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Biomedicine & Pharmacotherapy =... Aug 2023Male infertility is a worldwide problem but few treatments, especially irradiation-induced testicular injury. The aim of this research was to investigate novel drugs for...
Novel treatment and insight for irradiation-induced injuries: Dibucaine ameliorates irradiation-induced testicular injury by inhibiting fatty acid oxidation in primary Leydig cells.
BACKGROUND
Male infertility is a worldwide problem but few treatments, especially irradiation-induced testicular injury. The aim of this research was to investigate novel drugs for the treatment of irradiation-induced testicular injury.
METHODS
We administered dibucaine (0.8 mg/kg) intraperitoneally to male mice (6 mice per group) after five consecutive daily 0.5 Gy whole-body irradiation, and evaluated its ameliorating efficacy by testicular HE staining and morphological measurements. Drug affinity responsive target stability assay (Darts) were used to find target protein and pathway; mouse primary Leydig cells were isolated and to explore the mechanism (Flow cytometry, Western blot, and Seahorse palmitate oxidative stress assays); finally rescue experiments were completed by combining dibucaine with fatty acid oxidative pathway inhibitors and activators.
RESULTS
The testicular HE staining and morphological measurements in dibucaine treatment group was significantly better than that in irradiation group (P < 0.05); sperm motility and mRNA levels of spermatogenic cell markers were also higher than those in the latter (P < 0.05). Darts and Western blot results showed that dibucaine targets CPT1A and downregulate fatty acid oxidation. Flow cytometry, Western blot, and Palmitate oxidative stress assays of primary Leydig cells demonstrated that dibucaine inhibits fatty acid oxidation in Leydig cells. Dibucaine combined with etomoxir/baicalin confirmed that its inhibition of fatty acid oxidation was beneficial in ameliorating irradiation-induced testicular injury.
CONCLUSIONS
In conclusion, our data suggest that dibucaine ameliorates irradiation-induced testicular injury in mice by inhibiting fatty acid oxidation in Leydig cells. This will provide novel ideas for the treatment of irradiation-induced testicular injury.
Topics: Humans; Male; Mice; Animals; Leydig Cells; Dibucaine; Sperm Motility; Testis; Testicular Diseases; Fatty Acids; Palmitates
PubMed: 37224756
DOI: 10.1016/j.biopha.2023.114903 -
Contact Dermatitis Mar 2022The literature on systemic allergic dermatitis (SAD; also known as systemic contact dermatitis) is reviewed. Both topical drugs (from absorption through mucosae or skin)... (Review)
Review
The literature on systemic allergic dermatitis (SAD; also known as systemic contact dermatitis) is reviewed. Both topical drugs (from absorption through mucosae or skin) and systemic drugs (oral, parenteral, rectal) may be responsible for the disorder. The topical route appears to be rare with 41 culprit topical drugs found to cause SAD in 95 patients. Most reactions are caused by budesonide (especially from inhalation), bufexamac, and dibucaine. SAD from systemic drugs is infrequent with 95 culprit drugs found to cause SAD in 240 patients. The drugs most frequently implicated are mitomycin C, methylprednisolone (salt, ester), and hydrocortisone (salt). The largest group of culprit drugs consisted of corticosteroids (19%), being responsible for >30% of the reactions, of which nearly 40% were not caused by therapeutic drugs, but by drug provocation tests. The most frequent manifestations of SAD from drugs are eczematous eruptions (scattered, widespread, generalized, worsening, reactivation), maculopapular eruptions, symmetrical drug-related intertriginous and flexural exanthema (SDRIFE [baboon syndrome]) and widespread erythema or erythroderma. Therapeutic systemic drugs hardly ever cause reactivation of previously positive patch tests and infrequently of previous allergic contact dermatitis. The pathophysiology of SAD has received very little attention. Explanations for the rarity of SAD are suggested.
Topics: Dermatitis, Allergic Contact; Drug Eruptions; Drug-Related Side Effects and Adverse Reactions; Humans; Skin Tests
PubMed: 34837391
DOI: 10.1111/cod.14016 -
MBio Apr 2023The intracellular membrane domain (IMD) is a laterally discrete region of the mycobacterial plasma membrane, enriched in the subpolar region of the rod-shaped cell....
The intracellular membrane domain (IMD) is a laterally discrete region of the mycobacterial plasma membrane, enriched in the subpolar region of the rod-shaped cell. Here, we report genome-wide transposon sequencing to discover the controllers of membrane compartmentalization in Mycobacterium smegmatis. The putative gene showed the most significant effect on recovery from membrane compartment disruption by dibucaine. Enzymatic analysis of Cfa and lipidomic analysis of a deletion mutant (Δ) demonstrated that Cfa is an essential methyltransferase for the synthesis of major membrane phospholipids containing a C monomethyl-branched stearic acid, also known as tuberculostearic acid (TBSA). TBSA has been intensively studied due to its abundant and genus-specific production in mycobacteria, but its biosynthetic enzymes had remained elusive. Cfa catalyzed the -adenosyl-l-methionine-dependent methyltransferase reaction using oleic acid-containing lipid as a substrate, and Δ accumulated C oleic acid, suggesting that Cfa commits oleic acid to TBSA biosynthesis, likely contributing directly to lateral membrane partitioning. Consistent with this model, Δ displayed delayed restoration of subpolar IMD and delayed outgrowth after bacteriostatic dibucaine treatment. These results reveal the physiological significance of TBSA in controlling lateral membrane partitioning in mycobacteria. As its common name implies, tuberculostearic acid is an abundant and genus-specific branched-chain fatty acid in mycobacterial membranes. This fatty acid, 10-methyl octadecanoic acid, has been an intense focus of research, particularly as a diagnostic marker for tuberculosis. It was discovered in 1934, and yet the enzymes that mediate the biosynthesis of this fatty acid and the functions of this unusual fatty acid in cells have remained elusive. Through a genome-wide transposon sequencing screen, enzyme assay, and global lipidomic analysis, we show that Cfa is the long-sought enzyme that is specifically involved in the first step of generating tuberculostearic acid. By characterizing a deletion mutant, we further demonstrate that tuberculostearic acid actively regulates lateral membrane heterogeneity in mycobacteria. These findings indicate the role of branched fatty acids in controlling the functions of the plasma membrane, a critical barrier for the pathogen to survive in its human host.
Topics: Humans; Dibucaine; Mycobacterium; Stearic Acids; Fatty Acids; Oleic Acid; Methyltransferases
PubMed: 36976029
DOI: 10.1128/mbio.03396-22 -
Pain Practice : the Official Journal of... Feb 2024Over-the-counter (OTC) local anesthetics have historically been used to alleviate pain in several common conditions including toothache and sore throat. With a rise in... (Review)
Review
Over-the-counter (OTC) local anesthetics have historically been used to alleviate pain in several common conditions including toothache and sore throat. With a rise in chronic conditions and an aging population, there has been an increase in associated chronic pain-related disorders. Individuals with chronic pain often seek OTC treatments for quick and accessible pain relief. There are several common OTC local anesthetics, including benzocaine, lidocaine, and dibucaine, which are readily available to patients in several formulations. In order to appropriately advise patients on the use of local anesthetics, it is important to understand their key characteristics, including the mechanism of action, clinical properties, pharmacokinetics, clinical applications, and adverse reactions, which may occur.
Topics: Humans; Aged; Anesthetics, Local; Chronic Pain; Lidocaine; Benzocaine; Dibucaine; Anesthetics
PubMed: 37750534
DOI: 10.1111/papr.13298 -
Acta Pharmacologica Sinica Jan 2024Recent evidence shows a close link between Parkinson's disease (PD) and cardiac dysfunction with limited treatment options. Mitophagy plays a crucial role in the control...
Recent evidence shows a close link between Parkinson's disease (PD) and cardiac dysfunction with limited treatment options. Mitophagy plays a crucial role in the control of mitochondrial quantity, metabolic reprogramming and cell differentiation. Mutation of the mitophagy protein Parkin is directly associated with the onset of PD. Parkin-independent receptor-mediated mitophagy is also documented such as BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3) and FUN14 domain containing 1 (FUNDC1) for receptor-mediated mitophagy. In this study we investigated cardiac function and mitophagy including FUNDC1 in PD patients and mouse models, and evaluated the therapeutic potential of a SGLT2 inhibitor empagliflozin. MPTP-induced PD model was established. PD patients and MPTP mice not only displayed pronounced motor defects, but also low plasma FUNDC1 levels, as well as cardiac ultrastructural and geometric anomalies (cardiac atrophy, interstitial fibrosis), functional anomalies (reduced E/A ratio, fractional shortening, ejection fraction, cardiomyocyte contraction) and mitochondrial injury (ultrastructural damage, UCP2, PGC1α, elevated mitochondrial Ca uptake proteins MCU and VDAC1, and mitochondrial apoptotic protein calpain), dampened autophagy, FUNDC1 mitophagy and apoptosis. By Gene set enrichment analysis (GSEA), we found overtly altered glucose transmembrane transport in the midbrains of MPTP-treated mice. Intriguingly, administration of SGLT2 inhibitor empagliflozin (10 mg/kg, i.p., twice per week for 2 weeks) in MPTP-treated mice significantly ameliorated myocardial anomalies (with exception of VDAC1), but did not reconcile the motor defects or plasma FUNDC1. FUNDC1 global knockout (FUNDC1 mice) did not elicit any phenotype on cardiac geometry or function in the absence or presence of MPTP insult, but it nullified empagliflozin-caused cardioprotection against MPTP-induced cardiac anomalies including remodeling (atrophy and fibrosis), contractile dysfunction, Ca homeostasis, mitochondrial (including MCU, mitochondrial Ca overload, calpain, PARP1) and apoptotic anomalies. In neonatal and adult cardiomyocytes, treatment with PD neurotoxin preformed fibrils of α-synuclein (PFF) caused cytochrome c release and cardiomyocyte mechanical defects. These effects were mitigated by empagliflozin (10 μM) or MCU inhibitor Ru360 (10 μM). MCU activator kaempferol (10 μM) or calpain activator dibucaine (500 μM) nullified the empagliflozin-induced beneficial effects. These results suggest that empagliflozin protects against PD-induced cardiac anomalies, likely through FUNDC1-mediated regulation of mitochondrial integrity.
Topics: Adult; Humans; Mice; Animals; Sodium-Glucose Transporter 2 Inhibitors; Parkinson Disease; Calpain; Ventricular Remodeling; Mitochondrial Proteins; Ubiquitin-Protein Ligases; Atrophy; Fibrosis; Membrane Proteins
PubMed: 37679644
DOI: 10.1038/s41401-023-01144-0 -
Anesthesia and Analgesia Jun 2019The objective of the experiment was to assess the antinociceptive effect of dibucaine, bupivacaine, and epinephrine. To assess the mechanism of action of the interaction...
BACKGROUND
The objective of the experiment was to assess the antinociceptive effect of dibucaine, bupivacaine, and epinephrine. To assess the mechanism of action of the interaction between dibucaine and epinephrine, phentolamine, a nonselective α-adrenergic antagonist, was added to the mixture.
METHODS
We assessed sensory blockade with these drugs by injecting 0.6 mL of drug-in-saline in the dorsal thoracolumbar area of rats; pinprick of the "wheal" formed by the injectate was the area targeted for stimulation to elicit a cutaneous trunci muscle reflex. The sensory block of dibucaine was compared with that of bupivacaine or epinephrine. Drug-drug interactions were analyzed by isobologram. Phentolamine was added to investigate the antinociceptive effect of dibucaine coinjected with epinephrine.
RESULTS
We demonstrated that dibucaine, epinephrine, and bupivacaine produced dose-dependent skin antinociception. On the median effective dose (ED50) basis, the potency was higher for epinephrine (mean, 0.011 [95% confidence interval {CI}, 0.007-0.015] μmol) than for dibucaine (mean, 0.493 [95% CI, 0.435-0.560] μmol) (P < .01), while there were no significant differences between dibucaine and bupivacaine (mean, 0.450 [95% CI, 0.400-0.505] μmol). On the equipotent basis (75% effective dose, median effective dose, and 25% effective dose), sensory block duration provoked by epinephrine was greater (P < .01) than that provoked by dibucaine or bupivacaine. Coadministration of dibucaine with epinephrine produced a synergistic nociceptive block, whereas phentolamine blocked that synergistic block.
CONCLUSIONS
The preclinical data indicated that there is no statistically significant difference between the potency and duration of dibucaine and bupivacaine in this model. Epinephrine synergistically enhances the effects of dibucaine, while phentolamine partially blocked those effects. α-Adrenergic receptors play an important role in controlling synergistic analgesic effect of dibucaine combined with epinephrine.
Topics: Adrenergic alpha-Antagonists; Analgesia; Analgesics; Anesthetics, Local; Animals; Area Under Curve; Bupivacaine; Dibucaine; Dose-Response Relationship, Drug; Drug Interactions; Drug Synergism; Epinephrine; Injections, Subcutaneous; Male; Pain; Phentolamine; Rats; Rats, Sprague-Dawley; Skin
PubMed: 31094809
DOI: 10.1213/ANE.0000000000003421 -
Journal of Anesthesia Oct 2015In many anesthesia textbooks written in English, lidocaine, tetracaine, bupivacaine, ropivacaine, and chloroprocaine are listed as useful local anesthetics for spinal... (Review)
Review
In many anesthesia textbooks written in English, lidocaine, tetracaine, bupivacaine, ropivacaine, and chloroprocaine are listed as useful local anesthetics for spinal anesthesia. In contrast, T-cain is not included in these lists, even though it has been reported to be suitable for spinal anesthesia in Japan. T-cain was developed as a local anesthetic in the early 1940s by Teikoku Kagaku Sangyo Inc. in Itami, Japan, by replacing a methyl group on tetracaine (Pantocaine(®)) with an ethyl group. T-cain was clinically approved for topical use in Japan in November 1949, and a mixture of dibucaine and T-cain (Neo-Percamin S(®)) was approved for spinal use in May 1950. Simply because of a lack of foreign marketing strategy, T-cain has never attracted global attention as a local anesthetic. However, in Japan, T-cain has been used topically or intrathecally (as Neo-Percamin S(®)) for more than 60 years. Other than the side effects generally known for all local anesthetics, serious side effects have not been reported for T-cain. In fact, several articles have reported that T-cain decreases the neurotoxicity of dibucaine. In this historical review, the characteristics of T-cain and its rise to become a major spinal anesthetic in Japan are discussed.
Topics: Administration, Topical; Anesthesia, Local; Anesthesia, Spinal; Anesthetics, Local; Dibucaine; Humans; Japan; Neurotoxicity Syndromes; Tetracaine
PubMed: 26302690
DOI: 10.1007/s00540-015-2066-0 -
Frontiers in Cellular and Infection... 2024Picornaviruses, which are positive-stranded, non-enveloped RNA viruses, are known to infect people and animals with a broad spectrum of diseases. Among the nonstructural... (Review)
Review
Picornaviruses, which are positive-stranded, non-enveloped RNA viruses, are known to infect people and animals with a broad spectrum of diseases. Among the nonstructural proteins in picornaviruses, 2C proteins are highly conserved and exhibit multiple structural domains, including amphipathic α-helices, an ATPase structural domain, and a zinc finger structural domain. This review offers a comprehensive overview of the functional structures of picornaviruses' 2C protein. We summarize the mechanisms by which the 2C protein enhances viral replication. 2C protein interacts with various host factors to form the replication complex, ultimately promoting viral replication. We review the mechanisms through which picornaviruses' 2C proteins interact with the NF-κB, RIG-I, MDA5, NOD2, and IFN pathways, contributing to the evasion of the antiviral innate immune response. Additionally, we provide an overview of broad-spectrum antiviral drugs for treating various enterovirus infections, such as guanidine hydrochloride, fluoxetine, and dibucaine derivatives. These drugs may exert their inhibitory effects on viral infections by targeting interactions with 2C proteins. The review underscores the need for further research to elucidate the precise mechanisms of action of 2C proteins and to identify additional host factors for potential therapeutic intervention. Overall, this review contributes to a deeper understanding of picornaviruses and offers insights into the antiviral strategies against these significant viral pathogens.
Topics: Humans; Animals; Picornaviridae; NF-kappa B; RNA; Virus Replication; Antiviral Agents; Structure-Activity Relationship
PubMed: 38465233
DOI: 10.3389/fcimb.2024.1347615