Dopamine Binding Research Articles

Exploring the correlation between cardiovascular adverse events and antidepressant use: A retrospective pharmacovigilance analysis based on the FDA Adverse Event Reporting System database

BackgroundThe high comorbidity and mutually reinforcing relation between depression and cardiovascular disease have raised concerns about the cardiovascular risk of antidepressants. To gain a better understanding of this correlation, we performed a comprehensive evaluation regarding the types and degrees of cardiovascular adverse events (AEs) associated with 37 commonly prescribed antidepressants. MethodsAE reports from January 2004 to December 2023 were retrieved from the FDA Adverse Event Reporting System (FAERS) database. Disproportionality analysis was performed to identify antidepressant-related cardiovascular signals using the reporting odds ratio, proportional reporting ratio, and information component. Influencing factors of cardiovascular death, including age, sex, antidepressant choice, and concomitant medication, were explored. The underlying mechanisms of antidepressant-associated cardiovascular risk related to neurotransmitter transporters/receptors were further explored. ResultsThe use of antidepressants was associated with eight categories of Standardized MedDRA Queries of cardiovascular events. Different antidepressants exerted varying types and degrees of cardiovascular risks along with contributions to death in reports with cardiovascular AEs. Among them, monoamine oxidase inhibitors had the highest risk of developing six cardiovascular event categories: torsades de pointes (TdP)/QT prolongation, hypertension, cardiac arrhythmias, cardiomyopathy, pulmonary hypertension, and ischaemic heart disease. Age, male and the use of 24 types of antidepressants and concomitant medications were positively correlated with death in cardiovascular AEs. The highest risk associated with antidepressants was found in amoxapine (OR = 5.00 [2.13, 11.75], P < 0.001), followed by moclobemide (OR = 3.66 [1.85, 7.24], P < 0.001). Correlation analysis indicated the occurrence of antidepressant-related TdP/QT prolongation, hypertension and cardiomyopathy was associated with the binding and uptake inhibition of dopamine and norepinephrine transporters as well as their selectivity over serotonin transporters. ConclusionThe retrospective analysis revealed that cardiovascular AEs were connected with antidepressant use, and the binding/uptake inhibitory potency and selectivity of neurotransmitters of antidepressants played an important role, providing a preliminary basis for further in-depth study of antidepressant-related cardiovascular toxicity. However, as an exploratory study, prospective studies are needed to validate our findings in the future.

Selective and Comparative Study of B/nZVCu-Fe and B/nZVCu-Zn Nanoparticles as Fluorescent Probe for Dopamine in Presence of its Interference Molecules.

This work focuses on the synthesis of Bentonite supported nano zero valent bimetallic nanoparticles (B/nZVCu-M NPs) to be utilized for fast and highly sensitive, reversible, fluorescent determination of dopamine (DA) in the presence of dopamine, other biomolecules and ions. The X-ray Photoelectron Spectroscopy(XPS), Powder X-Ray Diffraction(PXRD) and Scanning Electron Microscopy(SEM) revealed the formation of nanoparticles with size ranging from 15 to 20nm. The composition was revealed by Fourier Transform Infrared(FTIR) Spectoscopy and Energy Dispersive X-Ray (EDX) Analysis. The Limits of Detection(LOD) were noted to be 5.57nM and 6.07nM. The binding of DA is noted to be reversible with respect to EDTA2-. Furthermore, the developed sensor exhibited good repeatability, satisfactory long-term stability, and was successfully used for the selective detection of dopamine sample with desired recoveries or reversibilities. The main aim of our work is to selectively detect dopamine in presence of its major interferents and biomolecules that are normally present/ co-exist with dopamine in biological systems.

Tailored portable electrochemical sensor for dopamine detection in human fluids using heteroatom-doped three-dimensional g-C3N4 hornet nest structure

BackgroundThere is widespread interest in the design of portable electrochemical sensors for the selective monitoring of biomolecules. Dopamine (DA) is one of the neurotransmitter molecules that play a key role in the monitoring of some neuronal disorders such as Alzheimer's and Parkinson's diseases. Facile synthesis of the highly active surface interface to design a portable electrochemical sensor for the sensitive and selective monitoring of biomolecules (i.e., DA) in its resources such as human fluids is highly required. ResultsThe designed sensor is based on a three-dimensional phosphorous and sulfur resembling a g-C3N4 hornet's nest (3D-PS-doped CNHN). The morphological structure of 3D-PS-doped CNHN features multi-open gates and numerous vacant voids, presenting a novel design reminiscent of a hornet's nest. The outer surface exhibits a heterogeneous structure with a wave orientation and rough surface texture. Each gate structure takes on a hexagonal shape with a wall size of approximately 100 nm. These structural characteristics, including high surface area and hierarchical design, facilitate the diffusion of electrolytes and enhance the binding and high loading of DA molecules on both inner and outer surfaces. The multifunctional nature of g-C3N4, incorporating phosphorous and sulfur atoms, contributes to a versatile surface that improves DA binding. Additionally, the phosphate and sulfate groups' functionalities enhance sensing properties, thereby outlining selectivity. The resulting portable 3D-PS-doped CNHN sensor demonstrates high sensitivity with a low limit of detection (7.8 nM) and a broad linear range spanning from 10 to 500 nM. SignificanceThe portable DA sensor based on the 3D-PS-doped CNHN/SPCE exhibits excellent recovery of DA molecules in human fluids, such as human serum and urine samples, demonstrating high stability and good reproducibility. The designed portable DA sensor could find utility in the detection of DA in clinical samples, showcasing its potential for practical applications in medical settings.

Highly sensitive and selective detection of dopamine using atomic layer deposited HfO2 ultra-thin films

The development of non-enzymatic and binder-free biosensors plays a vital role, and it possesses main benefits for effective biomolecule recognition with high sensitivity and preferred selectivity. Herein, an atomic layer deposition (ALD) was employed to develop the hafnium oxide (HfO2) nanofilm on silicon (Si) for fabricating binder-free selective and sensitive determination of the non-enzymatic electrochemical dopamine sensor. The prepared HfO2 nanofilm selectively acted as a local dopamine binding site because of the hydrophobic-hydrophobic interaction between fabricated film and dopamine, electrostatic attraction between negatively charged hydroxyl group on film surfaces, and positively charged amino group of dopamine. The developed insufficient oxygen vacancies on the HfO2 could have behaved as a charge-trapping site for better sensing properties. The developed sensor demonstrated excellent realization in sensing dopamine with a very low detection limit (0.4 pM) and swift response time of 3s which is quite precise compared with various reported literature. The fabricated HfO2/Si electrode sensor has exhibited high sensitivity, stability, and repeatability. The selectivity of dopamine sensors was at least three orders greater than other interfering biomolecules. This work proposes the essential track for the practical realization of dopamine detection in human serum and biomedical applications.

Synthetic and Pharmacological Expedition of Pyrazolo[1,5-a]pyridine: A Comprehensive Review

Abstract: Fused nitrogen-containing heterocyclic compounds have been identified to display a prominent role in medicinal chemistry, biochemistry, and other streams of science. Countless derivatives of pyrazolo[ 1,5-a] pyridine have been investigated by researchers for their distinct pharmacological characterization. In this article, we have revealed and arranged the various routes of synthesis and therapeutic activities such as dopamine binding affinity, kinase inhibitory activity, and PDE inhibitors of pyrazolo[1,5- a]pyridine-containing compounds which have been explored till now. The remarkable outcomes obtained via in vitro as well as in vivo profile screening of this moiety and its derivatives lead this scaffold to be recognized to a greater extent and examined further for better results. This review will give medicinal chemists a flying-bird eye catch view of pyrazolo[1,5-a] pyridine derivatives which will help them to design and synthesize potential compounds bearing this moiety.

Alkaline liquid-derived NaxTi11.5MoVOx/C-40 material with controlled electron transfer rate for sensitive electrochemical detection of dopamine

The neurotransmitter dopamine (DA) is associated with many physiological and pathological processes, so the importance of low detection limits and high sensitivity analysis cannot be overstated, especially for early disease detection. Here, 2 M NaOH aqueous solution is used to precipitate metal ions in an ethanol solution containing carbon black (CB), and then nanocomposite catalysts (NaxTi11.5MoVOx/C-40 (40 denoted as 40 mg CB)) were obtained by calcining the precipitation. When used for DA detection, NaxVOx acts as the main active site for electrochemical oxidation of DA and NaxTi11.5MoOx plays a role in facilitating the binding of DA to the active site and stabilizing the active site. The NaxTi11.5MoVOx/C-40 electrochemical biosensor has a limit of detection (LOD) of 0.003 μM with a linear range of 0.005–51.665 μM for DA. This sensor can be used to sensitively identify the concentration of DA in human blood and urine. Catalysts containing varying amounts of CB exhibit diverse electron transfer rates, and surprisingly, we found that the appropriate electron transfer rate is optimal for the detection of low concentrations of DA. Because the performance of the electrochemical biosensors is affected by both the activity of the catalysts and the accuracy of the electrochemical testing instrumentation. To better explain this phenomenon, we propose the concept of resolution (Rn) and present the formula to derive it, offering a new approach to evaluating the performance of electrochemical biosensors.

Interfacing Aptamer-Modified Nanopipettes with Neuronal Media and Ex Vivo Brain Tissue.

Aptamer-functionalized biosensors exhibit high selectivity for monitoring neurotransmitters in complex environments. We translated nanoscale aptamer-modified nanopipette sensors to detect endogenous dopamine release in vitro and ex vivo. These sensors employ quartz nanopipettes with nanoscale pores (ca. 10 nm diameter) that are functionalized with aptamers that enable the selective capture of dopamine through target-specific conformational changes. The dynamic behavior of aptamer structures upon dopamine binding leads to the rearrangement of surface charge within the nanopore, resulting in measurable changes in ionic current. To assess sensor performance in real time, we designed a fluidic platform to characterize the temporal dynamics of nanopipette sensors. We then conducted differential biosensing by deploying control sensors modified with nonspecific DNA alongside dopamine-specific sensors in biological milieu. Our results confirm the functionality of aptamer-modified nanopipettes for direct measurements in undiluted complex fluids, specifically in the culture media of human-induced pluripotent stem cell-derived dopaminergic neurons. Moreover, sensor implantation and repeated measurements in acute brain slices was possible, likely owing to the protected sensing area inside nanoscale DNA-filled orifices, minimizing exposure to nonspecific interferents and preventing clogging. Further, differential recordings of endogenous dopamine released through electrical stimulation in the dorsolateral striatum demonstrate the potential of aptamer-modified nanopipettes for ex vivo recordings with unprecedented spatial resolution and reduced tissue damage.

A Homogeneous Colorimetric Strategy Based on Rose-like CuS@Prussian Blue/Pt for Detection of Dopamine.

The development of effective methods for dopamine detection is critical. In this study, a homogeneous colorimetric strategy for the detection of dopamine based on a copper sulfide and Prussian blue/platinum (CuS@PB/Pt) composite was developed. A rose-like CuS@PB/Pt composite was synthesized for the first time, and it was discovered that when hydrogen peroxide was present, the 3,3',5,5'-tetramethylbenzidine (TMB) changed from colorless into blue-oxidized TMB. The CuS@PB/Pt composite was characterized with a scanning electron microscope (SEM), an energy dispersive spectrometer (EDS), and an X-ray photoelectron spectrometer (XPS). Moreover, the catalytic activity of the CuS@PB/Pt composite was inhibited by the binding of dopamine to the composite. The color change of TMB can be evaluated by the UV spectrum and a portable smartphone detection device. The developed colorimetric sensor can be used to quantitatively analyze dopamine between 1 and 60 µM with a detection limit of 0.28 μM. Furthermore, the sensor showed good long-term stability and good performance in human serum samples. Compared with other reported methods, this strategy can be performed rapidly (16 min) and has the advantage of smartphone visual detection. The portable smartphone detection device is portable and user-friendly, providing convenient colorimetric analysis for serum. This colorimetric strategy also has considerable potential for the development of in vitro diagnosis methods in combination with other test strips.

Dopaminergic and serotoninergic neurotoxicity of lanthanide phosphate (TbPO4) in developing zebrafish

Rare earth elements (REEs) are exploited for global use in manufacturing. Such activities result in their release into the environment and the transformation into more stable phosphate deposition. The objective of this study was to evaluate molecular and behavioral changes of zebrafish exposed to the synthesized terbium phosphate (TbPO4) at concentrations of 10, 20, and 50 mg/L and to determine its potential for neurotoxicity. Metabolomics related to neurotransmitters, and assessment of transcripts and proteins were conducted to uncover the molecular mechanisms underlying TbPO4 with emphasis on neurotransmitter systems. Exposure to 20 mg/L TbPO4 induced larval hyperactivity and perturbed the cholinergic system in zebrafish. Based on metabolomics related to neurotransmitters, dopamine (DA), serotonin (5-HT), and many of their precursors and metabolites were decreased in abundance by TbPO4. In addition, the expression levels of transcripts related to the synthesis, transport, receptor binding, and metabolism of DA and 5-HT were analyzed at the mRNA and protein levels. Transcript and protein levels for tyrosine hydroxylase (TH), the rate-limiting enzyme for DA synthesis, were down-regulated in larval fish. Monoamine oxidase (MAO), an enzyme that catabolizes monoamines DA and 5-HT, was also reduced in mRNA abundance. We hypothesize that DA synthesis and monoamine metabolism are associated with behavioral alterations. This study elucidates putative mechanisms and exposure risks to wildlife and humans by characterizing phosphatic REE-induced neurotoxicity in developing zebrafish.

Concept of a Crossed Czerny–Turner Spectrometer With an Integrated Automatic Sampling System for Biodetection Using Ultrastable Gold Nanoparticles

This work presents the design and implementation of a portable optofluidic system for biodetection based on ultrastable gold nanoparticles functionalized with a dopamine binding aptamer. The automatic sampling and mixing fluidic system integrated into a spectrometer is configured to measure the gold nanoparticles’ plasmon band position. The novel molecule detection method based on ultrastable gold nanoparticles has been previously tested using dopamine as the target molecule. The optofluidic system designed for automatic bathochromic shift detection has an optical resolution of 1nm using a 50 μm input slit. The proposed system, compared to other existing molecules detection techniques, has several advantages including portability and automatic detection for <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">in situ</i> applications.

Dopamine Transporter Deficiency Syndrome (DTDS): Expanding the Clinical Phenotype and Precision Medicine Approaches.

Infantile parkinsonism-dystonia due to dopamine transporter deficiency syndrome (DTDS) is an ultrarare childhood movement disorder caused by biallelic loss-of-function mutations in the SLC6A3 gene. Advances in genomic analysis have revealed an evolving spectrum of SLC6A3-related neurological and neuropsychiatric disorders. Since the initial clinical and genetic characterisation of DTDS in 2009, there have been thirty-one published cases with a variety of protein-truncating variants (nonsense variants, splice-site changes, and deletions) and missense changes. Amino acid substitutions result in mutant proteins with impaired dopamine transporter function due to reduced transporter activity, impaired dopamine binding, reduced cell-surface expression, and aberrant posttranslational protein modification with impaired glycosylation. In this review, we provide an overview of the expanding clinical phenotype of DTDS and the precision therapies in development, including pharmacochaperones and gene therapy.

Interactions between polysialic acid and dopamine-lead compounds as revealed by biochemical and in silico docking simulation analyses.

Polysialic acid is an important glyco-epitope in vertebrate brains, while altered expressions of polySia and biosynthetic enzyme have been reported in brain diseases such as schizophrenia and depression. Recently, the binding between polySia and dopamine and the involvement of this in Akt signaling has been demonstrated. However, the molecular mechanism underlying the binding of polySia and dopamine remains unknown. Therefore, here, we demonstrated the interaction between dopamine and polySia using frontal affinity chromatography alongside docking simulations. In addition, we prepared dopamine-lead compounds to understand the detailed molecular basis of polySia binding by frontal affinity chromatography, enzyme-linked immunosorbent assay, and docking simulations.

Dopamine in the dorsal bed nucleus of stria terminalis signals Pavlovian sign-tracking and reward violations.

Midbrain and striatal dopamine signals have been extremely well characterized over the past several decades, yet novel dopamine signals and functions in reward learning and motivation continue to emerge. A similar characterization of real-time sub-second dopamine signals in areas outside of the striatum has been limited. Recent advances in fluorescent sensor technology and fiber photometry permit the measurement of dopamine binding correlates, which can divulge basic functions of dopamine signaling in non-striatal dopamine terminal regions, like the dorsal bed nucleus of the stria terminalis (dBNST). Here, we record GRABDA signals in the dBNST during a Pavlovian lever autoshaping task. We observe greater Pavlovian cue-evoked dBNST GRABDA signals in sign-tracking (ST) compared to goal-tracking/intermediate (GT/INT) rats and the magnitude of cue-evoked dBNST GRABDA signals decreases immediately following reinforcer-specific satiety. When we deliver unexpected rewards or omit expected rewards, we find that dBNST dopamine signals encode bidirectional reward prediction errors in GT/INT rats, but only positive prediction errors in ST rats. Since sign- and goal-tracking approach strategies are associated with distinct drug relapse vulnerabilities, we examined the effects of experimenter-administered fentanyl on dBNST dopamine associative encoding. Systemic fentanyl injections do not disrupt cue discrimination but generally potentiate dBNST dopamine signals. These results reveal multiple dBNST dopamine correlates of learning and motivation that depend on the Pavlovian approach strategy employed.

The association between Adenosine A2A receptor gene polymorphisms and attention deficit hyperactivity disorder in Korean children

Attention deficit hyperactivity disorder (ADHD) is a common and heritable neurodevelopmental disorder. Particularly, ADHD is known to be related to the dopaminergic system. ADHD symptoms can appear when the dopamine binding affinity diminishes due to dopamine receptor abnormalities, such as the dopamine D2 receptor (D2R). This receptor interacts with the adenosine A2A receptor (A2AR). The A2AR acts as an antagonist of D2R, that is, the increased binding of adenosine with A2AR inhibits the D2R activity. Furthermore, it is found that the single nucleotide polymorphisms of the adenosine A2A receptor gene (ADORA2A) revealed a significant relationship with ADHD in various populations. Therefore, we examined the genetic relationship between ADORA2A polymorphisms (rs2297838, rs5751876, and rs4822492) and Korean ADHD children. A case-control study was performed for 150 cases and 322 controls. Genotyping of ADORA2A polymorphisms was conducted by PCR-RFLP. The results demonstrated that the rs5751876 TC genotype was associated with children with ADHD (p = 0.018). The rs2298383 CC genotype was significantly associated with children with ADHD/HI (p = 0.026). However, when Bonferroni correction was used, the significance vanished (padjusted = 0.054 and padjusted = 0.078, respectively). Haplotype analysis showed that TTC, TCC, and CTG demonstrated a significant difference between ADHD/C children and control groups (padjusted = 0.006, padjusted = 0.011, and padjusted = 0.028, respectively). In conclusion, we propose a possible association between ADORA2A polymorphisms with Korean children having ADHD.

A Recognition-Molecule-Free Photoelectrochemical Sensor Based on Ti3C2/TiO2 Heterostructure for Monitoring of Dopamine

Herein, a novel, recognition-molecule-free electrode based on Ti3C2/TiO2 composites was synthesized using Ti3C2 as the Ti source and TiO2 in situ formed by oxidation on the Ti3C2 surface for the selective detection of dopamine (DA). The TiO2 in situ formed by oxidation on the Ti3C2 surface not only increased the catalytically active surface for DA binding but also accelerated the carrier transfer due to the coupling between TiO2 and Ti3C2, resulting in a better photoelectric response than pure TiO2. Through a series of experimental conditions optimization, the photocurrent signals obtained by the MT100 electrode were proportional to the DA concentration from 0.125 to 400 µM, with a detection limit estimated at 0.045 µM. We also monitored DA in human blood serum samples using the MT100 electrode. The results showed good recovery, demonstrating the promising use of the sensor for the analysis of DA in real samples.

Foliglurax, a positive allosteric modulator of the metabotrophic glutamate receptor 4, protects dopaminergic neurons in MPTP-lesioned male mice

Overactivity of the corticostriatal glutamatergic pathway is documented in Parkinson's disease (PD) and stimulation of presynaptic metabotropic glutamate (mGlu) receptors 4 on these striatal afferents inhibits glutamate release normalizing neuronal activity in the basal ganglia. Moreover, mGlu4 receptors are also expressed in glial cells and are able to modulate glial function making this receptor a potential target for neuroprotection. Hence, we investigated whether foliglurax, a positive allosteric modulator of mGlu4 receptors with high brain exposure after oral administration, has neuroprotective effects in MPTP mice to model early PD. Male mice were treated daily from day 1 to 10 with 1, 3 or 10 mg/kg of foliglurax and administered MPTP on the 5th day then euthanized on the 11th day. Dopamine neuron integrity was assessed with measures of striatal dopamine and its metabolites levels, striatal and nigral dopamine transporter (DAT) binding and inflammation with markers of striatal astrocytes (GFAP) and microglia (Iba1). MPTP lesion produced a decrease in dopamine, its metabolites and striatal DAT specific binding that was prevented by treatment with 3 mg/kg of foliglurax, whereas 1 and 10 mg/kg had no beneficial effect. MPTP mice had increased levels of GFAP; foliglurax treatment (3 mg/kg) prevented this increase. Iba1 levels were unchanged in MPTP mice compared to control mice. There was a negative correlation between dopamine content and GFAP levels. Our results show that positive allosteric modulation of mGlu4 receptors with foliglurax provided neuroprotective effects in the MPTP mouse model of PD.

Associations of striatal dopamine transporter binding with motor and non-motor symptoms in early Parkinson's disease.

Dopamine transporter (DAT) imaging is an in vivo tool to assess presynaptic dopaminergic function in the clinical practices of Parkinson's disease (PD). Current clinical practices focused on qualitatively visual interpretation of DAT imaging, whereas quantitative analyses are potentially more helpful when monitoring the progression of PD. Previous cross-sectional studies indicated certain motor and non-motor features were associated with striatal DAT binding, whereas limited data were reported in terms of the longitudinal correlation between clinical features of PD with striatal DAT binding. The purpose of our study is to clarify current and longitudinal correlations between striatal DAT binding and clinical measures. A total of 352 untreated PD individuals and 167 healthy controls with complete baseline clinical measures and neuroimaging data were identified from the Parkinson's Progression and Markers Initiative (PPMI) database. Patients with PD underwent DAT imaging at the screening visit and following months 12, 24, and 48. Multiple linear regression models and linear mixed-effect models were respectively conducted to investigate the cross-sectional and longitudinal correlation between clinical characteristics and DAT binding. Associations between changes in clinical characteristics and changes in DAT binding were further evaluated and the Spearman rank correlation coefficients were reported. In the cross-sectional analysis, baseline striatal DAT binding was significantly associated with the Hoehn and Yahr scale, the Movement Disorder Society-Sponsored Revision of the Unified Parkinson Disease Rating Scale (MDS-UPDRS) scores, the rigidity scores, and the axial scores in PD individuals (false discovery rate [FDR]-adjusted p=0.0017 for all above). Patients who developed freezing of gait had lower striatal DAT binding (FDR-adjusted p=0.0161). Healthy controls who had higher tremor scores and suffered more severe olfactory dysfunction had lower striatal DAT binding (FDR-adjusted p=0.0257 for all above). Longitudinal analysis indicated that baseline severity of rapid-eye-movement sleep behavior disorder was significantly associated with longitudinal striatal DAT binding in patients with PD (FDR-adjusted p=0.0120). Furthermore, changes in MDS-UPDRS scores and the State-Trait Anxiety Inventory (STAI) scores demonstrated significant correlations with changes in striatal DAT binding over 4 years (p=0.005 and p=0.032, respectively). Our findings clarified quantitative associations between certain motor and non-motor features with current and future striatal dopamine binding, suggesting the feasibility of using DAT images as a progression predictive marker for PD. Further studies are needed to investigate correlations between different regional dopamine binding with specific clinical features.

Analysis of differentially expressed genes related to cerebral ischaemia in young rats based on the Gene Expression Omnibus database.

The incidence rate of cerebral infarction in young people is increasing day by day, the age of onset tends to be younger, and its internal pathogenesis and mechanism are very complicated, which leads to greater difficulties in treatment. Therefore, it is essential to analyze the key pathway that affects the onset of cerebral infarction in young people from the perspective of genetics. To compare the differentially expressed genes in the brain tissue of young and aged rats with middle cerebral artery occlusion and to analyse their effect on the key signalling pathway involved in the development of cerebral ischaemia in young rats. The Gene Expression Omnibus 2R online analysis tool was used to analyse the differentially expressed genes in the GSE166162 dataset regarding the development of cerebral ischaemia in young and aged groups of rats. DAVID 6.8 software was further used to filter the differentially expressed genes. These genes were subjected to Gene Ontology (GO) function analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis to determine the key gene pathway that affects the occurrence of cerebral ischaemia in young rats. Thirty-five differentially expressed genes (such as Igf2, Col1a2, and Sfrp1) were obtained; 73 GO enrichment analysis pathways are mainly involved in biological processes such as drug response, amino acid stimulation response, blood vessel development, various signalling pathways, and enzyme regulation. They are involved in molecular functions such as drug binding, protein binding, dopamine binding, metal ion binding, and dopamine neurotransmitter receptor activity. KEGG pathway enrichment analysis showed a significantly enriched pathway: The cyclic adenosine monophosphate (c-AMP) signalling pathway. The c-AMP signalling pathway might be the key pathway in the intervention of cerebral infarction in young people.

Overview of the structure and function of the dopamine transporter and its protein interactions.

The dopamine transporter (DAT) plays an integral role in dopamine neurotransmission through the clearance of dopamine from the extracellular space. Dysregulation of DAT is central to the pathophysiology of numerous neuropsychiatric disorders and as such is an attractive therapeutic target. DAT belongs to the solute carrier family 6 (SLC6) class of Na+/Cl- dependent transporters that move various cargo into neurons against their concentration gradient. This review focuses on DAT (SCL6A3 protein) while extending the narrative to the closely related transporters for serotonin and norepinephrine where needed for comparison or functional relevance. Cloning and site-directed mutagenesis experiments provided early structural knowledge of DAT but our contemporary understanding was achieved through a combination of crystallization of the related bacterial transporter LeuT, homology modeling, and subsequently the crystallization of drosophila DAT. These seminal findings enabled a better understanding of the conformational states involved in the transport of substrate, subsequently aiding state-specific drug design. Post-translational modifications to DAT such as phosphorylation, palmitoylation, ubiquitination also influence the plasma membrane localization and kinetics. Substrates and drugs can interact with multiple sites within DAT including the primary S1 and S2 sites involved in dopamine binding and novel allosteric sites. Major research has centered around the question what determines the substrate and inhibitor selectivity of DAT in comparison to serotonin and norepinephrine transporters. DAT has been implicated in many neurological disorders and may play a role in the pathology of HIV and Parkinson's disease via direct physical interaction with HIV-1 Tat and α-synuclein proteins respectively.

Effect of covalent-binding modes of osteogenic-related peptides with artificial carriers on their biological activities in vivo

Covalent binding between active substances and materials in different ways can significantly improve the bone inductivity and biological activity of bone repair materials. However, there is a lack of systematic understanding of how these binding modes affect the biological activity of active substances. In this study, four kinds of functionalized Multi-walled carbon nanotubes (MWCNTs) were prepared to ensure the same grafting rate of functional groups. Subsequently, two kinds of osteogenic-related peptides, including bone morphogenetic protein-2 mimicking peptides and osteogenic growth mimicking peptides, were covalently bound to functionalized MWCNTs, ensuring the same molar mass of peptides bound by different functionalized MWCNTs in this process. Then the same amount of functionalized MWCNTs/Peptides composites were introduced into the scaffolds, and through the ectopic osteogenesis model in rats and calvarial defect model in rabbits, the ectopic osteogenesis and bone repair ability of MWCNTs/Peptides composites were analyzed. Furthermore, the effects of different covalent binding modes on peptide-induced osteogenesis and bone repair were studied. The results showed that the negative influencing trend of different covalent binding modes of osteogenic-related peptides with artificial carriers on their biological activities was in the order as follows: amide binding (carboxyl) > silane coupling > dopamine binding > amide binding (amino), whose mechanism might be the covalent binding of peptides with different functional groups, resulting in different charges of peptides after covalent binding. We believed that the results of this study have important guiding significance for the research and development of active material covalently bound bone repair materials.