INTEDE: interactome of drug-metabolizing enzymes.

Drug-metabolizing enzymes (DMEs) are critical determinant of drug safety and efficacy, and the interactome of DMEs has attracted extensive attention. There are 3 major interaction types in an interactome: microbiome-DME interaction (MICBIO), xenobiotics-DME interaction (XEOTIC) and host protein-DME interaction (HOSPPI). The interaction data of each type are essential for drug metabolism, and the collective consideration of multiple types has implication for the future practice of precision medicine. However, no database was designed to systematically provide the data of all types of DME interactions. Here, a database of the Interactome of Drug-Metabolizing Enzymes (INTEDE) was therefore constructed to offer these interaction data. First, 1047 unique DMEs (448 host and 599 microbial) were confirmed, for the first time, using their metabolizing drugs. Second, for these newly confirmed DMEs, all types of their interactions (3359 MICBIOs between 225 microbial species and 185 DMEs; 47 778 XEOTICs between 4150 xenobiotics and 501 DMEs; 7849 HOSPPIs between 565 human proteins and 566 DMEs) were comprehensively collected and then provided, which enabled the crosstalk analysis among multiple types. Because of the huge amount of accumulated data, the INTEDE made it possible to generalize key features for revealing disease etiology and optimizing clinical treatment. INTEDE is freely accessible at: https://idrblab.org/intede/.

VARIDT 1.0: variability of drug transporter database.

The absorption, distribution and excretion of drugs are largely determined by their transporters (DTs), the variability of which has thus attracted considerable attention. There are three aspects of variability: epigenetic regulation and genetic polymorphism, species/tissue/disease-specific DT abundances, and exogenous factors modulating DT activity. The variability data of each aspect are essential for clinical study, and a collective consideration among multiple aspects becomes crucial in precision medicine. However, no database is constructed to provide the comprehensive data of all aspects of DT variability. Herein, the Variability of Drug Transporter Database (VARIDT) was introduced to provide such data. First, 177 and 146 DTs were confirmed, for the first time, by the transporting drugs approved and in clinical/preclinical, respectively. Second, for the confirmed DTs, VARIDT comprehensively collected all aspects of their variability (23 947 DNA methylations, 7317 noncoding RNA/histone regulations, 1278 genetic polymorphisms, differential abundance profiles of 257 DTs in 21 781 patients/healthy individuals, expression of 245 DTs in 67 tissues of human/model organism, 1225 exogenous factors altering the activity of 148 DTs), which allowed mutual connection between any aspects. Due to huge amount of accumulated data, VARIDT made it possible to generalize characteristics to reveal disease etiology and optimize clinical treatment, and is freely accessible at: https://db.idrblab.org/varidt/ and http://varidt.idrblab.net/.

Coexpression of delta- and mu-opioid receptors in nociceptive sensory neurons.

Morphine-induced analgesia and antinociceptive tolerance are known to be modulated by interaction between delta-opioid receptors (DORs) and mu-opioid receptors (MORs) in the pain pathway. However, evidence for expression of DORs in nociceptive small-diameter neurons in dorsal root ganglia (DRG) and for coexistence of DORs with MORs and neuropeptides has recently been challenged. We now report, using in situ hybridization, single-cell PCR, and immunostaining, that DORs are widely expressed not only in large DRG neurons but in small ones and coexist with MORs in peptidergic small DRG neurons, with protachykinin-dependent localization in large dense-core vesicles. Importantly, both DOR and MOR agonists reduce depolarization-induced Ca(2+) currents in single small DRG neurons and inhibit afferent C-fiber synaptic transmission in the dorsal spinal cord. Thus, coexistence of DORs and MORs in small DRG neurons is a basis for direct interaction of opioid receptors in modulation of nociceptive afferent transmission and opioid analgesia.

Identification of the key target profiles underlying the drugs of narrow therapeutic index for treating cancer and cardiovascular disease.

An appropriate therapeutic index is crucial for drug discovery and development since narrow therapeutic index (NTI) drugs with slight dosage variation may induce severe adverse drug reactions or potential treatment failure. To date, the shared characteristics underlying the targets of NTI drugs have been explored by several studies, which have been applied to identify potential drug targets. However, the association between the drug therapeutic index and the related disease has not been dissected, which is important for revealing the NTI drug mechanism and optimizing drug design. Therefore, in this study, two classes of disease (cancers and cardiovascular disorders) with the largest number of NTI drugs were selected, and the target property of the corresponding NTI drugs was analyzed. By calculating the biological system profiles and human protein-protein interaction (PPI) network properties of drug targets and adopting an AI-based algorithm, differentiated features between two diseases were discovered to reveal the distinct underlying mechanisms of NTI drugs in different diseases. Consequently, ten shared features and four unique features were identified for both diseases to distinguish NTI from NNTI drug targets. These computational discoveries, as well as the newly found features, suggest that in the clinical study of avoiding narrow therapeutic index in those diseases, the ability of target to be a hub and the efficiency of target signaling in the human PPI network should be considered, and it could thus provide novel guidance in the drug discovery and clinical research process and help to estimate the drug safety of cancer and cardiovascular disease.

Fibroblast growth factor 7 is a nociceptive modulator secreted via large dense-core vesicles.

Fibroblast growth factor (FGF) 7, a member of FGF family, is initially found to be secreted from mesenchymal cells to repair epithelial tissues. However, its functions in the nervous system are largely unknown. The present study showed that FGF7 was a neuromodulator localized in the large dense-core vesicles (LDCVs) in nociceptive neurons. FGF7 was mainly expressed in small-diameter neurons of the dorsal root ganglion and could be transported to the dorsal spinal cord. Interestingly, FGF7 was mostly stored in LDCVs that did not contain neuropeptide substance P. Electrophysiological recordings in the spinal cord slice showed that buffer-applied FGF7 increased the amplitude of excitatory post-synaptic current evoked by stimulating the sensory afferent fibers. Behavior tests showed that intrathecally applied FGF7 potentiated the formalin-induced acute nociceptive response. Moreover, both acute and inflammatory nociceptive responses were significantly reduced in Fgf7-deficient mice. These results suggest that FGF7 exerts an excitatory modulation of nociceptive afferent transmission.

Peripheral nerve injury induces trans-synaptic modification of channels, receptors and signal pathways in rat dorsal spinal cord.

Peripheral tissue injury-induced central sensitization may result from the altered biochemical properties of spinal dorsal horn. However, peripheral nerve injury-induced modification of genes in the dorsal horn remains largely unknown. Here we identified strong changes of 14 channels, 25 receptors and 42 signal transduction related molecules in Sprague-Dawley rat dorsal spinal cord 14 days after peripheral axotomy by cDNA microarray. Twenty-nine genes were further confirmed by semiquantitative RT-PCR, Northern blotting, in situ hybridization and immunohistochemistry. These regulated genes included Ca2+ channel alpha1E and alpha2/delta1 subunits, alpha subunits for Na+ channel 1 and 6, Na+ channel beta subunit, AMAP receptor GluR3 and 4, GABAA receptor alpha5 subunit, nicotinic acetylcholine receptor alpha5 and beta2 subunits, PKC alpha, betaI and delta isozymes, JNK1-3, ERK2-3, p38 MAPK and BatK and Lyn tyrosine-protein kinases, indicating that several signal transduction pathways were activated in dorsal spinal cord by peripheral nerve injury. These results demonstrate that peripheral nerve injury causes phenotypic changes in spinal dorsal horn. Increases in Ca2+ channel alpha2/delta1 subunit, GABAA receptor alpha5 subunit, Na+ channels and nicotinic acetylcholine receptors in both dorsal spinal cord and dorsal root ganglia indicate their potential roles in neuropathic pain control.