Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Osteoporosis is a common health problem. The endocannabinoid pathway has been implicated as an important regulator of bone turnover. Rimonabant is a potent cannabinoid receptor1 (CB1) receptor antagonist with wide therapeutic use as an antiobesity drug that has been withdrawn due to side effects in the form of depression and suicidal attacks. This study investigated whether glucocorticoid induced bone loss is linked to CB1 signaling and whether modulation of CB1 function affects the deleterious effects of glucocorticoid treatment on bone remodeling in rats. Sixty four rats were divided into two main groups: group 1 (G1) consisted of 12-14 month old rats and group 2 (G2) consisted of 3-4 month old rats. Each main group subdivided into four subgroups as follows: (NC1) and (NC2), the negative control groups, (MP1) and (MP2), received methylprednisolone (glucocorticoid), (RIM1) and (RIM2), received rimonabant, (MP + RIM1) and (MP + RIM2) received methylprednisolone with rimonabant. There was a significant decrease in bone mineral density (BMD) and bone mineral content (BMC) of the tibia bones together with a decrease in osteoprotegrin (OPG) expression but with a significant increase in receptor activator of nuclear factor kappa B ligand (RANKL) expression in osteoporotic rats. These parameters were reversed with co-administration of rimonabant with methylprednisolone in young rats, though it increased the severity of osteoporosis in older rats. Image analysis technique revealed that there was a significant improvement in cortical bone thickness (CBT) and mean trabecular bone density (TBD) in young group only after rimonabant either alone or with glucocorticoid. CB1 receptors play age related different roles in bone turnover. So, CB1 antagonist can be used to prevent corticosteroid induced osteoporosis in young age but should be avoided in old age.
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PMID:Effect of cannabinoid receptors 1 modulation on osteoporosis in a rat model of different ages. 2537 28

Piccolo and Bassoon are the two largest cytomatrix of the active zone (CAZ) proteins involved in scaffolding and regulating neurotransmitter release at presynaptic active zones (AZs), but have long been discussed as being functionally redundant. We employed genetic manipulation to bring forth and segregate the role of Piccolo from that of Bassoon at central auditory synapses of the cochlear nucleus-the endbulbs of Held. These synapses specialize in high frequency synaptic transmission, ideally poised to reveal even subtle deficits in the regulation of neurotransmitter release upon molecular perturbation. Combining semi-quantitative immunohistochemistry, electron microscopy, and in vitro and in vivo electrophysiology we first studied signal transmission in Piccolo-deficient mice. Our analysis was not confounded by a cochlear deficit, as a short isoform of Piccolo ("Piccolino") present at the upstream ribbon synapses of cochlear inner hair cells (IHC), is unaffected by the mutation. Disruption of Piccolo increased the abundance of Bassoon at the AZs of endbulbs, while that of RIM1 was reduced and other CAZ proteins remained unaltered. Presynaptic fiber stimulation revealed smaller amplitude of the evoked excitatory postsynaptic currents (eEPSC), while eEPSC kinetics as well as miniature EPSCs (mEPSCs) remained unchanged. Cumulative analysis of eEPSC trains indicated that the reduced eEPSC amplitude of Piccolo-deficient endbulb synapses is primarily due to a reduced readily releasable pool (RRP) of synaptic vesicles (SV), as was corroborated by a reduction of vesicles at the AZ found on an ultrastructural level. Release probability seemed largely unaltered. Recovery from short-term depression was slowed. We then performed a physiological analysis of endbulb synapses from mice which, in addition to Piccolo deficiency, lacked one functional allele of the Bassoon gene. Analysis of the double-mutant endbulbs revealed an increase in release probability, while the synapses still exhibited the reduced RRP, and the impairment in SV replenishment was exacerbated. We propose additive roles of Piccolo and Bassoon in SV replenishment which in turn influences the organization and size of the RRP, and an additional role of Bassoon in regulation of release probability.
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PMID:Piccolo Promotes Vesicle Replenishment at a Fast Central Auditory Synapse. 2911 9

The organization of proteins in the apposed nanodomains of pre- and postsynaptic compartments is thought to play a pivotal role in synaptic strength and plasticity. As such, the alignment between pre- and postsynaptic proteins may regulate, for example, the rate of presynaptic release or the strength of postsynaptic signaling. However, the analysis of these structures has mainly been restricted to subsets of synapses, providing a limited view of the diversity of synaptic protein cluster remodeling during synaptic plasticity. To characterize changes in the organization of synaptic nanodomains during synaptic plasticity over a large population of synapses, we combined STimulated Emission Depletion (STED) nanoscopy with a Python-based statistical object distance analysis (pySODA), in dissociated cultured hippocampal circuits exposed to treatments driving different forms of synaptic plasticity. The nanoscale organization, characterized in terms of coupling properties, of presynaptic (Bassoon, RIM1/2) and postsynaptic (PSD95, Homer1c) scaffold proteins was differently altered in response to plasticity-inducing stimuli. For the Bassoon - PSD95 pair, treatments driving synaptic potentiation caused an increase in their coupling probability, whereas a stimulus driving synaptic depression had an opposite effect. To enrich the characterization of the synaptic cluster remodeling at the population level, we applied unsupervised machine learning approaches to include selected morphological features into a multidimensional analysis. This combined analysis revealed a large diversity of synaptic protein cluster subtypes exhibiting differential activity-dependent remodeling, yet with common features depending on the expected direction of plasticity. The expanded palette of synaptic features revealed by our unbiased approach should provide a basis to further explore the widely diverse molecular mechanisms of synaptic plasticity.
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PMID:Activity-Dependent Remodeling of Synaptic Protein Organization Revealed by High Throughput Analysis of STED Nanoscopy Images. 3317 94