RESUMO
Drynariae Rhizoma has great significance in the clinical practice of osteoporosis treatment. Based on the perspective of integrative pharmacology, the study explored the mechanism of action of Drynariae Rhizoma in the treatment of osteoporosis. Six active components in Drynariae Rhizoma were obtained, mainly including glycosides and sterols. Taking the median of 2 times of "node connectivity" as the card value, the core node of the Chinese medicine target disease gene interaction network was selected. Based on this, three topological structural eigenvalues, such as "node connectivity" "node tightness" and "node connectivity" were calculated, thereby screening out four core targets of Drynariae Rhizoma treatment for osteoporosis, including thyroid parathyroid hormone 1 receptor (PTH1R), parathyroid hormone 2 receptor (PTH2R), calcitonin receptor gene (CALCR), and SPTBN1 gene (SPTBN1). Based on the gene ontology database GO and KEGG pathway database, the molecular function, intracellular localization, and biological reactions and pathways of proteins encoded by drug target genes were determined. Combined with enrichment calculation, it is predicted that osteoporosis may play a role in biosynthetic processes, such as circulatory system, nervous system, energy metabolism, prolactin signal pathway, GnRH signaling pathway, neurotrophic factor signaling pathway and other pathway. The conclusion of this study is certain with the existing research results, and the new target and new pathway could also be used as a theoretical basis for the further verification of osteoporosis.
Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Osteoporose/tratamento farmacológico , Polypodiaceae/química , Humanos , Receptor Tipo 1 de Hormônio Paratireóideo/metabolismo , Receptor Tipo 2 de Hormônio Paratireóideo/metabolismo , Receptores da Calcitonina/metabolismo , Rizoma/química , Espectrina/metabolismoRESUMO
Nociceptive information is modulated by a large number of endogenous signaling agents that change over the course of recovery from injury. This plasticity makes understanding regulatory mechanisms involved in descending inhibition of pain scientifically and clinically important. Neurons that synthesize the neuropeptide TIP39 project to many areas that modulate nociceptive information. These areas are enriched in its receptor, the parathyroid hormone 2 receptor (PTH2R). We previously found that TIP39 affects several acute nociceptive responses, leading us to now investigate its potential role in chronic pain. Following nerve injury, both PTH2R and TIP39 knockout mice developed less tactile and thermal hypersensitivity than controls and returned to baseline sensory thresholds faster. Effects of hindpaw inflammatory injury were similarly decreased in knockout mice. Blockade of α-2 adrenergic receptors increased the tactile and thermal sensitivity of apparently recovered knockout mice, returning it to levels of neuropathic controls. Mice with locus coeruleus (LC) area injection of lentivirus encoding a secreted PTH2R antagonist had a rapid, α-2 reversible, apparent recovery from neuropathic injury similar to the knockout mice. Ablation of LC area glutamatergic neurons led to local PTH2R-ir loss, and barley lectin was transferred from local glutamatergic neurons to GABA interneurons that surround the LC. These results suggest that TIP39 signaling modulates sensory thresholds via effects on glutamatergic transmission to brainstem GABAergic interneurons that innervate noradrenergic neurons. TIP39's normal role may be to inhibit release of hypoalgesic amounts of norepinephrine during chronic pain. The neuropeptide may help maintain central sensitization, which could serve to enhance guarding behavior.
Assuntos
Inflamação/fisiopatologia , Neuralgia/fisiopatologia , Neuropeptídeos/fisiologia , Receptor Tipo 2 de Hormônio Paratireóideo/fisiologia , Animais , Feminino , Neurônios GABAérgicos/metabolismo , Transportador de Glucose Tipo 2/genética , Transportador de Glucose Tipo 2/metabolismo , Ácido Glutâmico/metabolismo , Membro Posterior/patologia , Membro Posterior/fisiopatologia , Hiperalgesia/genética , Hiperalgesia/fisiopatologia , Inflamação/genética , Locus Cerúleo/citologia , Locus Cerúleo/metabolismo , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Neuralgia/genética , Neurônios/metabolismo , Neuropeptídeos/genética , Neuropeptídeos/metabolismo , Medição da Dor , Receptor Tipo 2 de Hormônio Paratireóideo/genética , Receptor Tipo 2 de Hormônio Paratireóideo/metabolismo , Receptores Adrenérgicos alfa 2/genética , Receptores Adrenérgicos alfa 2/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/fisiologiaRESUMO
This study reports the distribution of parathyroid hormone 2 receptor (PTH2R)-immunoreactive fibers in the hypothalamus using fluorescent amplification immunocytochemistry. The pattern of immunolabeling is strikingly similar to that of tuberoinfundibular peptide of 39 residues (TIP39), a peptide recently purified from bovine hypothalamus and proposed to be a ligand of the PTH2R based on pharmacological data. To investigate the anatomical basis of suggestions that TIP39 affects the secretion of several hypophysiotropic hormones we performed double-labeling studies and found that only somatostatin fibers contain PTH2R in the median eminence, which suggests that somatostatin release could be directly regulated via the PTH2R. However, several hypothalamic nuclei projecting to the median eminence contain a high density of both TIP39 and PTH2R fibers and terminals. We report here, that the PTH2R terminals also contain vesicular glutamate transporter-2, and suggest that TIP39 terminals are ideally positioned to modulate glutamatergic influences on hypophysiotropic neurons.