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BACKGROUND: The management of patients with ureteral calculi in the emergency department (ED) remains challenging due to high revisit rates. PURPOSE: To identify predictors of revisits among patients with ureteral calculi in the ED. DESIGN, SETTING, AND PARTICIPANTS: Data from patients who presented at a tertiary academic hospital in Seoul, Republic of Korea, between February 2018 and December 2019, were analyzed retrospectively. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Variables, including the respiratory rate (RR), estimated glomerular filtration rate (eGFR), duration of pain, number of analgesic doses, location of ureteral calculi, and ED length of stay (LOS) were examined using logistic regression. We also examined some additional variables included in the STONE and CHOKAI scoring systems to examine their association with revisit. RESULTS: Significant predictors of revisits included the number of analgesic doses and the location of ureteral calculi. Patients who required multiple analgesic doses or those with proximal or mid-ureteral calculi were more likely to revisit the ED. Although the STONE and CHOKAI scores could predict uncomplicated ureteral calculi, we found that the CHOKAI score is a valuable tool for predicting the likelihood of patient revisits (p = 0.021). CONCLUSIONS: Effective pain management and consideration of calculi location are important for predicting patient revisits. More research is required to validate findings, develop precise predictive models, and empower tailored care for high-risk patients. In patients with ureteral calculi in the ED, the number of analgesics given and stone location predict return visits. Proximal ureteral calculi on CT may require early urologic intervention to prevent pain-related revisits.
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Cálculos Ureterales , Humanos , Cálculos Ureterales/complicaciones , Cálculos Ureterales/terapia , Manejo del Dolor , Readmisión del Paciente , Estudios Retrospectivos , Dolor , AnalgésicosRESUMEN
Human CtIP maintains genomic integrity primarily by promoting 5' DNA end resection, an initial step of the homologous recombination (HR). A few mechanisms have been suggested as to how CtIP recruitment to damage sites is controlled, but it is likely that we do not yet have full understanding of the process. Here, we provide evidence that CtIP recruitment and functioning are controlled by the SIAH2 E3 ubiquitin ligase. We found that SIAH2 interacts and ubiquitinates CtIP at its N-terminal lysine residues. Mutating the key CtIP lysine residues impaired CtIP recruitment to DSBs and stalled replication forks, DSB end resection, overall HR repair capacity of cells, and recovery of stalled replication forks, suggesting that the SIAH2-induced ubiquitination is important for relocating CtIP to sites of damage. Depleting SIAH2 consistently phenocopied these results. Overall, our work suggests that SIAH2 is a new regulator of CtIP and HR repair, and emphasizes that SIAH2-mediated recruitment of the CtIP is an important step for CtIP's function during HR repair.
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Reparación del ADN , Replicación del ADN , Endodesoxirribonucleasas/metabolismo , Proteínas Nucleares/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Roturas del ADN de Doble Cadena , Endodesoxirribonucleasas/genética , Humanos , Ubiquitina-Proteína Ligasas/genética , UbiquitinaciónRESUMEN
The Organization for Economic Co-operation and Development (OECD) developed soil surface nutrient balance and made it mandatory for member countries to report annual nutrient budgets since 1990. This study aimed to evaluate the status of nitrogen (N) management in member countries and to figure out why N surplus levels differ across countries and how they relate to other agri-environmental indicators, by analyzing the N budgets from 35 OECD countries over the last 30 years. Of the three factors determining N balance (agricultural land area, N input, and N output), agricultural land area decreased in most OECD countries, negatively affecting N balance reduction. However, OECD's average N balance highly decreased from 91 to 46 kg ha-1 over the last 30 years due to the decrease in N input through inorganic fertilizers and manure, especially in EU countries with high N input levels, while N output did not meaningfully change. In comparison, in Japan and Korea, the N balance slightly increased and they became the highest N balance country recently. A higher N balance led to lower N use efficiency and higher ammonia (NH3) and nitrous oxide (N2O) emission intensities. More densely populated countries with smaller agricultural land per capita (ranging from 0.03 to 0.47 ha capita-1) showed a higher N balance (228-80 kg ha-1), presumably due to higher N input for more agricultural production on limited land. The most densely populated countries among OECD members (Belgium, the Netherlands, Korea, and Japan) had similar N input levels. However, two EU countries had much higher N output than two Asian countries due to higher pasture production, which led to a lower N balance and higher N use efficiency. Therefore, highly populated countries with small arable land areas per capita might need multilateral efforts to alleviate agricultural N balance.
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Nitrógeno , Organización para la Cooperación y el Desarrollo Económico , Nitrógeno/análisis , Agricultura , Suelo , Amoníaco/análisis , Fertilizantes/análisis , Estiércol , Óxido Nitroso/análisisRESUMEN
Background and Objectives: The Clinical Frailty Scale (CFS), used to screen for prehospital frailty in patients aged >65 years, is simple, time-efficient, and has been validated in emergency departments (EDs). In this study, we analyzed whether the Korean Triage and Acuity Scale (KTAS) classification by level in older patients determined to have frailty based on the Korean version of the CFS increases the triage performance of the current KTAS. Materials and Methods: The primary outcome was 30-day in-hospital mortality, and secondary outcomes were hospital and intensive care unit (ICU) admissions. This study retrospectively analyzed prospectively collected data from three ED centers. Patients with a CFS score ranging from five (mildly frail) to nine (terminally ill) were categorized into the frailty group. We upgraded the KTAS classification of the frailty group by one level of urgency and defined this as the CFS-KTAS. Results: The cutoff values for predicting admission were three and two for the KTAS and CFS-KTAS, respectively. A significant difference was observed in the area under the receiver operating characteristic (AUROC) curve between the KTAS and CFS-KTAS. To predict ICU admission, the cutoff score was two for both scales. A significant difference was observed in the AUROC curve between the KTAS and CFS-KTAS. For predicting in-hospital mortality, the cutoff score was two for both scales. A significant difference was observed in the AUROC curve between the KTAS and CFS-KTAS. Conclusions: This study showed that the CFS-adjusted KTAS has a more useful prognostic value than the KTAS alone for predicting hospital outcomes in older patients.
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Servicio de Urgencia en Hospital , Fragilidad , Triaje , Humanos , Anciano , Masculino , Femenino , República de Corea , Servicio de Urgencia en Hospital/estadística & datos numéricos , Triaje/métodos , Triaje/normas , Anciano de 80 o más Años , Estudios Retrospectivos , Fragilidad/diagnóstico , Fragilidad/clasificación , Mortalidad Hospitalaria , Evaluación Geriátrica/métodos , Curva ROC , Gravedad del Paciente , Anciano Frágil/estadística & datos numéricosRESUMEN
Oxytocin and vasopressin are neurohypophyseal hormones with sequence similarity and play a central role in bodily homeostatic regulation. Pain is currently understood to be an important phenotype that those two neurohormones strongly downregulate. Nociceptors, the first component of the ascending neural circuit for pain signals, have constantly been shown to be modulated by those peptides. The nociceptor modulation appears to be critical in pain attenuation, which has led to a gradual increase in scientific interest about their physiological processes and also drawn attention to their translational potentials. This review focused on what are recently understood and stay under investigation in the functional modulation of nociceptors by oxytocin and vasopressin. Effort to produce a nociceptor-specific view could help to construct a more systematic picture of the peripheral pain modulation by oxytocin and vasopressin.
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Nociceptores , Oxitocina , Humanos , Dolor , Receptores de Oxitocina , Receptores de Vasopresinas , VasopresinasRESUMEN
BACKGROUND: Suicide is a significant public health problem worldwide. Suicide rates among elderly persons (≥ 65 years of age) are three times higher than those of younger people in Korea. The emergency department is an important entry of drug-related suicide attempt patients. In this study, we compared the frequency of drug types by age subgroup. Furthermore, we provide suggestions for preventing suicide attempts in the elderly. METHODS: We investigated 433 patients who were admitted to the emergency department for drug-related suicide attempts between 1 May 2015 and 30 April 2017. RESULTS: The proportion of patients who overdosed on antidepressants was 32.5% in the non-elderly age group and 8.0% in the elderly group (≥ 65 years of age) (P < 0.001). Among the elderly, the most commonly ingested agent was hypnotics (59.1%) (P < 0.001). Compared with the non-elderly, the results showed that the elderly used fewer antidepressants (P < 0.001) and analgesics (P < 0.001). Meanwhile, the elderly used more hypnotics (P < 0.001). Over-the-counter drugs and other medications showed similar usage trends in both age groups (P = 0.664, P = 0.193). CONCLUSION: The categories of drugs ingested for suicide attempts vary widely between different age groups. Younger people used antidepressants more frequently in suicide attempts, while the elderly used hypnotics more frequently. And the elderly required longer hospital stays. Suicide ideation and depressive mood in older patients who are prescribed hypnotics for various reasons should not be neglected. Further prevention efforts are needed to prevent suicide among the elderly.
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Antidepresivos/envenenamiento , Hipnóticos y Sedantes/envenenamiento , Intento de Suicidio/prevención & control , Anciano , Analgésicos/envenenamiento , Servicio de Urgencia en Hospital , Femenino , Humanos , Masculino , Persona de Mediana Edad , Medicamentos sin Prescripción/envenenamiento , Intento de Suicidio/psicologíaRESUMEN
KCNK1 (K(+) channel, subfamily K, member 1) is a member of the inwardly rectifying K(+) channel family, which drives the membrane potential towards the K(+) balance potential. Here, we investigated its functional relevance during osteoclast differentiation. KCNK1 was significantly induced during osteoclast differentiation, but its functional overexpression significantly inhibited osteoclast differentiation induced by RANKL (also known as TNFSF11), which was accompanied by the attenuation of the RANKL-induced Ca(2+) oscillation, JNK activation and NFATc1 expression. In contrast, KCNK1 knockdown enhanced the RANKL-induced osteoclast differentiation, JNK activation and NFATc1 expression. In conclusion, we suggest that KCNK1 is a negative regulator of osteoclast differentiation; the increase of K(+) influx by its functional blockade might inhibit osteoclast differentiation by inhibiting Ca(2+) oscillation and the JNK-NFATc1 signaling axis. Together with the increased attention on the pharmacological possibilities of using channel inhibition in the treatment of osteoclast-related disorders, further understanding of the functional roles and mechanisms of K(+) channels underlying osteoclast-related diseases could be helpful in developing relevant therapeutic strategies.
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Señalización del Calcio , Sistema de Señalización de MAP Quinasas , Osteoclastos/metabolismo , Canales de Potasio de Dominio Poro en Tándem/metabolismo , Animales , Diferenciación Celular , Células Cultivadas , Regulación hacia Abajo , Técnicas de Silenciamiento del Gen , Ratones , Factores de Transcripción NFATC/metabolismo , Osteoclastos/citología , Canales de Potasio de Dominio Poro en Tándem/genética , Ligando RANK/metabolismoRESUMEN
TRPV1 is well known as a sensor ion channel that transduces a potentially harmful environment into electrical depolarization of the peripheral terminal of the nociceptive primary afferents. Although TRPV1 is also expressed in central regions of the nervous system, its roles in the area remain unclear. A series of recent reports on the spinal cord synapses have provided evidence that TRPV1 plays an important role in synaptic transmission in the pain pathway. Particularly, in pathologic pain states, TRPV1 in the central terminal of sensory neurons and interneurons is suggested to commonly contribute to pain exacerbation. These observations may lead to insights regarding novel synaptic mechanisms revealing veiled roles of spinal cord TRPV1 and may offer another opportunity to modulate pathological pain by controlling TRPV1. In this review, we introduce historical perspectives of this view and details of the recent promising results. We also focus on extended issues and unsolved problems to fully understand the role of TRPV1 in pathological pain. Together with recent findings, further efforts for fine analysis of TRPV1's plastic roles in pain synapses at different levels in the central nervous system will promote a better understanding of pathologic pain mechanisms and assist in developing novel analgesic strategies.
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Dolor/metabolismo , Médula Espinal/metabolismo , Transmisión Sináptica/fisiología , Canales Catiónicos TRPV/metabolismo , Animales , HumanosRESUMEN
Oxidative stress induces numerous biological problems. Lipid oxidation and peroxidation appear to be important steps by which exposure to oxidative stress leads the body to a disease state. For its protection, the body has evolved to respond to and eliminate peroxidation products through the acquisition of binding proteins, reducing and conjugating enzymes, and excretion systems. During the past decade, researchers have identified a group of ion channel molecules that are activated by oxidized lipids: transient receptor potential (TRP) channels expressed in sensory neurons. These ion channels are fundamentally detectors and signal converters for body-damaging environments such as heat and cold temperatures, mechanical attacks, and potentially toxic substances. When messages initiated by TRP activation arrive at the brain, we perceive pain, which results in our preparing defensive responses. Excessive activation of the sensory neuronal TRP channels upon prolonged stimulations sometimes deteriorates the inflammatory state of damaged tissues by promoting neuropeptide release from expresser neurons. These same paradigms may also work for pathologic changes in the internal lipid environment upon exposure to oxidative stress. Here, we provide an overview of the role of TRP channels and oxidized lipid connections during abnormally increased oxidative signaling, and consider the sensory mechanism of TRP detection as an alert system.
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Peroxidación de Lípido , Canales de Potencial de Receptor Transitorio/metabolismo , Animales , Humanos , Ligandos , Dolor/metabolismo , Dolor/patología , Especies Reactivas de Oxígeno/metabolismo , Células Receptoras Sensoriales/metabolismo , Canales de Potencial de Receptor Transitorio/químicaRESUMEN
Lipids have long been studied as constituents of the cellular architecture and energy stores in the body. Evidence is now rapidly growing that particular lipid species are also important for molecular and cellular signaling. Here we review the current information on interactions between lipids and transient receptor potential (TRP) ion channels in nociceptive sensory afferents that mediate pain signaling. Sensory neuronal TRP channels play a crucial role in the detection of a variety of external and internal changes, particularly with damaging or pain-eliciting potentials that include noxiously high or low temperatures, stretching, and harmful substances. In addition, recent findings suggest that TRPs also contribute to altering synaptic plasticity that deteriorates chronic pain states. In both of these processes, specific lipids are often generated and have been found to strongly modulate TRP activities, resulting primarily in pain exacerbation. This review summarizes three standpoints viewing those lipid functions for TRP modulations as second messengers, intercellular transmitters, or bilayer building blocks. Based on these hypotheses, we discuss perspectives that account for how the TRP-lipid interaction contributes to the peripheral pain mechanism. Still a number of blurred aspects remain to be examined, which will be answered by future efforts and may help to better control pain states.
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Lípidos/fisiología , Nocicepción/fisiología , Dolor/metabolismo , Canales de Potencial de Receptor Transitorio/metabolismo , Animales , Expresión Génica , Humanos , Activación del Canal Iónico/fisiología , Plasticidad Neuronal , Dolor/genética , Dolor/fisiopatología , Transducción de Señal , Canales de Potencial de Receptor Transitorio/clasificación , Canales de Potencial de Receptor Transitorio/genéticaRESUMEN
The function of peripheral nociceptors, the neurons that relay pain signals to the brain, are frequently tuned by local and systemic modulator substances. In this context, neurohormonal effects are emerging as an important modulatory mechanism, but many aspects remain to be elucidated. Here we report that gonadotropin-releasing hormone (GnRH), a brain-specific neurohormone, can aggravate pain by acting on nociceptors in mice. GnRH and GnRHR, the receptor for GnRH, are expressed in a nociceptor subpopulation. Administration of GnRH and its analogue, localized for selectively affecting the peripheral neurons, deteriorated mechanical pain, which was reproducible in neuropathic conditions. Nociceptor function was promoted by GnRH treatment in vitro, which appears to involve specific sensory transient receptor potential ion channels. These data suggest that peripheral GnRH can positively modulate nociceptor activities in its receptor-specific manner, contributing to pain exacerbation. Our study indicates that GnRH plays an important role in neurohormonal pain modulation via a peripheral mechanism.
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Chronic dermatitis is a disease with large unmet need for pharmacological improvement. Dermatitis conditions are maintained and exacerbated by various cytokine actions in the context of inflammation. Interleukin 6 signal transducer (Il6st), also known as glycoprotein 130 (Gp130), is a key component for surface reception of a multitude of cytokines and transduction and amplification of their pro-inflammatory signals. We hypothesized accordingly that pharmacological inhibition of Il6st can alter dermatitis pathology. Treatment with SC-144 and bazedoxifene, two representative small molecule Il6st inhibitors with different binding modes led to moderate but significant improvement of skin conditions in a 1-chloro-2,4-dinitrobenzene animal model. Part of cytokine expressions indicating the dermatological index were normalized particularly when treated with SC-144. Pruritic behaviors were blunted, also possibly giving limited contribution to disease improvement. In psoriatic skin and itch of an imiquimod animal model, those two treatments appeared to be relatively moderate. Collectively, pharmacological inhibition of Il6st seems to lessen pathological irritation. Inversely, this experimental attempt newly implies that Il6st participates in pathological mechanisms. In conclusion, we suggest Il6st as a novel target for improving dermatitis, and that agents with suitable efficacy and safety for its modulation are translatable.
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Receptor gp130 de Citocinas , Prurito , Animales , Prurito/tratamiento farmacológico , Prurito/metabolismo , Receptor gp130 de Citocinas/metabolismo , Receptor gp130 de Citocinas/antagonistas & inhibidores , Inflamación/tratamiento farmacológico , Ratones , Modelos Animales de Enfermedad , Dermatitis/tratamiento farmacológico , Dermatitis/metabolismo , Dermatitis/patología , Indoles/farmacología , Indoles/uso terapéutico , Masculino , Piel/efectos de los fármacos , Piel/patología , Piel/metabolismo , Femenino , Citocinas/metabolismo , Psoriasis/tratamiento farmacológicoRESUMEN
OBJECTIVE: Alzheimer disease (AD) brains are deficient in brain-derived neurotrophic factor (BDNF), which regulates synaptic plasticity and memory. MicroRNAs (miRNAs) are â¼22-nucleotide small noncoding RNAs that control a variety of physiological and disease processes. Here, we show that miR-206 regulates BDNF and memory function in AD mice. METHODS: Expression of miRNAs was analyzed in Tg2576 AD transgenic mice and human AD brain samples. Regulation of BDNF by a selected miRNA was validated by in silico prediction, target gene luciferase assay, and dendritic spine responses in neurons. AM206, a neutralizing inhibitor of miR-206 (antagomir), was injected into the third ventricle of Tg2576 mice, after which memory function, synaptogenesis, neurogenesis, and target gene expression were assessed. For noninvasive delivery, antagomirs were administered intranasally. RESULTS: The brains of Tg2576 mice and the temporal cortex of human AD brains had increased levels of miR-206. This miRNA targeted BDNF transcripts, and AM206 prevented the detrimental effects of amyloid-ß42 on BDNF and dendritic spine degeneration in Tg2576 neurons. Injection of AM206 into the cerebral ventricles of AD mice increased the brain levels of BDNF and improved their memory function. In parallel, AM206 enhanced the hippocampal synaptic density and neurogenesis. Furthermore, intranasally administered AM206 also reached the brain and increased BDNF levels and memory function in AD mice. INTERPRETATION: Our findings demonstrate a novel miRNA-dependent regulation of BDNF in AD and suggest possible therapeutic approaches, such as noninvasive intranasal delivery of AM206.
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Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Encéfalo/metabolismo , MicroARNs/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Animales , Bencilaminas/uso terapéutico , Encéfalo/efectos de los fármacos , Encéfalo/patología , Espinas Dendríticas/efectos de los fármacos , Espinas Dendríticas/patología , Modelos Animales de Enfermedad , Miedo/efectos de los fármacos , Miedo/psicología , Regulación de la Expresión Génica/genética , Proteína Ácida Fibrilar de la Glía/metabolismo , Humanos , Aprendizaje/efectos de los fármacos , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Transgénicos , Análisis por Micromatrices , Neurogénesis/efectos de los fármacos , Niacina/análogos & derivados , Niacina/uso terapéutico , Oligodesoxirribonucleótidos Antisentido/uso terapéutico , Estadísticas no Paramétricas , Sinaptofisina/metabolismoAsunto(s)
Doxilamina/envenenamiento , Antagonistas de los Receptores Histamínicos H1/envenenamiento , Rabdomiólisis/inducido químicamente , Adulto , Antídotos/administración & dosificación , Tampones (Química) , Carbón Orgánico/administración & dosificación , Sobredosis de Droga/terapia , Sobredosis de Droga/orina , Quimioterapia Combinada , Femenino , Fluidoterapia/métodos , Fluidoterapia/estadística & datos numéricos , Lavado Gástrico/estadística & datos numéricos , Humanos , Infusiones Intravenosas , Inyecciones Intravenosas , Tiempo de Internación/estadística & datos numéricos , Masculino , Rabdomiólisis/prevención & control , Rabdomiólisis/orina , Solución Salina/administración & dosificación , Bicarbonato de Sodio/administración & dosificación , Resultado del TratamientoRESUMEN
The efficacy of many of pain-relieving drugs is based on mechanisms by which the drugs interfere with the body's natural pain-mediating pathways. By contrast, although it is less popular, other drugs including opioids exert more powerful analgesic actions by augmenting endogenous inhibitory neural circuits for pain mediation. Recently, a novel endogenous pain-inhibitory principle was suggested and is now attracting both scientific and clinical attentions. The central players for the actions are particular body lipids: resolvins. Although research is in the preclinical phase, multiple hypotheses have actively been matured regarding the potency and molecular and neural processes of the analgesic effects of these substances. Consistently, accumulating experimental evidence has been demonstrating that treatment with these lipid substances is strongly effective at controlling diverse types of pain. Treatment of resolvins does not appear to disturb the body homeostasis as severely as many other therapeutic agents that interrupt the body's natural signaling flow, which enables us to predict their fewer adverse effects. This paper serves as a review of currently documented painkilling actions of resolvins, summarizes the potential cellular and receptor-mediated mechanisms to date, and discusses the many clinical uses for these therapeutic lipids that have not yet been tested. Future scientific efforts will more concentrate to unveil such aspects of the substances and to construct clear proofs of concept for pain relief.
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The aim of this study was to examine the neutrophil-to-lymphocyte ratio (NLR) in patients diagnosed with a deep neck infection (DNI) to identify helpful indicators for the initial differential diagnosis. This study was conducted as a single-center, retrospective cohort study that utilized data from the electronic medical records of patients who visited the emergency department in a tertiary university hospital between February 2018 and April 2022. The study enrolled patients aged ≥18 years who were diagnosed with tonsillitis with or without DNI during the study period. The NLR of patients without DNI was 6.1 ± 5.03, and the NLR of patients with acute tonsillitis with DNI was 8.0 ± 5.67, showing significant differences. The rate of admission in the general wards (GWs) and ICUs was significantly higher in patients with DNI, and the length of hospital stay was also significantly longer in patients with DNI. Older age, male, lower body temperature, C-reactive protein, and NLR were significant independent risk factors for DNI in patients with tonsillitis. The cutoff value for predicting DNI in patients with body temperature <37.5 was 3.09. The NLR of patients with tonsillitis, especially those with normal body temperature, can be used to predict their prognosis.
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BACKGROUND AND PURPOSE: Pruritic dermatitis is a disease with a considerable unmet need for treatment and appears to present with not only epidermal but also peripheral neuronal complications. Here, we propose a novel pharmacological modulation targeting both peripheral dorsal root ganglion (DRG) sensory neurons and skin keratinocytes. GPR35 is an orphan G-protein-coupled receptor expressed in DRG neurons and has been predicted to downregulate neuronal excitability when activated. Modulator information is currently increasing for GPR35, and pamoic acid (PA), a salt-forming agent for drugs, has been shown to be an activator solely specific for GPR35. Here, we investigated its effects on dermatitic pathology. EXPERIMENTAL APPROACH: We confirmed GPR35 expression in peripheral neurons and tissues. The effect of PA treatment was pharmacologically evaluated in cultured cells in vitro and in in vivo animal models for acute and chronic pruritus. KEY RESULTS: Local PA application mitigated acute non-histaminergic itch and, consistently, obstructed DRG neuronal responses. Keratinocyte fragmentation under dermatitic simulation was also dampened following PA incubation. Chronic pruritus in 1-chloro-2,4-dinitrobenzene and psoriasis models were also moderately but significantly reversed by the repeated applications of PA. Dermatitic scores in the 1-chloro-2,4-dinitrobenzene and psoriatic models were also improved by its application, indicating that it is beneficial for mitigating disease pathology. CONCLUSION AND IMPLICATIONS: Our findings suggest that pamoic acid activation of peripheral GPR35 can contribute to the improvement of pruritus and its associated diseases.
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Dermatitis , Dinitroclorobenceno , Animales , Dinitroclorobenceno/metabolismo , Dinitroclorobenceno/farmacología , Prurito/tratamiento farmacológico , Prurito/metabolismo , Piel/metabolismo , Dermatitis/metabolismo , Ganglios Espinales/metabolismoRESUMEN
The function of peripheral nociceptors is frequently tuned by the action of G protein-coupled receptors (GPRs) that are expressed in them, which contribute to pain alteration. Expanding new information on such GPRs and predicting their potential outcomes can help to construct new analgesic strategies based on their modulations. In this context, we attempted to present a new GPR not yet acknowledged for its pain association. Gpr83 exhibits relatively high expressions in the peripheral nervous system compared to other tissues when we mined and reconstructed Gene Expression Omnibus (GEO) metadata, which we confirmed using immunohistochemistry on murine dorsal root ganglia (DRG). When Gpr83 expression was silenced in DRG, neuronal and behavioral nociception were all downregulated. Pathologic pain in hind paw inflammation and chemotherapy-induced peripheral neuropathy were also alleviated by this Gpr83 knockdown. Dependent on exposure time, the application of a known endogenous Gpr83 ligand PEN showed differential effects on nociceptor responses in vitro. Localized PEN administration mitigated pain in vivo, probably following Gq/11-involved GPR downregulation caused by the relatively constant exposure. Collectively, this study suggests that Gpr83 action contributes to the tuning of peripheral pain sensitivity and thus indicates that Gpr83 can be among the potential GPR targets for pain modulation.
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Ganglios Espinales , Nociceptores , Umbral del Dolor , Dolor , Receptores Acoplados a Proteínas G , Animales , Ratones , Ganglios Espinales/química , Ganglios Espinales/metabolismo , Neuronas/metabolismo , Nociceptores/metabolismo , Dolor/genética , Dolor/metabolismo , Umbral del Dolor/fisiología , Receptores Acoplados a Proteínas G/análisis , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Nocicepción/fisiologíaRESUMEN
Cisplatin resistance along with chemotherapy-induced neuropathic pain is an important cause of treatment failure for many cancer types and represents an unmet clinical need. Therefore, future studies should provide evidence regarding the mechanisms of potential targets that can overcome the resistance as well as alleviate pain. Here, we show that the emergence of cisplatin resistance is highly associated with EGFR hyperactivation, and that EGFR hyperactivation is arisen by a transcriptional increase in the pain-generating channel, TRPV1, via NANOG. Furthermore, TRPV1 promotes autophagy-mediated EGF secretion via Ca2+ influx, which activates the EGFR-AKT signaling and, consequentially, the acquisition of cisplatin resistance. Importantly, TRPV1 inhibition renders tumors susceptible to cisplatin. Thus, our findings indicate a link among cisplatin resistance, EGFR hyperactivation, and TRPV1-mediated autophagic secretion, and implicate that TRPV1 could be a crucial drug target that could not only overcome cisplatin resistance but also alleviate pain in NANOG+ cisplatin-resistant cancer.
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Antineoplásicos , Cisplatino , Antineoplásicos/farmacología , Autofagia , Línea Celular Tumoral , Cisplatino/farmacología , Resistencia a Antineoplásicos , Receptores ErbB/metabolismo , Transducción de Señal , Canales Catiónicos TRPV/antagonistas & inhibidoresRESUMEN
In Drosophila larvae, nociceptive mdIV sensory neurons detect diverse noxious stimuli and prompt a nociceptive rolling response. Intriguingly, the same neurons also regulate stereotyped larval movement. The channels responsible for transducing these stimuli into electric signals are not yet fully identified. Here we undertook genetic and electrophysiological analysis of Ppk19, a member of the Deg/ENaC family of cationic channels. ppk19 mutants exhibited an impaired nociceptive rolling response upon mechanical force and acid, but no impairment in response to noxious temperature and gentle touch. Mutants also exhibited defective larval movement. RNAi against ppk19 in mdIV neurons likewise produced larvae with defects in mechanical and acid nociception and larval movement, but no impairment in detection of heat and gentle touch. Cultured cells transfected with ppk19 produced currents in acid and hypotonic solution, suggesting that ppk19 encodes an ion channel that responds to acid and cell swelling. Taken together, these findings suggest that Ppk19 acts in mdIV neurons as a proton- and mechano-gated ion channel to mediate acid- and mechano-responsive nociception and larval movement.