Search

Abstract Background The persistently rising complication, pseudotumor, after hip arthroplasty required surgeons’ vigilance. Although the remaining controversial relationship between metal ions and pseudotumor, metal ion detection had been widely employed in clinic. The aim of this study is to evaluate the correlation between metal ions and pseudotumor, as well as the effectiveness of metal ion analysis in the screening and diagnosis of pseudotumor through systematic review and meta-analysis. Methods The Medline and Embase databases were searched for studies evaluating metal ions and patients with pseudotumors after hip arthroplasty. A systematic review of risk ratio and diagnostic performance for metal ions was conducted. Results Seven studies were included in the systematic review. The mean Methodological Index for Non-Randomized Studies (MINORS) score of the included studies was 19 (range, 14 to 22). Pooled risk ratio (RR) value was 2.01(95% CI: 1.25–3.24; P = 0.004) for cobalt ions level and 1.44 (95% CI: 1.10–1.88; P = 0.008) for chromium ions level. The pooled sensitivity, specificity and the area under the curve (AUC) for cobalt and chromium ions were determined to be 0.59, 0.82, 0.73 and 0.34, 0.82, 0.56, respectively. Conclusions The metal ions level has a low diagnostic value. It is of certain value for confirmation, but should not be used as a routine screening indicator. The diagnostic value of cobalt ions is higher than that of chromium. Level of Evidence: Diagnostic Level IV.

Thymus is the important immune organ, responsible for T cell development and differentiation. The lower circulating T counts have been observed in patients who died from COVID-19 compared with survivors. Azvudine, also known as FNC, is a thymus-homing anti-SARS-CoV-2 drug in treating COVID-19 patients. In this study, single-cell transcriptome, proteomics, and parallel reaction monitoring (PRM) were applied to insight into the activation process of FNC in rat and SARS-CoV-2 rhesus monkey thymus. The results indicated that thymic immune cells possess a robust metabolic capacity for cytidine-analogue drugs such as FNC. Key enzymes involved in the FNC phosphorylation process, such as Dck, Cmpk1, and Nme2, were highly expressed in CD4+ T cells, CD8+ T cells, and DP (CD4+ CD8+) cells. Additionally, FNC could upregulate multiple phosphorylated kinases in various cell types while downregulating the phosphatases, phosphoribosyl transferases, and deaminases, respectively. The robust phosphorylation capacity of the thymus for cytidine analogue drug FNC, and the activation effect of FNC on the NAs metabolism system potentially contribute to its enrichment in the thymus and immune protection effect. This suggests that it is crucial to consider the expression level of phosphorylation kinases when evaluating NA drug properties, as an important factor during antiviral drug design.

ABSTRACT Introduction Alzheimer's disease (AD) is a neurodegenerative disease characterized by Amyloid plaques and neurofibrillary tangles. We explored the potential mechanism by which Danggui Shaoyao San (DSS) modulates central glucose metabolism via the insulin receptor substrate 1 (IRS1)/glycogen synthase kinase‐3β (GSK3β)/Wnt3a‐β‐catenin pathway, thereby exerting protective effects on cognitive functions. Methods In vitro, HT22 cells were induced with streptozotocin (STZ) to investigate the impact of GSK3β on pathway transduction. The active components in the DSS stock solution were validated using mass spectrometry. Subsequently, an AD model in C57BL/6J mice was established through STZ injection into both ventricles. The success of the model was validated behaviorally and pathologically. The Morris Water Maze (MWM) test, immunohistochemistry, Western blotting, quantitative reverse transcription‐PCR, and 18F‐fluorodeoxyglucose‐positron emission tomography (FDG‐PET) were employed to evaluate the influence of DSS on memory and pathological changes in AD. Results The DSS stock solution, rich in active components, ameliorated the memory deficits in AD mice in the MWM. In vitro, GSK3β exhibited regulatory control over Wnt and β‐catenin, with GSK3β inhibition mitigating β‐amyloid and tau redundancies at protein and gene levels, facilitating signal transduction. In vivo, DSS impacted key targets in the IRS1/GSK3β/Wnt3a‐β‐catenin pathway, mitigated senile plaques resulting from amyloid β (Aβ) deposition and neurofiber tangles induced by tau hyperphosphorylation, and alleviated the decline in central glucose metabolism observed in FDG‐PET. Conclusions Our findings suggest that DSS potentially confers cognitive protection by alleviating central hypoglycemia through the IRS1/GSK3β/Wnt3a‐β‐catenin pathway. This may serve as a promising therapeutic avenue for AD.

Abstract Background Open reduction and plate internal fixation (ORIF) is one of the most common treatment methods for proximal humeral fractures. Complications associated with the greater tuberosity (GT) are rarely reported, therefore, the purpose of this study was to analyze the complications associated with the GT and the risk factors after locked-plate internal fixation. Methods We retrospectively analyzed the medical and radiographic data of patients with proximal humeral fractures involving the GT treated with locking plates between January 2016 and July 2019. We divided all patients into two groups, the anatomic GT healing group and the nonanatomic GT healing group, depending on the radiographic outcomes of the GT. Clinical outcome was assessed by the Constant scoring system. Potential risk factors included preoperative and intraoperative factors. Preoperative factors included sex, age, body mass index, fracture type, fracture-dislocation, proximal humeral bone mineral density, humeral head extension, hinge integrity, comminuted GT, volume and surface area of the main GT fragment, and displacement of the main GT fragment. Intraoperative factors were adequate medial support, residual head-shaft displacement, head-shaft angle and residual GT displacement. Univariate logistic regression and multivariate logistic regression were used to identify risk factors. Results There were 207 patients (130 women and 77 men; mean age, 55 years). GT anatomic healing was observed in 139 (67.1%) patients and nonanatomic healing in 68 (32.9%). Patients with GT nonanatomic healing had significantly inferior Constant scores than those with GT anatomic healing (75.0 ± 13.9 vs. 83.9 ± 11.8, P

Bone regeneration following trauma, tumor resection, infection, or congenital disease is challenging. Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia. It can result in complications affecting multiple systems including the musculoskeletal system. The increased number of diabetes-related fractures poses a great challenge to clinical specialties, particularly orthopedics and dentistry. Various pathological factors underlying DM may directly impair the process of bone regeneration, leading to delayed or even non-union of fractures. This review summarizes the mechanisms by which DM hampers bone regeneration, including immune abnormalities, inflammation, reactive oxygen species (ROS) accumulation, vascular system damage, insulin/insulin-like growth factor (IGF) deficiency, hyperglycemia, and the production of advanced glycation end products (AGEs). Based on published data, it also summarizes bone repair strategies in diabetic conditions, which include immune regulation, inhibition of inflammation, reduction of oxidative stress, promotion of angiogenesis, restoration of stem cell mobilization, and promotion of osteogenic differentiation, in addition to the challenges and future prospects of such approaches.

Abstract Mitochondrial bioenergetic deficits and their resulting glucose hypometabolism are the key pathophysiological modulators that promote neurodegeneration. However, there are no specific potential molecules that have been identified to treat neurological diseases by regulating energy metabolism and repairing mitochondrial damage. Pyruvate dehydrogenase (PDH) complex (PDC), which can be phosphorylated by pyruvate dehydrogenase kinase (PDK), is the gate‐keeping enzyme for mitochondrial glucose oxidation. In this study, a small‐molecule scutellarin (SG) is discovered that can significantly alleviate the neuropathological changes in hippocampal CA1 of cerebral hypoperfusion model rats, rescued the morphological changes of abnormal mitochondria, and restored mitochondrial homeostasis. Mitochondrial proteomics, energy metabolism monitoring, and 13C‐metabolic flux analysis targeted SG activity on PDK2, thus regulating PDK‐PDC‐mediated glycolytic metabolism to TCA cycle during mitochondrial OXPHOS damage. The knockdown of PDK2 in the SK‐N‐SH cells validated that SG could rescue mitochondrial damage via the PDK‐PDC axis, promote the MMP level and reduce the mitochondria‐dependent apoptosis. Collectively, this study explored the novel therapeutic approach: the PDK‐PDC axis for neurological injury and cognitive impairment and uncovered the effect of SG on mitochondrial protection via the PDK‐PDC axis and mitochondrial glucose oxidation. The findings indicate that active components ameliorating mitochondrial bioenergetic deficits could be of significant value for neurological disease therapy.

ObjectiveThe study aimed to investigate the relationship between Life’s Simple 7 (LS7) and the risk of rheumatoid arthritis (RA) in adult Americans.MethodsA total of 17,532 participants were included in this study. The association between LS7 and the risk of RA was assessed using a weighted logistic regression model, with odds ratios (ORs) and 95% confidence intervals (CIs) calculated. Moreover, the nonlinear relationship was further characterized through smooth curve fitting (SCF) and weighted generalized additive model (GAM) analysis.ResultsAfter adjusting for all covariates, the weighted logistic regression model demonstrated that the LS7 was negatively correlated with the risk of RA. Compared to quintile 1 of LS7, the OR between the risk of RA and quartile 4 of LS7 (LS7.Q4) was 0.261 (95% CI, 0.203, 0.337) in males under 50 years old, while in females of the same age group, the OR was 0.183 (95% CI, 0.142, 0.234). For females aged between 50 and 70 years old, the OR between the risk of RA and LS7.Q4 was 0.313 (95% CI, 0.264, 0.371). In females aged 70 years or older, the OR between the risk of RA and LS7.Q4 was 0.632 (95% CI, 0.486, 0.822).ConclusionThis finding suggested the healthy lifestyle behaviors represented by LS7 have a negative association with RA. However, further prospective studies are needed to verify the causal relationship in the results.

The precise segmentation of tumor regions plays a pivotal role in the diagnosis and treatment of brain tumors. However, due to the variable location, size, and shape of brain tumors, the automatic segmentation of brain tumors is a relatively challenging application. Recently, U-Net related methods, which largely improve the segmentation accuracy of brain tumors, have become the mainstream of this task. Following merits of the 3D U-Net architecture, this work constructs a novel 3D U-Net model called SGEResU-Net to segment brain tumors. SGEResU-Net simultaneously embeds residual blocks and spatial group-wise enhance (SGE) attention blocks into a single 3D U-Net architecture, in which SGE attention blocks are employed to enhance the feature learning of semantic regions and reduce possible noise and interference with almost no extra parameters. Besides, the self-ensemble module is also utilized to improve the segmentation accuracy of brain tumors. Evaluation experiments on the Brain Tumor Segmentation (BraTS) Challenge 2020 and 2021 benchmarks demonstrate the effectiveness of the proposed SGEResU-Net for this medical application. Moreover, it achieves DSC values of 83.31, 91.64 and 86.85%, as well as Hausdorff distances (95%) of 19.278, 5.945 and 7.567 for the enhancing tumor, whole tumor, and tumor core on BraTS 2021 dataset, respectively.

PurposeThe objective of this study was to evaluate the association between thyroid hormone and bone mineral density (BMD) among euthyroid adults.MethodsThis cross-sectional study researched the information from the National Health and Nutrition Examination Survey 2007–2010. We included 3,759 euthyroid participants finally. We used multivariate linear regression models to evaluate the linear relationship between the thyroid hormone profile and BMD. Subgroup analyses stratified by gender and age were further performed. Moreover, the nonlinear relationship was characterized by fitted smoothing curves and generalized additive models, and logistic regression models were used to determine the association of thyroid-stimulating hormone (TSH) and thyroxine (T4) with previous fractures.ResultsThe weighted multivariable linear regression models showed no association between TSH and BMD. Free thyroxine (FT4), T4, free triiodothyronine (FT3), and total triiodothyronine (T3) were negatively associated with the total femur BMD and the total spine BMD after adjusting for all covariates. Subgroup analyses demonstrated that all groups had a negative association between T4 and BMD, even in patients with osteopenia/osteoporosis. The nonlinear relationship characterized by smooth curve fittings and generalized additive models suggested that an obvious U-shaped, an inverted U -shaped, and an L - shaped curve was exhibited between thyroid hormone and BMD in the different subgroups. In addition, normal high-level T4 was associated with an increased prevalence of previous fractures than normal low-level T4.ConclusionsIn this sample of euthyroid adults, T4 exhibits a negative correlation with BMD, regardless of age and gender, in subjects with either normal or lowered BMD. Moreover, high-normal FT4 was associated with an increased prevalence of previous fractures. TSH was not associated with variations of BMD and the fracture risk.

Abstract Azvudine (FNC) is a nucleoside analog that inhibits HIV-1 RNA-dependent RNA polymerase (RdRp). Recently, we discovered FNC an agent against SARS-CoV-2, and have taken it into Phase III trial for COVID-19 patients. FNC monophosphate analog inhibited SARS-CoV-2 and HCoV-OC43 coronavirus with an EC50 between 1.2 and 4.3 μM, depending on viruses or cells, and selective index (SI) in 15–83 range. Oral administration of FNC in rats revealed a substantial thymus-homing feature, with FNC triphosphate (the active form) concentrated in the thymus and peripheral blood mononuclear cells (PBMC). Treating SARS-CoV-2 infected rhesus macaques with FNC (0.07 mg/kg, qd, orally) reduced viral load, recuperated the thymus, improved lymphocyte profiles, alleviated inflammation and organ damage, and lessened ground-glass opacities in chest X-ray. Single-cell sequencing suggested the promotion of thymus function by FNC. A randomized, single-arm clinical trial of FNC on compassionate use (n = 31) showed that oral FNC (5 mg, qd) cured all COVID-19 patients, with 100% viral ribonucleic acid negative conversion in 3.29 ± 2.22 days (range: 1–9 days) and 100% hospital discharge rate in 9.00 ± 4.93 days (range: 2–25 days). The side-effect of FNC is minor and transient dizziness and nausea in 16.12% (5/31) patients. Thus, FNC might cure COVID-19 through its anti-SARS-CoV-2 activity concentrated in the thymus, followed by promoted immunity.

There is an urgent need to elucidate the pathogenesis of myocardial ischemia (MI) and potential drug treatments. Here, the anti-MI mechanism and material basis of Ginkgo biloba L. extract (GBE) were studied from the perspective of energy metabolism flux regulation. Metabolic flux analysis (MFA) was performed to investigate energy metabolism flux disorder and the regulatory nodes of GBE components in isoproterenol (ISO)-induced ischemia-like cardiomyocytes. It showed that [U–13C] glucose derived m+2 isotopologues from the upstream tricarboxylic acid (TCA) cycle metabolites were markedly accumulated in ISO-injured cardiomyocytes, but the opposite was seen for the downstream metabolites, while their total cellular concentrations were increased. This indicates a blockage of carbon flow from glycolysis and enhanced anaplerosis from other carbon sources. A Seahorse test was used to screen for GBE components with regulatory effects on mitochondrial aerobic respiratory dysfunction. It showed that bilobalide protected against impaired mitochondrial aerobic respiration. MFA also showed that bilobalide significantly modulated the TCA cycle flux, reduced abnormal metabolite accumulation, and balanced the demand of different carbon sources. Western blotting and PCR analysis showed that bilobalide decreased the enhanced expression of key metabolic enzymes in injured cells. Bilobalide's efficacy was verified by in vivo experiments in rats. This is the first report to show that bilobalide, the active ingredient of GBE, protects against MI by rescuing impaired TCA cycle flux. This provides a new mechanism and potential drug treatment for MI. It also shows the potential of MFA/Seahorse combination as a powerful strategy for pharmacological research on herbal medicine.

Tumor segmentation using magnetic resonance imaging (MRI) plays a significant role in assisting brain tumor diagnosis and treatment. Recently, U-Net architecture with its variants have become prevalent in the field of brain tumor segmentation. However, the existing U-Net models mainly exploit coarse first-order features for tumor segmentation, and they seldom consider the more powerful second-order statistics of deep features. Therefore, in this work, we aim to explore the effectiveness of second-order statistical features for brain tumor segmentation application, and further propose a novel second-order residual brain tumor segmentation network, i.e., SoResU-Net. SoResU-Net utilizes a number of second-order modules to replace the original skip connection operations, thus augmenting the series of transformation operations and increasing the non-linearity of the segmentation network. Extensive experimental results on the BraTS 2018 and BraTS 2019 datasets demonstrate that SoResU-Net outperforms its baseline, especially on core tumor and enhancing tumor segmentation, illuminating the effectiveness of second-order statistical features for the brain tumor segmentation application.

This paper investigates command filter backstepping fault-tolerant control for a class of nonlinear systems with nonlinear faults. In particular, the system nonlinear faults are non-affine, which are handled by the filtered signal and fuzzy logic systems approximate Lemma. Command filter is used in this paper, which eliminates the “explosion of complexity” of the classical backstepping and compensates the output of the filter to the derivative of the virtual control. In addition, the controller design procedure has been shown in detail, while the stability of the closed-loop system and the convergence of the tracking error are proved via Lyapunov Theorem. Simulation examples are given to illustrate the feasibility and effectiveness of the proposed scheme.

BackgroundThe geriatric nutritional risk index (GNRI) has been used as a significant tool to access the nutritional status of the elderly. However, the relationship between the GNRI and femur bone mineral density (BMD) and the risk of osteoporosis remains unclear in American postmenopausal women.ObjectivesWe aimed to explore associations between the GNRI with femur BMD and the risk of osteoporosis in American postmenopausal women.MethodsWe merged the continuous National Health and Nutrition Examination Survey (NHANES) 2005–2006, 2007–2008, 2009–2010, 2013–2014, and 2017–2018 to ensure a large and representative sample, including 3,152 participants. The linear relationship between the GNRI and femur BMD was assessed via a weighted multivariate linear regression model. The odds ratios (ORs) and 95% confidence intervals (95% CIs) for the association between the GNRI and the risk of osteoporosis were assessed by a weighted logistic regression model. Moreover, the nonlinear relationship was also characterized by smooth curve fitting (SCF) and a weighted generalized additive model (GAM).ResultsAfter adjusting for all covariates, the weighted multivariable linear regression models demonstrated that the GNRI was positively correlated with femur BMD. The weighted logistic regression models demonstrated that each unit of increased GNRI value was associated with a decreased risk of osteoporosis of 4.13%. When categorizing GNRI based on quartiles, ORs between the risk of osteoporosis and the GNRI across quintiles 2, 3, and 4 compared with quintile 1 were 0.5565 (95% CI: 0.4791, 0.6463; P < 0.000001), 0.5580 (95% CI: 0.4600, 0.6769; P < 0.000001), and 0.3475 (95% CI: 0.2681, 0.4505; P < 0.000001). The trends similar to the above were also observed in SCF and GAM.ConclusionThis study indicated that nutritional status, represented by the GNRI, was positively associated with femur BMD and negatively associated with the risk of osteoporosis in American postmenopausal women. The GNRI may be a good tool to identify American postmenopausal women who need further bone health nutritional support.

ObjectivesThe study aimed to explore the associations between dietary magnesium (Mg) intake and magnesium depletion score (MDS) among American adults with osteoporosis.MethodsThe continuous data from the National Health and Nutrition Examination Survey 2005–2006, 2007–2008, 2009–2010, 2013–2014, and 2017–2018 were merged to ensure a large and representative sample and a total of 14,566 participants were enrolled for the analysis. The weighted multivariate linear regression model was performed to assess the linear relationship between dietary Mg intake and osteoporosis. Further, the non-linear relationship was also characterized by smooth curve fitting (SCF) and weighted generalized additive model (GAM). In addition, the odds ratios (ORs) and 95% confidence intervals (95% CIs) for associations between the MDS and osteoporosis were assessed by weighted logistic regression models.ResultsAfter adjusting all covariates, the weighted multivariable linear regression models demonstrated that the dietary Mg intake negatively correlated with osteoporosis, especially in participants aged 55 years or older. In addition, the non-linear relationship characterized by SCF and weighted GAM showed that the dietary Mg intake presented an L-shaped association with osteoporosis among females aged 55 years or older. Moreover, the weighted logistic regression model demonstrated that compared with MDS 0, the OR between MDS ≥3 and osteoporosis was 2.987 (95% CI 1.904, 4.686) in the male-middle intake group. Moreover, compared with MDS 0, the ORs between MDS ≥3 and osteoporosis was 5.666 (95% CI 3.188, 10.069) in the female-low intake group and 1.691 (95% CI 1.394, 2.051) in the female-middle intake group.ConclusionThe present study indicated that in people with a daily intake of Mg level below the recommended daily intake (RDI), the dietary Mg intake and Mg bioavailability represented by MDS have a negative correlation with osteoporosis. According to the results, the combination of MDS and dietary Mg intake may be more comprehensive and rigorous in screening the population with osteoporosis. Therefore, early monitoring and interventions for osteoporosis may be necessary for those with insufficient dietary Mg intake or high MDS scores.

With the rapidly emerging user-generated images, perception compression for color image is an inevitable mission. Whilst in existing just noticeable difference (JND) models, color-oriented features are not fully taken into account for coinciding with HVS perception characteristics, such as sensitivity, attention, and masking. To fully imitate the color perception process, we extract color-related feature parameters as local features, including color edge intensity and color complexity, as well as region-wise features, including color area proportion, color distribution position and color distribution dispersion, and inherent feature irrelevant to color content called color perception difference. Then, the potential interaction among them is analyzed and modeled as color contrast intensity. To utilize them, color uncertainty and color saliency are envisaged to emanate from feature integration in the information communication framework. Finally, color and uncertainty saliency models are applied to improve the conventional JND model, taking the masking and attention effect into consideration. Subjective and objective experiments validate the effectiveness of the proposed model, delivering superior noise concealment capacity compared with start-of-the-art works.

Protein complementation assays (PCA) are used as pharmacological tools, enabling a wide array of applications, ranging from studies of protein–protein interactions to second messenger effects. Methods to detect activities of G protein-coupled receptors (GPCRs) have particular relevance for drug screening. Recent development of an engineered luciferase NanoLuc created the possibility of generating a novel PCA, which in turn could open a new avenue for developing drug screening assays. Here we identified a novel split position for NanoLuc and demonstrated its use in a series of fusion constructs to detect the activity of GPCRs. The split construct can be applied to a variety of pharmacological screening systems.

A main rationale for the role of G protein-coupled receptor (GPCR) heteromers as targets for drug development is the putative ability of selective ligands for specific GPCRs to change their pharmacological properties upon GPCR heteromerization. The present study provides a proof of concept for this rationale by demonstrating that heteromerization of dopamine D1 and D3 receptors (D1R and D3R) influences the pharmacological properties of three structurally similar selective dopamine D3R ligands, the phenylpiperazine derivatives PG01042, PG01037 and VK4-116. By using D1R-D3R heteromer-disrupting peptides, it could be demonstrated that the three D3R ligands display different D1R-D3R heteromer-dependent pharmacological properties: PG01042, acting as G protein-biased agonist, counteracted D1R-mediated signaling in the D1R-D3R heteromer; PG01037, acting as a D3R antagonist cross-antagonized D1R-mediated signaling in the D1R-D3R heteromer; and VK4-116 specifically acted as a ß-arrestin-biased agonist in the D1R-D3R heteromer. Molecular dynamics simulations predicted potential molecular mechanisms mediating these qualitatively different pharmacological properties of the selective D3R ligands that are dependent on D1R-D3R heteromerization. The results of in vitro experiments were paralleled by qualitatively different pharmacological properties of the D3R ligands in vivo. The results supported the involvement of D1R-D3R heteromers in the locomotor activation by D1R agonists in reserpinized mice and L-DOPA-induced dyskinesia in rats, highlighting the D1R-D3R heteromer as a main pharmacological target for L-DOPA-induced dyskinesia in Parkinsons disease. More generally, the present study implies that when suspecting its pathogenetic role, a GPCR heteromer, and not its individual GPCR units, should be considered as main target for drug development.

In the title compound, [Ni(C13H11N2O)(H2O)]NO3·H2O, the Ni(II) ion is coordinated by one O atom and two N atoms of the Schiff base ligand and the O atom from a water molecule, forming a slightly distorted square-planar geometry. A one-dimensional double-chain structure is formed along [001] by O...H—O hydrogen bonds and the Ni...O [2.617 (3) Å] interactions.

The title compound, [Zn(C19H13N3O2)], has been synthesized by the reaction of Zn(ClO4)2·6H2O and the tetradentate Schiff base ligand 2,2′-[pyridine-3,4-diylbis(nitrilomethylidyne)]diphenol (L). The coordination geometry of the ZnII ion is slightly distorted square-planar, formed by two N atoms and two O atoms from the L ligand.

In the title molecule, [Zn(C14H13N2O2)Cl], the Zn(II) ion is coordinated by one O and two N atoms from the Schiff base ligand, and a chloride anion in a distorted square-planar geometry. In the crystal structure, π–π interactions link the approximately planar (mean deviation 0.0569 Å) molecules into stacks parallel to the a axis.

Methamphetamine (METH) is an illicit drug which is neurotoxic to the mammalian brain. Numerous studies have revealed significant decreases in dopamine and serotonin levels in the brains of animals exposed to moderate-to-large METH doses given within short intervals of time. In contrast, repeated injections of small nontoxic doses of the drug followed by a challenge with toxic METH doses afford significant protection against monoamine depletion. The present study was undertaken to test the possibility that repeated injections of the drug might be accompanied by transcriptional changes involved in rendering the nigrostriatal dopaminergic system refractory to METH toxicity. Our results confirm that METH preconditioning can provide significant protection against METH-induced striatal dopamine depletion. In addition, the presence and absence of METH preconditioning were associated with substantial differences in the identity of the genes whose expression was affected by a toxic METH challenge. Quantitative PCR confirmed METH-induced changes in genes of interest and identified additional genes that were differentially impacted by the toxic METH challenge in the presence of METH preconditioning. These genes include small heat shock 27 kD 27 protein 2 (HspB2), thyrotropin-releasing hormone (TRH), brain derived neurotrophic factor (BDNF), c-fos, and some encoding antioxidant proteins including CuZn superoxide dismutase (CuZnSOD), glutathione peroxidase (GPx)-1, and heme oxygenase-1 (Hmox-1). These observations are consistent, in part, with the transcriptional alterations reported in models of lethal ischemic injuries which are preceded by ischemic or pharmacological preconditioning. Our findings suggest that multiple molecular pathways might work in tandem to protect the nigrostriatal dopaminergic pathway against the deleterious effects of the toxic psychostimulant. Further analysis of the molecular and cellular pathways regulated by these genes should help to provide some insight into the neuroadaptive potentials of the brain when repeatedly exposed to drugs of abuse.

In the title complex, [Fe(C19H12BrClN3O2)(C3H7NO)], the FeIII atom is coordinated by an N,N,O,O-tetradentate Schiff base ligand and trans coordinated by a chloride anion and the O atom of an N,N-dimethylformamide molecule. The resulting geometry is distorted octahedral within a ClN2O3 donor set.

Introduction The opioid epidemic represents a severe public health crisis (1). Maintenance treatment with the ^-opioid receptor (MOR) agonist methadone is the most highly researched and evidence-based treatment for opioid [...], Identifying nonaddictive opioid medications is a high priority in medical science, but [mu]-opioid receptors (MORs) mediate both the analgesic and addictive effects of opioids. We found a significant pharmacodynamic difference between morphine and methadone that is determined entirely by heteromerization of MORs with galanin Gal1 receptors (Gal1Rs), rendering a profound decrease in the potency of methadone. This finding was explained by the weaker proficiency of methadone in activating the dopaminergic system as compared with morphine and predicted a dissociation of the therapeutic and euphoric effects of methadone, which was corroborated by a significantly lower incidence of self-reports of feeling "high" in methadone-medicated patients. These results suggest that [mu]-opioid-Gal1R heteromers mediate the dopaminergic effects of opioids. The results further suggest a lower addictive liability of some opioids, such as methadone, due to their selective low potency for the [mu]-opioid-Gal1R heteromer.