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BACKGROUND: Severe trauma accounts for a main factor inducing mortality for individuals aged < 45 years in China, which requires admission to intensive care unit (ICU) to receive comprehensive treatment. Family members of patients with unanticipated and life-threatening trauma during their ICU stays often experience psychosocial distress due to illness uncertainty. Previous research has shown that family function and psychological resilience are associated with illness uncertainty, respectively. However, little is known about the current situation and interacting mechanism between family function, psychological resilience, and illness uncertainty of family members for ICU trauma patients. Therefore, this study focused on exploring the current situation and relationships between these three factors in family members for ICU trauma patients. METHODS: The convenience sampling approach was adopted in the present cross-sectional survey, which involved 230 family members for ICU trauma patients from 34 hospitals in Chongqing, China. Related data were extracted with self-reporting questionnaires, which included sociodemographic characteristic questionnaire, the Family Adaptability, Partnership, Growth, Affection and Resolve Scale (APGAR), the 10-item Connor-Davidson Resilience Scale (10-CD-RISC) and the Mishel's Illness Uncertainty Scale for Family Members (MUIS-FM). Pearson correlation analysis was conducted to examine the correlations between various variables. Additionally, a structural equation model was adopted to assess the mediating effect of psychological resilience on family function and illness uncertainty. RESULTS: According to our results, family members for ICU trauma patients experienced high illness uncertainty with moderate family dysfunction and low psychological resilience. Family function directly affected illness uncertainty and indirectly affected illness uncertainty through psychological resilience in family members of ICU trauma patients. CONCLUSIONS: Family function and psychological resilience are the protective factors for reducing illness uncertainty. Healthcare providers should take effective measures, including family-functioning improvement and resilience-focused interventions, for alleviating illness uncertainty in family members of ICU trauma patients.
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Família , Unidades de Terapia Intensiva , Resiliência Psicológica , Ferimentos e Lesões , Humanos , Masculino , Feminino , Família/psicologia , Incerteza , Adulto , Estudos Transversais , Pessoa de Meia-Idade , China , Ferimentos e Lesões/psicologia , Idoso , Adulto JovemRESUMO
Shapes from the diffuse polarization method effectively realize the three-dimensional (3D) reconstruction of the object surface by using the polarization information of the diffuse reflection light. However, due to the nonconvexity of the particle surface, the reconstruction often falls into a local optimal solution. Indeed, the depth image obtained by the scanning electron microscope has serious stripe noise, which distorts the surface texture of the particle. In this Letter, a variable exponential function regularization method is proposed to realize 3D reconstruction for the nonconvexity of the surface and inclination of the particles. We focus on the gradient unintegrability caused by the skew and surface undulation of the specimen. An adaptive 3D reconstruction method is proposed based on variable exponential function regularization to fit the surface function of the particle. Experimental results of finite-difference time-domain simulations and actual imaging demonstrate the effectiveness of the method.
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BACKGROUND: Wide applications of nanoparticles (NPs) have raised increasing concerns about safety to humans. Oxidative stress and inflammation are extensively investigated as mechanisms for NPs-induced toxicity. Autophagy and lysosomal dysfunction are emerging molecular mechanisms. Inhalation is one of the main pathways of exposing humans to NPs, which has been reported to induce severe pulmonary inflammation. However, the underlying mechanisms and, more specifically, the interplays of above-mentioned mechanisms in NPs-induced pulmonary inflammation are still largely obscure. Considered that NPs exposure in modern society is often unavoidable, it is highly desirable to develop effective strategies that could help to prevent nanomaterials-induced pulmonary inflammation. RESULTS: Pulmonary inflammation induced by intratracheal instillation of silica nanoparticles (SiNPs) in C57BL/6 mice was prevented by PJ34, a poly (ADP-ribose) polymerase (PARP) inhibitor. In human lung bronchial epithelial (BEAS-2B) cells, exposure to SiNPs reduced cell viability, and induced ROS generation, impairment in lysosome function and autophagic flux. Inhibition of ROS generation, PARP and TRPM2 channel suppressed SiNPs-induced lysosome impairment and autophagy dysfunction and consequent inflammatory responses. Consistently, SiNPs-induced pulmonary inflammation was prevented in TRPM2 deficient mice. CONCLUSION: The ROS/PARP/TRPM2 signaling is critical in SiNPs-induced pulmonary inflammation, providing novel mechanistic insights into NPs-induced lung injury. Our study identifies TRPM2 channel as a new target for the development of preventive and therapeutic strategies to mitigate nanomaterials-induced lung inflammation.
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Autofagia/efeitos dos fármacos , Lisossomos/efeitos dos fármacos , Nanopartículas/toxicidade , Pneumonia/induzido quimicamente , Poli(ADP-Ribose) Polimerases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Dióxido de Silício/toxicidade , Canais de Cátion TRPM/metabolismo , Animais , Exposição por Inalação , Lisossomos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Tamanho da Partícula , Pneumonia/metabolismo , Pneumonia/patologia , Transdução de Sinais , Propriedades de SuperfícieRESUMO
This publisher's note corrects the author listing in Appl. Opt.59, 7114 (2020).APOPAI0003-693510.1364/AO.397357.
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We propose a comprehensive point spread function (PSF) degradation model, which considers multiple factors consisting of degradation of specimen retardant sampling and polarization angularly anamorphic sampling, to indicate the image degradation characteristics of polarization imaging systems. First, a one-layer optical coherence tomography (OCT) model was established to express the retardancy of medium-loading specimens. Then, a PSF degradation model of angularly anamorphic polarization sampling was deduced through the retrieval of Stokes parameters. Finally, maximum a posteriori probability (MAP) was adopted to assess the distribution of the proposed model. Hypothesis testing using actual data and numerical simulations demonstrated that the error of the system followed an asymmetric generalized Gaussian distribution (AGGD). Finite-difference time-domain (FDTD) simulation results and an actual imaging experiment demonstrate the consistency of the proposed model and the degradation characteristics of the PSF, which provide support for the improved accuracy and enhanced image quality of the optical field retrieval of nanoparticles.
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Nicotinamide adenine dinucleotide (NAD+) is an essential cofactor for redox enzymes, but also moonlights as a regulator for ion channels, the same as its metabolites. Ca2+ homeostasis is dysregulated in cancer cells and affects processes such as tumorigenesis, angiogenesis, autophagy, progression, and metastasis. Herein, we summarize the regulation of the most common calcium channels (TRPM2, TPCs, RyRs, and TRPML1) by NAD+ and its metabolites, with a particular focus on their roles in cancers. Although the mechanisms of NAD+ metabolites in these pathological processes are yet to be clearly elucidated, these ion channels are emerging as potential candidates of alternative targets for anticancer therapy.
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Canais de Cálcio/genética , Cálcio/metabolismo , NAD/metabolismo , Neoplasias/metabolismo , Canais de Cálcio/metabolismo , Sinalização do Cálcio/genética , Carcinogênese/genética , Humanos , Neoplasias/patologia , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Canais de Cátion TRPM/genética , Canais de Potencial de Receptor Transitório/genéticaRESUMO
Capsaicin bestows spiciness by activating TRPV1 channel with exquisite potency and selectivity. Although a capsaicin-bound channel structure was previously resolved by cryo-EM at 4.2- to 4.5-Å resolution, capsaicin was registered as a small electron density, reflecting neither its chemical structure nor specific ligand-channel interactions--important details required for mechanistic understanding. We obtained the missing atomic-level details by iterative computation and confirmed them by systematic site-specific functional tests. We observed that the bound capsaicin takes a 'tail-up, head-down' configuration. The vanillyl and amide groups form specific interactions to anchor its bound position, while the aliphatic tail may sample a range of conformations, making it invisible in cryo-EM images. Capsaicin stabilizes TRPV1's open state by 'pull-and-contact' interactions between the vanillyl group and the S4-S5 linker. Our study provides a structural mechanism for the agonistic function of capsaicin and its analogs, and demonstrates an effective approach to obtain atomic-level information from cryo-EM structures.
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Capsaicina/química , Canais de Cátion TRPV/agonistas , Canais de Cátion TRPV/química , Sequência de Aminoácidos , Animais , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Galinhas , Microscopia Crioeletrônica , Expressão Gênica , Células HEK293 , Humanos , Ativação do Canal Iônico , Cinética , Proteínas Luminescentes/química , Proteínas Luminescentes/genética , Camundongos , Simulação de Acoplamento Molecular , Dados de Sequência Molecular , Técnicas de Patch-Clamp , Mutação Puntual , Ligação Proteica , Coelhos , Ratos , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/genética , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Especificidade da Espécie , Canais de Cátion TRPV/genéticaRESUMO
Ischemia/reperfusion (I/R) injury is the main cause of tissue damage and dysfunction. I/R injury is characterized by Ca(2+) overload and production of reactive oxygen species (ROS), which play critical roles in the process of I/R injury to the brain, heart and kidney, but the underlying mechanisms are largely elusive. Recent evidence demonstrates that TRPM2, a Ca(2+)-permeable cationic channel and ROS sensor, is involved in I/R injury, but whether TRPM2 plays a protective or detrimental role in this process remains controversial. In this review, we discuss the recent progress in understanding the role of TRPM2 in reperfusion process after brain, heart and kidney ischemia and the potential of targeting TRPM2 for the development of therapeutic drugs to treat I/R injury.
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Traumatismo por Reperfusão/metabolismo , Canais de Cátion TRPM/fisiologia , Animais , Isquemia Encefálica/metabolismo , Humanos , Rim/irrigação sanguínea , Traumatismo por Reperfusão Miocárdica/metabolismoRESUMO
Multiwalled carbon nanotubes (MWCNTs) have been explored in pharmaceutical applications such as tumor targeting and delivery of drugs, in which MWCNTs are given through intravenous injection. However, the biosafety of MWCNTs is of concern for such application. Therefore, in the current study, we used a fatty liver model to investigate the possible toxicity of MWCNTs to the liver, as MWCNTs were retained mainly in the liver of mice after intravenous injection. Male Sprague Dawley rats were used to generate the fatty liver model, and the effects of intravenous administration of MWCNTs on fatty liver were studied. Hematoxylin and eosin staining for hepatocellular anatomy and Masson trichrome staining for hepatic fibrosis were conducted. Histologically, MWCNTs aggravated steatohepatitis with higher nonalcoholic fatty liver disease scores. Analysis of liver injury markers indicated that MWCNTs administration resulted in chronic hepatitis, along with increased liver fat and altered liver oxidation, including the increase of P6 protein and the depletion of glutathione. In conclusion, our results suggest that MWCNTs can aggravate nonalcoholic steatohepatitis in Sprague Dawley rats, and oxidative injury may be involved in this process.
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Fígado/efeitos dos fármacos , Nanotubos de Carbono/toxicidade , Hepatopatia Gordurosa não Alcoólica , Animais , Aspartato Aminotransferases/sangue , Dieta Hiperlipídica , Ácidos Graxos não Esterificados/metabolismo , Glutationa/metabolismo , Glutationa Peroxidase/sangue , Injeções Intravenosas , Fígado/metabolismo , Fígado/patologia , Masculino , Malondialdeído/metabolismo , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Ratos Sprague-Dawley , Superóxido Dismutase/metabolismo , Triglicerídeos/metabolismo , gama-Glutamiltransferase/sangueRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: The proper application of toxic medicines is one of the characteristics of traditional Chinese medicines, and the use of traditional Chinese medicines follows the principle of dialectical treatment. It is necessary to combine different "syndrome" or "disease" states with the toxicity of traditional Chinese medicines to form a reliable toxicity evaluation system. Fuzi, the lateral root of Aconitum carmichaelii Debx, is recognized as a panacea for kidney yang deficiency syndrome, however, its toxic effects significantly limit its clinical application. AIM OF THE STUDY: Herein, our research aimed to explore the toxic effects of Fuzi on syndrome models, and tried to reveal the underlying mechanisms. MATERIALS AND METHODS: Firstly, the mouse model of kidney yang deficiency syndrome was established through intramuscular injection of 25 mg/kg hydrocortisone per day for 10 consecutive days. Then, the acute toxicity of Fuzi in normal mice and kidney yang deficiency model mice was explored. Finally, the plasma metabolite concentrations and liver CYP3A4 enzyme activity were analyzed to reveal the possible mechanisms of the different pharmacological and toxicological effects of Fuzi in individuals with different physical constitutions. RESULTS: It was found that the treatment with Fuzi (138 g/kg) had serious toxic effects on kidney yang deficiency mice, leading to the death of 80% of the mice, whereas it showed no lethal toxicity in normal mice. This indicates that Fuzi induced greater toxicity in kidney yang deficiency mice than in normal ones. The liver CYP3A4 enzyme activity in kidney yang deficiency mice was decreased by 20% compared to the controls, resulting in slower metabolism of the toxic diester diterpenoid alkaloids in Fuzi. CONCLUSION: In conclusion, our study showed that changes of the metabolic enzyme activity in individuals with different syndromes led to different toxic effects of Chinese medicines, emphasizing the crucial importance of considering individual physical syndromes in the clinical application of traditional Chinese medicine, and the significance of conducting safety evaluations and dose predictions on animal models with specific syndromes for traditional Chinese medicines.
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Aconitum , Diterpenos , Medicamentos de Ervas Chinesas , Camundongos , Animais , Medicina Tradicional Chinesa , Deficiência da Energia Yang/induzido quimicamente , Deficiência da Energia Yang/tratamento farmacológico , Citocromo P-450 CYP3A , Medicamentos de Ervas Chinesas/farmacologia , Diterpenos/toxicidade , Diterpenos/uso terapêutico , RimRESUMO
BACKGROUND: This study aimed to systematically evaluate the clinical effectiveness and safety of acupoint herbal patching in the treatment of postherpetic neuralgia. METHODS: Eight databases including PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, Wan-Fang Database, China Biomedical Literature Service System, and Chongqing VIP Chinese Science were searched. The search time was set to October 2023. Two researchers independently screened the literature according to the inclusion and exclusion criteria; extracted the basic information, acupoints, Chinese herbal medicine, pain score, sleep score, depression score, and other information of the subjects, and independently assessed the risk of bias by 2 researchers. Meta-analysis of the included studies was performed using the StataMP 16 software. RESULTS: Fifteen studies with 1362 participants were included in this meta-analysis. Ashi is the acupoint frequency at the forefront, and Borneol is the Chinese herbal medicine frequency at the forefront. The acupoint herbal patching group showed significant improvements in visual analog score (SMD: -2.09; 95% Cl: -2.77, -1.42; Pâ <â .001), sleep score (SMD: -1.58; 95% Cl: -2.11, -1.05; Pâ <â .001), depression score (SMD: -1.61; 95% Cl: -2.22, -0.99; Pâ <â .001), Chinese medicine syndrome score (SMD: -2.32; 95% Cl: -2.84, -1.80; Pâ =â .06), dermatology life quality index (weighted mean differences: -4.11; 95% Cl: -4.58, -3.63; Pâ =â .98), and related laboratory indicators compared to the control group, and the total effective rate was significantly higher (relative risk: 1.20; 95% confidence interval: 1.15, 1.26; Pâ =â .99) than the control group. Two studies reported adverse reactions, but the 2 groups were not statistically significant. CONCLUSIONS: Acupoint herbal patching intervention in postherpetic neuralgia is effective in improving the pain, sleep, anxiety, depression, quality of life of patients, and related laboratory indicators.
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Medicamentos de Ervas Chinesas , Neuralgia Pós-Herpética , Humanos , Medicamentos de Ervas Chinesas/uso terapêutico , Neuralgia Pós-Herpética/tratamento farmacológico , Pontos de Acupuntura , Qualidade de Vida , FitoterapiaRESUMO
The global health implications of fine particulate matter (PM2.5) underscore the imperative need for research into its toxicity and chemical composition. In this study, zebrafish embryos exposed to the water-soluble components of PM2.5 from two cities (Harbin and Hangzhou) with differences in air quality, underwent microscopic examination to identify primary target organs. The Harbin PM2.5 induced dose-dependent organ malformation in zebrafish, indicating a higher level of toxicity than that of the Hangzhou sample. Harbin PM2.5 led to severe deformities such as pericardial edema and a high mortality rate, while the Hangzhou sample exhibited hepatotoxicity, causing delayed yolk sac absorption. The experimental determination of PM2.5 constituents was followed by the application of four algorithms for predictive toxicological assessment. The random forest algorithm correctly predicted each of the effect classes and showed the best performance, suggesting that zebrafish malformation rates were strongly correlated with water-soluble components of PM2.5. Feature selection identified the water-soluble ions F- and Cl- and metallic elements Al, K, Mn, and Be as potential key components affecting zebrafish development. This study provides new insights into the developmental toxicity of PM2.5 and offers a new approach for predicting and exploring the health effects of PM2.5.
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Poluentes Atmosféricos , Aprendizado de Máquina , Material Particulado , Peixe-Zebra , Material Particulado/toxicidade , Material Particulado/análise , Animais , Poluentes Atmosféricos/toxicidade , Poluentes Atmosféricos/análise , Cidades , China , Embrião não Mamífero/efeitos dos fármacos , Monitoramento Ambiental/métodosRESUMO
Ion channel activation upon ligand gating triggers a myriad of biological events and, therefore, evolution of ligand gating mechanism is of fundamental importance. TRPM2, a typical ancient ion channel, is activated by adenosine diphosphate ribose (ADPR) and calcium and its activation has evolved from a simple mode in invertebrates to a more complex one in vertebrates, but the evolutionary process is still unknown. Molecular evolutionary analysis of TRPM2s from more than 280 different animal species has revealed that, the C-terminal NUDT9-H domain has evolved from an enzyme to a ligand binding site for activation, while the N-terminal MHR domain maintains a conserved ligand binding site. Calcium gating pattern has also evolved, from one Ca2+-binding site as in sea anemones to three sites as in human. Importantly, we identified a new group represented by olTRPM2, which has a novel gating mode and fills the missing link of the channel gating evolution. We conclude that the TRPM2 ligand binding or activation mode evolved through at least three identifiable stages in the past billion years from simple to complicated and coordinated. Such findings benefit the evolutionary investigations of other channels and proteins.
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Cyclic adenosine diphosphate ribose is an endogenous Ca(2+) mobilizer involved in diverse cellular processes. A cell membrane-permeable cyclic adenosine diphosphate ribose analogue, cyclic inosine diphosphoribose ether (cIDPRE), can induce Ca(2+) increase in intact human Jurkat T-lymphocytes. Here we synthesized a coumarin-caged analogue of cIDPRE (Co-i-cIDPRE), aiming to have a precisely temporal and spatial control of bioactive cIDPRE release inside the cell using UV uncaging. We showed that Co-i-cIDPRE accumulated inside Jurkat cells quickly and efficiently. Uncaging of Co-i-cIDPRE evoked Ca(2+) release from endoplasmic reticulum, with concomitant Ca(2+) influx in Jurkat cells. Ca(2+) release evoked by uncaged Co-i-cIDPRE was blocked by knockdown of ryanodine receptors (RyRs) 2 and 3 in Jurkat cells. The associated Ca(2+) influx, on the other hand, was abolished by double knockdown of Stim1 and TRPM2 in Jurkat cells. Furthermore, Ca(2+) release or influx evoked by uncaged Co-i-cIDPRE was recapitulated in HEK293 cells that overexpress RyRs or TRPM2, respectively, but not in wild-type cells lacking these channels. In summary, our results indicate that uncaging of Co-i-cIDPRE incites Ca(2+) release from endoplasmic reticulum via RyRs and triggers Ca(2+) influx via TRPM2.
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Membrana Celular/metabolismo , ADP-Ribose Cíclica/análogos & derivados , Alcenos/metabolismo , Western Blotting , Cálcio , Linhagem Celular , Cumarínicos/metabolismo , ADP-Ribose Cíclica/metabolismo , Fluorescência , Células HEK293 , Humanos , Células Jurkat , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Molécula 1 de Interação Estromal , Canais de Cátion TRPM/genética , Canais de Cátion TRPM/metabolismoRESUMO
Objectives: Adverse childhood experiences (ACEs) and anxiety-depression co-morbidity are attracting widespread attention. Previous studies have shown the relationship between individual psychiatric disorders and ACEs. This study will analyze the correlation between anxiety-depression co-morbidity and different levels of ACEs. Methods: Seven categories of ACE and four classifications of psychiatric disorders were defined in a sample of 126,064 participants identified by the UK Biobank from 2006-2022, and correlations were investigated using logistic regression models. Then, to explore nonlinear relationships, restricted spline models were developed to examine differences in sex and age across cohorts (n = 126,064 for the full cohort and n = 121,934 for the European cohort). Finally, the impact of the category of ACEs on psychiatric disorders was examined. Results: After controlling for confounders, ACEs scores showed dose-dependent relationships with depression, anxiety, anxiety-depression co-morbidity, and at least one (any of the first three outcomes) in all models. ACEs with different scores were significantly positively correlated with the four psychiatric disorders classifications, with the highest odds of anxiety-depression co-morbidity (odds ratio [OR] = 4.87, 95% confidence intervals [CI]: 4.37 ~ 5.43), p = 6.08 × 10-178. In the restricted cubic spline models, the risk was relatively flat for females at ACEs = 0-1 and males at ACEs = 0-2/3 (except in males, where ACEs were associated with a lower risk of anxiety, all other psychiatric disorders had an increased risk of morbidity after risk smoothing). In addition, the risk of having anxiety, depression, anxiety-depression co-morbidity, and at least one of these disorders varies with each category of ACEs. Conclusion: The prevalence of anxiety-depression comorbidity was highest across ACE scores after controlling for confounding factors and had a significant effect on each category of ACEs.
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Pathological dry skin is a disturbing and intractable healthcare burden, characterized by epithelial hyperplasia and severe itch. Atopic dermatitis (AD) and psoriasis models with complications of dry skin have been studied using single-cell RNA sequencing (scRNA-seq). However, scRNA-seq analysis of the dry skin mouse model (acetone/ether/water (AEW)-treated model) is still lacking. Here, we used scRNA-seq and in situ hybridization to identify a novel proliferative basal cell (PBC) state that exclusively expresses transcription factor CUT-like homeobox 1 (Cux1). Further in vitro study demonstrated that Cux1 is vital for keratinocyte proliferation by regulating a series of cyclin-dependent kinases (CDKs) and cyclins. Clinically, Cux1+ PBCs were increased in patients with psoriasis, suggesting that Cux1+ PBCs play an important part in epidermal hyperplasia. This study presents a systematic knowledge of the transcriptomic changes in a chronic dry skin mouse model, as well as a potential therapeutic target against dry skin-related dermatoses.
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BACKGROUND: HCC is one of the most common causes of cancer-related deaths. Transient receptor potential melastatin 2 (TRPM2), a Ca2+-permeable cation channel, was reported to be involved in carcinogenesis and tumor growth recently. However, whether TRPM2 is involved in the pathogenesis and progression of HCC remains unclear. Herein, we systematically elucidated the functional role of TRPM2 in HCC cell cycle regulation and proliferation. APPROACH AND RESULTS: We determine TRPM2 expression to be strongly upregulated in the tumor tissues of HCC patients and associated with a negative prognosis. TRPM2 is highly expressed in HCC cell lines Huh-7 and HepG2 cells, rather than in normal hepatocytes. Inhibition or silencing of TRPM2, or inhibition of the downstream Ca2+-CaM-CaMKII signaling pathway, significantly suppressed the proliferation of Huh-7 and HepG2 cells by arresting the cell cycle at the G1/S phase, accompanied with reduced expression of G1/S checkpoint proteins. Importantly, inhibition or depletion of TRPM2 remarkably slowed down the growth of patient-derived xenografts and Huh-7 xenografts in mice. CONCLUSION: Our results indicate that TRPM2 promotes HCC cell proliferation via activating the Ca2+-CaM-CaMKII signaling pathway to induce the expression of the key G1/S regulatory proteins and accelerate the cell cycle. This study provides compelling evidence of TRPM2 involvement in a previously unrecognized mechanism that drives HCC progression and demonstrates that TRPM2 is a potential target for HCC treatment.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Canais de Cátion TRPM , Humanos , Animais , Camundongos , Carcinoma Hepatocelular/patologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Cálcio/metabolismo , Neoplasias Hepáticas/patologia , Canais de Cátion TRPM/genética , Canais de Cátion TRPM/metabolismo , Ciclo Celular/genética , Transdução de SinaisRESUMO
Purpose: The uncoordinated-51 like kinase 1 (ULK1) is an important serine/threonine protein kinase involved in autophagy, especially for the initiation stage. Previous studies have shown that ULK1 could be used as a prognostic marker in predicting poor progression-free survival and a therapeutic target for hepatocellular carcinoma (HCC) when treated with sorafenib; however, its role during hepatocarcinogenesis remains to be elucidated. Methods: CCK8 and colony formation assay were used to detect cell growth ability. Western blotting was performed to determine expression level of protein. Data from public database were downloaded to analyze expression of ULK1 at mRNA level and predict survival time. RNA-seq was conducted to reveal disturbed gene profile orchestrated by ULK1 depletion. A diethylnitrosamine (DEN)-induced HCC mice model was used to uncover the role of ULK1 in hepatocarcinogenesis. Results: ULK1 was up-regulated in liver cancer tissues and cell lines, and knockdown of ULK1 promoted apoptosis and suppressed proliferation of liver cancer cells. In in vivo experiments, Ulk1 depletion attenuated starvation-induced autophagy in mice liver, reduced diethylnitrosamine (DEN)-induced hepatic tumor number and size, and prevented tumor progression. Further, RNA-seq analysis revealed a close relationship between Ulk1 and immunity with significant changes in gene sets enriched in the interleukin and interferon pathways. Conclusion: ULK1 deficiency prevented hepatocarcinogenesis and inhibited hepatic tumor growth, and might be a molecular target for the prevention and treatment of HCC.
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Near-infrared (NIR) photothermal manipulation has emerged as a promising and noninvasive technology for neuroscience research and disease therapy for its deep tissue penetration. NIR stimulated techniques have been used to modulate neural activity. However, due to the lack of suitable in vivo control systems, most studies are limited to the cellular level. Here, a NIR photothermal technique is developed to modulate cellular excitability and animal behaviors in Caenorhabditis elegans in vivo via the thermosensitive transient receptor potential vanilloid 1 (TRPV1) channel with an FDA-approved photothermal agent indocyanine green (ICG). Upon NIR stimuli, exogenous expression of TRPV1 in AFD sensory neurons causes Ca2+ influx, leading to increased neural excitability and reversal behaviors, in the presence of ICG. The GABAergic D-class motor neurons can also be activated by NIR irradiation, resulting in slower thrashing behaviors. Moreover, the photothermal manipulation is successfully applied in different types of muscle cells (striated muscles and nonstriated muscles), enhancing muscular excitability, causing muscle contractions and behavior changes in vivo. Altogether, this study demonstrates a noninvasive method to precisely regulate the excitability of different types of cells and related behaviors in vivo by NIR photothermal manipulation, which may be applied in mammals and clinical therapy.
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Antineoplásicos , Caenorhabditis elegans , Animais , Verde de Indocianina , Linhagem Celular Tumoral , Comportamento Animal , MamíferosRESUMO
Hepatic ischemia-reperfusion (IR) injury is a serious clinical problem that complicates liver resection and transplantation. Despite recent advances in understanding of the pathophysiology of hepatic IR injury, effective interventions and therapeutics are still lacking. Here, we examined the role of transient receptor potential melastatin 2 (TRPM2), a Ca2+-permeable, non-selective cation channel, in mediating hepatic IR injury. Our data showed that TRPM2 deficiency attenuated IR-induced liver dysfunction, inflammation, and cell death in mice. Moreover, RNA sequencing analysis indicated that TRPM2-induced IR injury occurs via ferroptosis-related pathways. Consistently, as a ferroptosis inducer, (1S,3R)-RSL3 treatment induced mitochondrial dysfunction in hepatocytes and a TRPM2 inhibitor suppressed this. Interestingly, TRPM2-mediated calcium influx caused mitochondrial calcium accumulation via the mitochondrial Ca2+-selective uniporter and increased the expression level of arachidonate 12-lipoxygenase (ALOX12), which results in mitochondrial lipid peroxidation during hepatic IR injury. Furthermore, hepatic IR injury-induced ferroptosis was obviously relieved by a TRPM2 inhibitor or calcium depletion, both in vitro and in vivo. Collectively, these findings demonstrate a crucial role for TRPM2-mediated ferroptosis in hepatic IR injury via increased Ca2+-induced ALOX12 expression, indicating that pharmacological inhibition of TRPM2 may provide an effective therapeutic strategy for hepatic IR injury-related diseases, such as during liver resection and transplantation.