Vitamin D and the anti-viral state

Vitamin D has long been recognized as essential to the skeletal system. Newer evidence suggests that it also plays a major role regulating the immune system, perhaps including immune responses to viral infection. Interventional and observational epidemiological studies provide evidence that vitamin D deficiency may confer increased risk of influenza and respiratory tract infection. Vitamin D deficiency is also prevalent among patients with HIV infection. Cell culture experiments support the thesis that vitamin D has direct anti-viral effects particularly against enveloped viruses. Though vitamin D's anti-viral mechanism has not been fully established, it may be linked to vitamin D's ability to up-regulate the anti-microbial peptides LL-37 and human beta defensin 2. Additional studies are necessary to fully elucidate the efficacy and mechanism of vitamin D as an anti-viral agent.     

Structures of D14 and D14L in the strigolactone and karrikin signaling pathways

Strigolactones (SLs) are plant hormones that inhibit shoot branching. DWARF14 (D14) inhibits rice tillering and is an SL receptor candidate in the branching inhibition pathway, whereas the close homologue DWARF14‐LIKE (D14L) participates in the signaling pathway of karrikins (KARs), which are derived from burnt vegetation as smoke stimulants of seed germination. We provide the first evidence for direct binding of the bioactive SL analogue GR24 to D14. Isothermal titration calorimetry measurements show a D14–GR24 binding affinity in the sub‐micromolar range. Similarly, bioactive KAR1 directly binds D14L in the micromolar range. The crystal structure of rice D14 shows a compact α‐/β‐fold hydrolase domain forming a deep ligand‐binding pocket capable of accommodating GR24. Insertion of four α‐helices between β6 strand and αD helix forms the helical cap of the pocket, although the pocket is open to the solvent. The pocket contains the conserved catalytic triad Ser‐His‐Asp aligned with the oxyanion hole, suggesting hydrolase activity. Although these structural characteristics are conserved in D14L, the D14L pocket is smaller than that of D14. The KAR‐insensitive mutation kai2‐1 is located at the prominent long β6‐αD1 loop, which is characteristic in D14 and D14L, but not in related α‐/β‐fold hydrolases.     

Human immunoglobulin D segments: isolation of a new D segment and polymorphic deletion of the D1 segment

We have isolated and identified a new human germline D segment which is not physically linked to the known D cluster. The nucleotide sequence of the new D segment was highly homologous with the known D segments. Frequent polymorphic deletion of the D1 segment was found in the Japanese population. Nucleotide sequences surrounding the deletion indicate that homologous recombination is likely to be responsible for the deletion of the D1 segment.     

Potentiation of the D2 mutant motor phenotype in mice lacking dopamine D2 and D3 receptors.

Within the D2-class of dopamine receptors, the D2 and D3 subtypes share the highest degree of similarity in their primary structure. However, the extent to which these two receptor subtypes have similar or different functional properties is unclear. The present study used gene targeting to generate mice deficient for D2, D3, and D2/D3 receptors. A comparative analysis of D2 and D3 single mutants and D2/D3 double mutants revealed that D2/D3 double mutants develop motor phenotypes that, although qualitatively similar to those seen in D2 single mutants, are significantly more severe. Furthermore, increased levels of the dopamine metabolites dihydroxyphenyl acetic acid and homovanillic acid are found in the dorsal striatum of D2 single mutants. The levels of these metabolites, however, are significantly higher in mice lacking D2 and D3 receptors. In addition, results of immunoprecipitation experiments revealed that D2 single mutants express higher levels of D3 receptor proteins during later stages of their postnatal development. These results suggest that D3 receptors compensate for some of the lacking D2 receptor functions and that these functional properties of D3 receptors, detected in mice with a D2 mutant genetic background, remain masked when the abundant D2 receptor is expressed.     

Autoradiographic localization of D1 and D2 dopamine receptors in the human brain

The distribution of dopamine D1 and D2 receptors in several human brain regions was investigated using autoradiography with the radioligands [3H]SCH 23390 and [3H]spiroperidol. The highest densities of both dopamine receptor types are seen in the nucleus caudatus, putamen and nucleus accumbens. Whereas the density of the D2 receptors is similar in the two segments of the globus pallidus, the pars medialis of the globus pallidus contains a three-fold higher concentration of D1 receptors than the pars lateralis. D1 and D2 receptors are present in the amygdala and substantia nigra. Both receptor types are absent in the cerebellum. The thalamus contains low densities of D1 receptors but no D2 receptors. Only D2 receptors are seen in the anterior lobe of the pituitary gland. The whole cerebral cortex is rich in D1 receptors, while D2 receptors, in low concentrations, are confined to the entorhinal area and cingulate cortex.     

维生素D对骨质疏松的影响及适宜补充量

维生素D缺乏在世界各地普遍存在,受到全球关注.近几年有很多相关文献报道补充足够的维生素D能增强肌力、减少跌倒相关风险以及预防骨质疏松和骨质疏松性骨折的风险,因此如何指导国人补充适量的维生素D以及研究体内维生素D的检测标准具有重要意义.     

Role of D1 and D2 receptors in the regulation of voluntary movements

The effect of dopamine receptor agonist cabergoline on muscle tone and contractility was studied in healthy volunteers. Variations in muscle tone were evaluated by means of transcranial magnetic stimulation under resting conditions. Muscle contractility was estimated from kinematic parameters of voluntary movements. Oral administration of cabergoline in a dose of 2 mg was followed by a decrease in muscle tone and increase in muscle contractility. Our findings indicate that the brain dopaminergic system regulates voluntary movements by decreasing the tone and increasing contractility of skeletal muscles. Under resting conditions, prolonged exposure of D1 receptors to dopamine in a low concentration decreases excitability threshold of the motor cortex and reduces muscle tone. During voluntary movements, short-term stimulation of D2 receptors with dopamine in a high concentration increases excitability of the motor cortex and induces muscle contraction. The movement occurs when D2 receptor-mediated excitation of the cortex and induced muscle contraction exceed the decrease in muscle tone and excitability threshold caused by stimulation of D1 receptors. __________ Translated from Byulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 146, No. 7, pp. 18–21, July, 2008     

Distribution of D1 and D5 dopamine receptors in the primate and rat basolateral amygdala

Dopamine, acting at the D1 family receptors (D1R) is critical for the functioning of the amygdala, including fear conditioning and cue-induced reinstatement of drug self administration. However, little is known about the different contributions of the two D1R subtypes, D₁ and D₅. We identified D₁-immunoreactive patches in the primate that appear similar to the intercalated cell masses reported in the rodent; however, both receptors were present across the subdivisions of the primate amygdala including the basolateral amygdala (BLA). Using immunoelectron microscopy, we established that both receptors have widespread distributions in BLA. The D1R subtypes colocalize in dendritic spines and terminals, with D₁ predominant in spines and D₅ in terminals. Single-cell RT-PCR confirmed that individual BLA projection neurons express both D₁ and D₅ mRNA. The responses of primate BLA neurons to dopamine and D1R drugs were studied using in vitro slices. We found that responses were similar to those previously reported in rat BLA neurons and included a mixture of postsynaptic and presynaptic actions. We investigated the distribution of D1R in the rat BLA and found that there were similarities between the species, such as more prominent D₅ localization to presynaptic structures. The higher affinity of D₅ for dopamine suggests that presynaptic actions may predominate in the BLA at low levels of dopamine, while postsynaptic effects increase and dominate as dopaminergic drive increases. The results presented here suggest a complex action of dopamine on BLA circuitry that may evolve with different degrees of dopaminergic stimulation.     

Kinematics of the wrist using 2D and 3D analysis: biomechanical and clinical deductions

Surgery of the wrist relies on the known notions of biomechanics of the wrist. But these notions are incomplete. For a better understanding of the movements of the wrist, we studied five wrists of healthy volunteers with CT scanning. Each wrist was studied in neutral position, and in the four extreme positions: flexion, extension, radial and ulnar deviations. Using oblique reformatted CT sections, we measured the angular displacements in frontal and sagittal views of every carpal bone in the different positions of the wrist. This allowed us to construct a table of intracarpal mobility. By comparing the angle values and the three-dimensional pictures of these wrists, we illustrate some fundamental points regarding intracarpal movement. The dynamics of the wrist are like those of two superimposed mobile cups with different movements. The proximal row is malleable with flattening and torsion according to the transverse axis and its behavior is like that of an articular meniscus. The distal row, more rigid but deformable, behaves like a T-handle giving attachment to the hand and articulating under the proximal row around the head of the capitate and the proximal pole of the hamate. During radial and ulnar deviations of the wrist, the movement between the two rows is like an inverse pronation-supination shearing. During flexion-extension, the distortion of the two rows allows maximal congruence to be maintained between the different carpal bones.     

D2 and D4 dopamine receptor polymorphisms and personality

The relationship of various dimensions of temperament, measured by the Tridimensional Personality Questionnaire (TPQ), to polymorphisms of the D₂ dopamine receptor (DRD2) and D₄ dopamine receptor (DRD4) genes was determined in 119 healthy Caucasian boys who had not yet begun to consume alcohol and other drugs of abuse. Total Novelty Seeking score of the TPQ was significantly higher in boys having, in common, all three minor (A1,B1, and Intron 6 1) alleles of the DRD2 compared to boys without any of these alleles. Boys with the DRD4 7 repeat (7R) allele also had a significantly higher Novelty Seeking score than those without this allele. However, the greatest difference in Novelty Seeking score was found when boys having all three minor DRD2 alleles and the DRD4 7R allele were contrasted to those without any of these alleles. Neither the DRD2 nor the DRD4 polymorphisms differentiated total Harm Avoidance score. Whereas subjects having all three minor DRD2 alleles had a significantly higher Reward Dependence 2 (Persistence) score than subjects without any of these alleles, no significant difference in this personality score was found between subjects with and without the DRD4 7R allele. In conclusion, DRD2 and DRD4 polymorphisms individually associate with Novelty Seeking behavior. However, the combined DRD2 and DRD4 polymorphisms contribute more markedly to this behavior than when these two gene polymorphisms are individually considered. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 81:257–267, 1998. © 1998 Wiley-Liss, Inc.     

Interaction between dopamine D1 and D2 receptors in modulation of the immune response

The interaction between dopamine D₁ and D₂ receptors plays a role in immunomodulation. The results of thus interaction depends on the degree of receptor activation with selective agonists in different doses. Combined treatment with agonists of D₁ and D₂ receptors in high doses had a synergistic effect in the mechanisms of immunomodulation. Receptor agonists in low doses suppressed the immune response. Our results suggest that weak activation of one of these receptors is accompanied by inactivation of the other receptor type. __________ Translated from Byulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 141, No. 5, pp. 488–490, May, 2006     

Behavioral interactions between muscimol and compounds selective for the D1 and D2 dopamine receptor subtypes

The present study investigated the effects of the GABA agonist muscimol on the behaviors produced by acute injections of selective D1 and D2 agonists and antagonists. Muscimol potentiated the intensity of stereotyped behaviors shown by rats treated with the D2 agonist quinpirole; in contrast, it suppressed the repetitive bouts of grooming shown by rats treated with SKF38393. Muscimol potentiated the catalepsy produced by either a D1 (SCH23390) or D2 (metoclopramide) antagonist, suggesting that the cataleptic behaviors produced by these compounds may contain a common GABAergic mechanism.     

No Association Between Polymorphisms in the Human Dopamine D3 and D4 Receptors Genes and Alcoholism

The human dopamine D₂ receptor gene (DRD₂) has received considerable attention for the past several years as a potential candidate that may affect susceptibility to alcoholism. The association studies that compared the frequencies of alleles of DRD₂ gene between alcoholics and control groups have produced equivocal results. Dopamine D₃ and D₄ receptor genes (DRD₃ and DRD₄) are in the same class as DRD₂ but with different pharmacological properties. We have used relative risk and haplotype relative risk approaches to test associations between alleles of DRD₃ and DRD₄ genes and alcoholism. For relative risk studies 162 probands from multiple incidence alcoholic families have been compared to 89 psychiatrically normal controls. Haplotype relative risk approaches have used 29 alcoholic probands in which both parents were available for genotyping. The Bal I restriction enzyme site in DRD₃ and tandem repeat (VNTR) in DRD₄ genes polymorphisms were used to genotype the above samples. The results of relative risk approaches for both DRD₃ and DRD₄ genes were negative for comparisons of alcoholics and subtypes of alcoholics with normal controls. Haplotype relative risk approaches also were negative for both genes. These results suggest that any role played by these receptors may account for only part of the variation in susceptibility to alcoholism. Am. J. Med. Genet. 74:281–285, 1997. © 1997 Wiley-Liss, Inc.     

Dopamine D1 and D2 receptor agents and their interaction influence the synaptic density of the rat prefrontal cortex

The transfection efficiency of a disulfide-containing cationic lipid, 1',2' dioleoyl-sn-glycero-3'-succinyl-2-hydroxyethyl disulfide ornithine conjugate (DOGSDSO) and its non-disulfide analog (DOGSHDO) were compared in neuronal, astroglial and microglial cultures from newborn rat cerebral cortex. We hypothesized that the relatively high intracellular concentrations of reductive substances in the cytoplasm may help to cleave the reversible disulfide bond in DOGSDSO, thus increasing free DNA and decreasing toxicity due to rapid degradation of the lipid. We have demonstrated through mass spectrometric analysis that a reductive compound, e.g. dithiothreitol (DTT) could degrade the disulfide lipid. DOGSDSO was more efficient at transfecting each type of brain cell than were the non-disulfide DOGSHDO and DOTAP (1,2-dioleoyl-3-trimethyl-ammonium-propane) liposomes. These results demonstrate that disulfide-containing cationic liposomes facilitate gene transfection in cultured rat brain cells.     

Inflammation and vitamin D: the infection connection

Introduction

Inflammation is believed to be a contributing factor to many chronic diseases. The influence of vitamin D deficiency on inflammation is being explored but studies have not demonstrated a causative effect.

Methods

Low serum 25(OH)D is also found in healthy persons exposed to adequate sunlight. Despite increased vitamin D supplementation inflammatory diseases are increasing. The current method of determining vitamin D status may be at fault. The level of 25(OH)D does not always reflect the level of 1,25(OH)2D. Assessment of both metabolites often reveals elevated 1,25(OH)2D, indicating abnormal vitamin D endocrine function.

Findings

This article reviews vitamin D's influence on the immune system, examines the myths regarding vitamin D photosynthesis, discusses ways to accurately assess vitamin D status, describes the risks of supplementation, explains the effect of persistent infection on vitamin D metabolism and presents a novel immunotherapy which provides evidence of an infection connection to inflammation.

Conclusion

Some authorities now believe that low 25(OH)D is a consequence of chronic inflammation rather than the cause. Research points to a bacterial etiology pathogenesis for an inflammatory disease process which results in high 1,25(OH)2D and low 25(OH)D. Immunotherapy, directed at eradicating persistent intracellular pathogens, corrects dysregulated vitamin D metabolism and resolves inflammatory symptoms.     

Vitamin D,the immune system and asthma

The effects of vitamin-D on bone metabolism and calcium homeostasis have long been recognized. Emerging evidence has implicated vitamin-D as a critical regulator of immunity, playing a role in both the innate and cell-mediated immune systems. Vitamin-D deficiency has been found to be associated with several immune-mediated diseases, susceptibility to infection and cancer. Recently, there has been increasing interest in the possible link between vitamin-D and asthma. Further elucidation of the role of vitamin-D in lung development and immune system function may hold profound implications for the prevention and treatment of asthma.