobacter species and found that the metabolome was impacted in a way that suggests gastrointestinal cell metabolism is affected during infection, which is some of the first data indicating how gastrointestinal health in these patients may be affected.

Microdialysis perfusion of COA-Cl enhances dopamine metabolism in the dorsal striatum of freely moving mice.

We performed a microdialysis study to examine the effects of local perfusion of COA‑Cl on the extracellular levels of dopamine (DA) and its metabolites in the dorsal striatum of mice in vivo. The mice were perfused with Ringer's solution (control) and COA‑Cl (0.05, 0.1, or 0.5 mM) into the dorsal striatum. Dialysate samples were collected every 30 min and then analyzed using high‑performance liquid chromatography coupled with an electrochemical detector. We found that local perfusion of COA‑Cl (0.1 or 0.5 mM) into the dorsal striatum of living mice produced a significant and dose‑dependent increase in extracellular levels of DA, 3‑methoxytyramine (3‑MT), and homovanillic acid (HVA), where only 0.5 mM COA‑Cl increased dihydroxyphenylacetic acid (DOPAC) levels. However, 0.05 mM of COA‑Cl did not significantly affect either DA levels or its metabolites. Then, we administered the monoamine oxidase (MAO) inhibitor clorgyline alone or in combination with COA‑Cl (0.1 mM) to test whether COA‑Cl‑induced increases in DOPAC and HVA are mediated by increased MAO activity. Clorgyline alone increased 3‑MT levels and decreased DOPAC and HVA levels but not DA levels. When combined with COA‑Cl, clorgyline increased 3‑MT levels and reversed the decrease in DOPAC and HVA levels caused by clorgyline. The increase in DA metabolism induced by COA‑Cl suggests that some DA was further metabolized into DOPAC, 3‑MT, and HVA. This indicates that COA‑Cl plays a role in DA metabolism via increased DA release and/or activation of MAO, offering new insights into the effects of COA‑Cl on DA metabolism in the brain.

Assessment of Urinary Dopamine and Serotonin Metabolites in Relation to Dysbiosis Indicators in Patients with Functional Constipation.

The causes of functional constipation (FC) in adults are unclear, but changes in the gut microbiome may play an important role. The present study aimed to assess the relationship between urinary metabolites of dopamine and serotonin and some dysbiosis indicators in patients with FC. The study included 40 healthy women and 40 women with FC aged 21-46 years. Urinary levels of homovanillic acid (HVA), 5-hydoxyindoleacetic acid (5-HIAA), p-hydroxyphenylacetic acid (PhAc), and 3-indoxyl sulfate, as final metabolites of dopamine, serotonin, and indole pathway, respectively, were determined using the LC-Ms/Ms method. However, hydrogen-methane and ammonia breath tests were performed. The GA-map Dysbiosis Test was used to identify and characterize the dysbiosis index (DI). In patients with FC, the DI was significantly higher than in the control group: 4.05 ± 0.53 vs. 1.52 ± 0.81 points (p < 0.001), but the number of many types of bacteria varied among individuals. The levels of HVA were higher, while 5-HIAA levels were lower in patients. Moreover, the HVA/5-HIAA ratio had a positive correlation with DI as well as with the severity of symptoms. In patients with functional constipation, the balance in dopamine and serotonin secretion is disturbed, which is associated with changes in the gut microbiome.

Associations of cerebrospinal fluid monoamine metabolites with striatal dopamine transporter binding and 123I-meta-iodobenzylguanidine cardiac scintigraphy in Parkinson's disease: Multivariate analyses

Cerebrospinal fluid (CSF) homovanillic acid (HVA) and 5-hydroxyindole acetic acid (5-HIAA), dopamine and serotonin metabolites, are decreased in Parkinson's disease (PD). Although some reported associations between HVA and striatal dopamine transporter (DAT) or 5-HIAA and cardiac 123I-meta-iodobenzylguanidine (MIBG) findings, respectively, whether these are direct associations remained unknown. We retrospectively reviewed 57 drug-naïve patients with PD who underwent CSF analyses and DAT and cardiac MIBG imaging. Z-score of striatal DAT specific binding ratio (Z-SBR) was measured, and the positivity of MIBG abnormalities were judged by an expert. The mean age was 75.5 ± 8.7 years. Thirty-three were MIBG-positive and 24 were MIBG-negative. 5-HIAA levels were significantly lower in the MIBG-positive group. Logistic regression analysis showed that MIBG positivity was associated with 5-HIAA level (odds ratio = 0.751, p = 0.006) but not with age, sex, and HVA. DAT Z-SBR correlated with both HVA and 5-HIAA. Multiple regression analysis showed that HVA was the only significant variable associated with Z-SBR (t = 3.510, p < 0.001). We confirmed direct associations between 5-HIAA and cardiac MIBG, and between HVA and striatal DAT binding.

CE-UV method for the determination of catecholamine metabolites from baby pee-covered diapers

A method has been developed for the analysis of vanillylmandelic acid, homovanillic acid, and 5-hydroxyindoleacetic acid from baby urine as biomarkers of neuroblastoma in infants. Disposable diapers were employed as sampling devices in order to guarantee a low invasiveness during this step. The proposed method consists on a simple extraction step with water from the used diaper followed by the measurement using capillary electrophoresis with UV detection. The Box-Behnken design (BBD) was utilized to optimize the process of extracting catecholamine metabolites from the examined samples. The variables of the sample preparation step were optimized and the method was validated obtaining limits of quantification of 1.65 μg mL−1, good intraday and inter-day precision with RSDs under 15 %. Finally the method was applied to real samples collected from the Department of Neonatology, University Clinical Centre (Gdańsk, Poland). The greenness of the proposed method was also evaluated with different tools (i.e., AGREEPrep and GAPI) with satisfactory results, which allow to state that the method can be considered green. Moreover, its practicality was evaluated by application of BAGI tool, proving to be a practical and economical method to be applied in routine laboratories for determination of catecholamine metabolites in urine-type samples.

Non-target metabolomics unravels the effect and mechanism of Lianpu Drink on spleen-stomach damp-heat syndrome

BackgroundLianpu Drink (LPY) is a classic prescription for treating spleen-stomach damp-heat syndrome (SSDHS), known for its ability to clear heat and eliminate dampness. However, the underlying mechanisms of LPY in treating SSDHS remain unclear. ObjectivesThis study aims to use non-target metabolomics to unravel the effects and mechanisms of LPY on SSDHS. MethodsA metabolomics technique based on ultra-high-performance liquid chromatography-tandem quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) was used to identify the endogenous small-molecule metabolites in the urine of SSDHS model rats and find the metabolites associated with the LPY treatment of SSDHS. Furthermore, a network pharmacological analysis and molecular docking experiments were used to screen and validate the key metabolic pathways regulated by LPY. ResultsLPY exerted therapeutic effects on SSDHS by increasing the levels of motilin and gastrin, reducing the rectal temperature, alleviating the pathological changes in gastric and colonic tissues, and regulating the metabolic pattern in SSDHS rats. A total of 25 different metabolites, including L-histidine, citric acid and isocitric acid, were identified as the potential biomarkers for SSDHS via metabolomics. Among them, 11 metabolites were substantially reversed by LPY, including L-histidine, citric acid, isocitric acid, pantothenic acid, homovanillic acid sulfate, hippuric acid, indole-3-carboxilic acid-O-sulphate, 6-hydroxy-5-methoxyindole glucuronide, 2-phenylethan-ol glucuronide, 3-hydroxydodecanedioic acid and 3-methoxy-4-hydroxy-phenylethyleneglyclol sulfate. The results of network pharmacological analysis and molecular docking experiments validated that LPY ameliorated SSDHS by regulating the citrate cycle and histidine metabolism. ConclusionWe preliminarily investigated the effects and mechanisms of LPY on SSDHS at the level of endogenous small-molecule metabolites. Furthermore, this study provides a novel perspective for objectively evaluating the therapeutic effects, and exploring the mechanisms of Chinese medicinal formulas on SSDHS.

Etched-suppressed gold nanorods providing highly distinctive plasmonic patterns: Towards multiplex analysis of neuroblastoma biomarkers

BackgroundOn-site monitoring of vanillylmandelic acid (VMA), homovanillic acid (HVA), and dopamine (DA) as key diagnostic biomarkers for a wide range of neurological disorders holds utmost significance in clinical settings. Numerous colorimetric sensors with mechanistic approaches based on aggregation or silver metallization have been introduced for this purpose. However, these mechanisms have drawbacks, such as sensitivity to environmental factors and probe toxicity. Therefore, there is a great demand for a robust yet non-toxic colorimetric sensor that employs a novel route to monitor these biomarkers effectively. ResultsHere, we present a single-component multi-colorimetric probe based on the controllable etching suppression of gold nanorods (AuNRs) upon exposure to the mild etchant N-bromosuccinimide (NBS), designed to accurately detect and discriminate VMA, HVA, DA, and their corresponding mixtures, i.e., VMA:HVA, VMA:DA, HVA:DA, and VMA:HVA:DA. To enhance the sensitivity and automation capabilities of the designed multi-colorimetric sensor, two machine learning techniques were employed: linear discriminant analysis (LDA) for the qualitative classification and partial least-squares regression (PLSR) for the quantitative analysis of pure biomarkers and their mixtures. The outcomes revealed a high correlation between measured and predicted values, covering a linear range of 0.8–25, 1.2–25, and 2.7–100 μmol L−1, with remarkably low detection limits of 0.260, 0.397, and 0.913 μmol L−1 for VMA, HVA, and DA, respectively. Lastly, the performance of the probe was validated by successfully detecting the neuroblastoma biomarker VMA:HVA in human urine. SignificanceOur designed multi-colorimetric probe introduces a rapid, cost-effective, user-friendly, non-toxic, and non-invasive approach to detecting and discriminating not only the pure biomarkers but also their corresponding binary and ternary mixtures. The distinctive response profiles produced by the probe in the presence of different mixture ratios can indicate various disease states in patients, which is highly crucial in clinical diagnostics.

Copper Overload Increased Rat Striatal Levels of Both Dopamine and Its Main Metabolite Homovanillic Acid in Extracellular Fluid.

Copper is a trace element whose electronic configuration provides it with essential structural and catalytic functions. However, in excess, both its high protein affinity and redox-catalyzing properties can lead to hazardous consequences. In addition to promoting oxidative stress, copper is gaining interest for its effects on neurotransmission through modulation of GABAergic and glutamatergic receptors and interaction with the dopamine reuptake transporter. The aim of the present study was to investigate the effects of copper overexposure on the levels of dopamine, noradrenaline, and serotonin, or their main metabolites in rat's striatum extracellular fluid. Copper was injected intraperitoneally using our previously developed model, which ensured striatal overconcentration (2 mg CuCl2/kg for 30 days). Subsequently, extracellular fluid was collected by microdialysis on days 0, 15, and 30. Dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and noradrenaline (NA) levels were then determined by HPLC coupled with electrochemical detection. We observed a significant increase in the basal levels of DA and HVA after 15 days of treatment (310% and 351%), which was maintained after 30 days (358% and 402%), with no significant changes in the concentrations of 5-HIAA, DOPAC, and NA. Copper overload led to a marked increase in synaptic DA concentration, which could contribute to the psychoneurological alterations and the increased oxidative toxicity observed in Wilson's disease and other copper dysregulation states.

Antidepressant effect of new coumarin derivatives

BACKGROUND: The incidence of bipolar disorder is increasing worldwide. The search for new compounds with antidepressant activity and milder adverse drug reactions is an urgent task of modern psychopharmacology. AIM: This study aimed to analyze the effect of new neuroactive coumarin derivatives on the level of depressive behavior and monoamine metabolism in the brain structures of rats. MATERIALS AND METHODS: The antidepressant effects of LVM-091, LVM-099, LVM-S144, and IEM-2886 were evaluated in rats subjected to the Porsolt forced swimming test and the metabolism of monoamines in brain structures (LVM-099) using high-performance liquid chromatography. RESULTS: LVM-091, LVM-099, LVM-S144, and IEM-2886, synthesized from coumarin, decreased the immobilization time of the experimental rats in the Porsolt forced swimming test, indicating the antidepressant effect of these substances. The administration of LVM-099 at a dose of 10 mg/kg increased the level of homovanillic acid and the homovanillic acid-to-dopamine ratio in the nucleus accumbens. LVM-099 also increased 5-hydroxyindoleacetic acid levels and the 5-hydroxyindoleacetic acid-to-serotonin ratio in the nucleus accumbens. In the amygdala, the levels of norepinephrine, dopamine, serotonin, and their metabolites did not change after LVM-099 administration. CONCLUSIONS: New coumarin derivatives exert antidepressant effects and increase the metabolism of dopamine and serotonin in rat nucleus accumbens, which can be used in the development of new highly effective antidepressants.

Age- and sex-dependent cardiovascular impact of maternal perinatal stress and altered dopaminergic metabolism in the medulla oblongata of the offspring.

M Maternal Major Depressive Disorder with Peripartum Onset presents health risks to the mother and the developing fetus. Using a rat model of chronic mild stress, we previously reported on the neurodevelopmental impact of maternal perinatal stress on their offspring; the present study examined the cardiovascular impact of maternal perinatal stress on their offspring. The cardiovascular impact was assessed in terms of blood pressure and echocardiographic parameters. The results examined by a three-way ANOVA showed a significant association of cardiovascular parameters with maternal perinatal stress, and offspring sex and age. Increased blood pressure was observed in adolescent female and adult male offspring of stress-exposed dams. Echocardiography showed an increase in left atrial dimension and a reduction in left ventricular systolic function in adolescent stress-exposed female offspring. Increased interventricular septum thickness at end-diastole and left ventricular diastolic dysfunction were observed in adult stress-exposed male offspring. The underlying mechanisms of cardiovascular impact were examined in stress-exposed adult offspring by assessing the levels of neurotransmitters and their metabolites in the medulla oblongata using high-performance liquid chromatography. A significant decrease in homovanillic acid, a dopamine metabolite and indicator of dopaminergic activity, was observed in adult stress-exposed female offspring. These results suggest a significant sex- and age-dependent impact of maternal stress during the peripartum period on the cardiovascular system in the offspring that extends to adulthood and suggests a multigenerational effect. The presented data urgently need a follow-up to confirm its potential clinical and public health relevance.

6-shogaol against 3-Nitropropionic acid-induced Huntington's disease in rodents: Based on molecular docking/targeting pro-inflammatory cytokines/NF-κB-BDNF-Nrf2 pathway.

Huntington's disease (HD) is an extremely harmful autosomal inherited neurodegenerative disease. Motor dysfunction, mental disorder, and cognitive deficits are the characteristic features of this disease. The current study examined whether 6-shogaol has a protective effect against 3-Nitropropionic Acid (3-NPA)-induced HD in rats. A total of thirty male Wistar rats received 6-shogaol (10 and 20 mg/kg, per oral) an hour before injection of 3-NPA (10 mg/kg i.p.) for 15 days. Behavioral tests were performed, including narrow beam walk, rotarod test, and grip strength test. Biochemical tests promoting oxidative stress were evaluated [superoxide dismutase (SOD), reduced glutathione (GSH), catalase (CAT) and malondialdehyde (MDA)], including changes to neurotransmitters serotonin (5-HT), dopamine (DA), norepinephrine (NE), homovanillic acid (HVA), (3,4-dihydroxyphenylacetic acid (DOPAC), γ-aminobutyric acid (GABA), and 5-hydroxy indole acetic acid (5-HIAA), nuclear factor kappa-B (NF-κB), tumor necrosis factor-α (TNF-α), interleukins-1β (IL-1β), IL-6, brain-derived neurotrophic factor (BDNF), and nuclear factor erythroid 2-related factor 2 (Nrf2). The 6-shogaol was docked to the active site of TNF-α (2AZ5), NF-κB (1SVC), BDNF) [1B8M], and Nrf2 [5FZN] proteins using AutoDock tools. The 6-shogaol group significantly improved behavioral activity over the 3-NPA-injected control rats. Moreover, 3-NPA-induced significantly altered neurotransmitters, biochemical and neuroinflammatory indices, which could efficiently be reversed by 6-shogaol. The 6-shogaol showed favorable negative binding energies at -9.271 (BDNF) kcal/mol. The present investigation demonstrated the neuroprotective effects of 6-shogaol in an experimental animal paradigm against 3-NPA-induced HD in rats. The suggested mechanism is supported by immunohistochemical analysis and western blots, although more research is necessary for definite confirmation.

Changes in DOPAC, 3-MT, DOPAC/DA, HVA/DA, 3-MT/DA in the Hippocampus After Simulated Septoplasty and Maxillary Sinusotomy

Objective: to evaluate changes in DOPAC, 3-MT, DOPAC/DA, HVA/DA, 3-MT/DA in the hippocampus after simulation of septoplasty and maxillofacial surgery in rats. Materials and methods. Simulation of operations was carried out on male Wistar rats under general anesthesia with Zoletil 100 solution. In group 1, septoplasty (n=10) was simulated by the standard method by zigzag scarification of the nasal mucosa. In group 2 (n=10), dental implantation with a titanium implant was performed after the implant bed was formed using drill. In group 3 (n=10), only implant bed was made in the alveolar ridge of the upper jaw without subsequent manipulations. In group 4, 10 rats underwent sinus lifting with bone chips with immediate implantation of a titanium implant. In group 5 (n=10)– with the help of a micro drill through a pre-formed implant bed in the alveolar ridge of the upper jaw, a maxillary sinusotomy was performed with damage to the mucous membrane of the ipsilateral maxillary sinus. Liquid chromatography with electrochemical detection was used to determine the concentration of dopamine (DA), homovanilic acid (HVA), 3,4-dihydroxyphenylacetic acid (DOPAC), 3- methoxytiramine (3-MT) in the hippocampal formation. DOPAC/DA, HVA/DA, 3-MT/DA were also determined. Results. The concentration of dopamine in the hippocampus, compared with the control, was significantly higher in group 5 and lower in group 4. The HVA concentration was significantly higher in group 2, group 5 (p&lt;0.01) and group 1 (p&lt;0.05). An intergroup comparison determined that the concentration of HVA was significantly higher in group 2, compared with the rest of the experimental groups (p&lt;0.001). In groups 1, 3 and 4, this indicator was significantly lower compared to group 5 (p&lt;0.01). The DOPAC level was significantly higher (p&lt;0.01) compared to the control data. The concentration of 3-MT was significantly higher in groups 4 and 5 (p&lt;0.001), as well as in group 1 (p&lt;0.05) and in group 3 (p&lt;0.01). Conclusion. After simulating sinus lifting with immediate implantation and dental implantation complicated by maxillary sinusotomy, there is an increase in the concentration of dopamine metabolites 3-MT, HVA and DOPAC, but at the same time a decrease in dopaminergic activity of the hippocampal formation, compared with simulation of septoplasty and simple damage to the alveolar ridge of the upper jaw. Such changes are markers of disruption of adaptation processes after surgery in the head and neck.