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Acute pancreatitis (AP) is an inflammatory disease of the exocrine pancreas. Disruptions in organelle homeostasis, including macroautophagy/autophagy dysfunction and endoplasmic reticulum (ER) stress, have been implicated in human and rodent pancreatitis. Syntaxin 17 (STX17) belongs to the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) subfamily. The Qa-SNARE STX17 is an autophagosomal SNARE protein that interacts with SNAP29 (Qbc-SNARE) and the lysosomal SNARE VAMP8 (R-SNARE) to drive autophagosome-lysosome fusion. In this study, we investigated the role of STX17 in the pathogenesis of AP in male mice or rats induced by repeated intraperitoneal injections of cerulein. We showed that cerulein hyperstimulation induced AP in mouse and rat models, which was characterized by increased serum amylase and lipase activities, pancreatic edema, necrotic cell death and the infiltration of inflammatory cells, as well as markedly decreased pancreatic STX17 expression. A similar reduction in STX17 levels was observed in primary and AR42J pancreatic acinar cells treated with CCK (100 nM) in vitro. By analyzing autophagic flux, we found that the decrease in STX17 blocked autophagosome-lysosome fusion and autophagic degradation, as well as the activation of ER stress. Pancreas-specific STX17 knockdown using adenovirus-shSTX17 further exacerbated pancreatic edema, inflammatory cell infiltration and necrotic cell death after cerulein injection. These data demonstrate a critical role of STX17 in maintaining pancreatic homeostasis and provide new evidence that autophagy serves as a protective mechanism against AP.
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Ceruletida , Pancreatitis , Masculino , Ratones , Animales , Ratas , Humanos , Enfermedad Aguda , Ceruletida/toxicidad , Modelos Animales de Enfermedad , Pancreatitis/inducido químicamente , Autofagia/fisiología , Proteínas SNARE/metabolismo , EdemaRESUMEN
Bronchial asthma is not considered a singular disease, but rather a collection of syndromes with multiple phenotypes and mechanisms that involve various signaling pathways. It typically emerges during the preschool years, and its etiology is intricate and diverse. In recent years, the advancement of high-throughput sequencing technology has revealed that early alterations in lung microbiota may be associated with asthma incidence and progression. Moreover, significant variations in lung microbiota have been observed among different airway inflammation profiles, known as asthma endotypes. Hence, a comprehensive understanding of the characteristics of lung microbiota in children with asthma can aid in managing disease progression and improving long-term prognosis. Additionally, such insights may spark novel approaches to diagnosing and treating childhood asthma.
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Asma , Microbiota , Niño , Preescolar , Humanos , Asma/etiología , Asma/diagnóstico , Pulmón , Inflamación , FenotipoRESUMEN
Reduction of expression and activity of sirtuin 3 (SIRT3) contributes to the pathogenesis of cardiomyopathy via inducing mitochondrial injury and energy metabolism disorder. However, development of effective ways and agents to modulate SIRT3 remains a big challenge. In this study we explored the upstream suppressor of SIRT3 in angiotensin II (Ang II)-induced cardiac hypertrophy in mice. We first found that SIRT3 deficiency exacerbated Ang II-induced cardiac hypertrophy, and resulted in the development of spontaneous heart failure. Since miRNAs play crucial roles in the pathogenesis of cardiac hypertrophy, we performed miRNA sequencing on myocardium tissues from Ang II-infused Sirt3-/- and wild type mice, and identified microRNA-214 (miR-214) was significantly up-regulated in Ang II-infused mice. Similar results were also obtained in Ang II-treated neonatal mouse cardiomyocytes (NMCMs). Using dual-luciferase reporter assay we demonstrated that SIRT3 was a direct target of miR-214. Overexpression of miR-214 in vitro and in vivo decreased the expression of SIRT3, which resulted in extensive mitochondrial damages, thereby facilitating the onset of hypertrophy. In contrast, knockdown of miR-214 counteracted Ang II-induced detrimental effects via restoring SIRT3, and ameliorated mitochondrial morphology and respiratory activity. Collectively, these results demonstrate that miR-214 participates in Ang II-induced cardiac hypertrophy by directly suppressing SIRT3, and subsequently leading to mitochondrial malfunction, suggesting the potential of miR-214 as a promising intervention target for antihypertrophic therapy.
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Cardiomegalia/metabolismo , MicroARNs/metabolismo , Mitocondrias Cardíacas/metabolismo , Sirtuina 3/metabolismo , Angiotensina II/farmacología , Animales , Cardiomegalia/inducido químicamente , Cardiomegalia/genética , Cardiomegalia/patología , Línea Celular , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , MicroARNs/genética , MicroARNs/fisiología , Miocardio/metabolismo , Miocardio/patología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Ratas Sprague-Dawley , Sirtuina 3/genéticaRESUMEN
Phosphodiesterase-9A (PDE9A) expression is upregulated during cardiac hypertrophy and heart failure. Accumulating evidence suggests that PDE9A might be a promising therapeutic target for heart diseases. The present study sought to investigate the effects and underlying mechanisms of C33(S), a novel selective PDE9A inhibitor, on cardiac hypertrophy in vitro and in vivo. Treatment of neonatal rat cardiomyocytes (NRCMs) with PE (100 µmol/L) or ISO (1 µmol/L) induced cardiac hypertrophy characterized by significantly increased cell surface areas and increased expression of fetal genes (ANF and BNP). Furthermore, PE or ISO significantly increased the expression of PDE9A in the cells; whereas knockdown of PDE9A significantly alleviated PE-induced hypertrophic responses. Moreover, pretreatment with PDE9A inhibitor C33(S) (50 and 500 nmol/L) or PF-7943 (2 µmol/L) also alleviated the cardiac hypertrophic responses in PE-treated NRCMs. Abdominal aortic constriction (AAC)-induced cardiac hypertrophy and ISO-induced heart failure were established in SD rats. In ISO-treated rats, oral administration of C33(S) (9, 3, and 1 mg·kg-1·d-1, for 3 consecutive weeks) significantly increased fractional shortening (43.55%±3.98%, 54.79%±1.95%, 43.98%±7.96% vs 32.18%±6.28%), ejection fraction (72.97%±4.64%, 84.29%±1.56%, 73.41%±9.37% vs 49.17%±4.20%) and cardiac output (60.01±9.11, 69.40±11.63, 58.08±8.47 mL/min vs 48.97±2.11 mL/min) but decreased the left ventricular internal diameter, suggesting that the transition to heart failure was postponed by C33(S). We further revealed that C33(S) significantly elevated intracellular cGMP levels, phosphorylation of phospholamban (PLB) and expression of SERCA2a in PE-treated NRCMs in vitro and in ISO-induced heart failure model in vivo. Our results demonstrate that C33(S) effectively protects against cardiac hypertrophy and postpones the transition to heart failure, suggesting that it is a promising agent in the treatment of cardiac diseases.
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3',5'-AMP Cíclico Fosfodiesterasas/antagonistas & inhibidores , Cardiomegalia/tratamiento farmacológico , GMP Cíclico/metabolismo , Inhibidores Enzimáticos/farmacología , Pirazoles/farmacología , Pirimidinas/farmacología , Transducción de Señal/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacos , 3',5'-AMP Cíclico Fosfodiesterasas/metabolismo , Animales , Cardiomegalia/metabolismo , Cardiomegalia/patología , Células Cultivadas , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/química , Masculino , Miocitos Cardíacos/efectos de los fármacos , Pirazoles/administración & dosificación , Pirazoles/química , Pirimidinas/administración & dosificación , Pirimidinas/química , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
OBJECTIVE: To explore the predictors of condom-use self-efficacy in Chinese college students according to the extended parallel process model (EPPM)-based integrated model. METHODS: A total of 3,081 college students were anonymously surveyed through self-administered questionnaires in Guangzhou and Harbin, China. A structural equation model was applied to assess the integrated model. RESULTS: Among the participants, 1,387 (46.7%) were male, 1,586 (53.3%) were female, and the average age was 18.6 years. The final integrated model was acceptable. Apart from the direct effect (r = 0.23), perceived severity had two indirect effects on condom-use self-efficacy through the attitude to HIV education (r = 0.40) and intention to engage in premarital sex (r = -0.16), respectively. However, the perceived susceptibility mediated through the intention to engage in premarital sex (intent-to-premarital-sex) had a poor indirect impact on condom-use self-efficacy (total effect was -0.06). Furthermore, attitude toward HIV health education (r = 0.49) and intent-to-premarital-sex (r = -0.31) had a strong direct effect on condom-use self-efficacy. In addition, male students perceived higher susceptibility, stronger intent-to-premarital-sex, and lower condom-use self-efficacy than female students. CONCLUSION: The integrated model may be used to assess the determinants of condom-use self-efficacy among Chinese college students. Future research should focus on raising the severity perception, HIV-risk-reduction motivation, and the premarital abstinence intention among college students. Furthermore, considering the gender differences observed in the present survey, single-sex HIV education is required in school-based HIV/sex intervention.
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Pueblo Asiatico , Condones/estadística & datos numéricos , Modelos Teóricos , Autoeficacia , Conducta Sexual , Adolescente , Femenino , Conocimientos, Actitudes y Práctica en Salud , Humanos , Masculino , Factores de Riesgo , Estudiantes , Universidades , Adulto JovenRESUMEN
Viscosity loss of high-molecular-weight partially hydrolyzed polyacrylamide (HPAM) solution was observed in a water injection pipeline before being injected into subterranean oil wells. In order to investigate the possible involvement of microorganisms in HPAM viscosity loss, both bacterial and archaeal community compositions of four samples collected from different points of the transportation pipeline were analyzed using PCR-amplification of the 16S rRNA gene and clone library construction method together with the analysis of physicochemical properties of HPAM solution and environmental factors. Further, the relationship between environmental factors and HPAM properties with microorganisms were delineated by canonical correspondence analysis (CCA). Diverse bacterial and archaeal groups were detected in the four samples. The microbial community of initial solution S1 gathered from the make-up tank is similar to solution S2 gathered from the first filter, and that of solution S3 obtained between the first and the second filter is similar to that of solution S4 obtained between the second filter and the injection well. Members of the genus Acinetobacter sp. were detected with high abundance in S3 and S4 in which HPAM viscosity was considerably reduced, suggesting that they likely played a considerable role in HPAM viscosity loss. This study presents information on microbial community diversity in the HPAM transportation pipeline and the possible involvement of microorganisms in HPAM viscosity loss and biodegradation. The results will help to understand the microbial community contribution made to viscosity change and are beneficial for providing information for microbial control in oil fields.
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Resinas Acrílicas/química , Archaea/genética , Bacterias/genética , Yacimiento de Petróleo y Gas/microbiología , Biodegradación Ambiental , Biodiversidad , Peso Molecular , Filogenia , ARN Ribosómico 16S/genética , Soluciones/química , Transportes/métodos , Viscosidad , Microbiología del AguaRESUMEN
Nuclear receptor coactive 4 (NCOA4), which functions as a selective cargo receptor, is a critical regulator of the particularly autophagic degradation of ferritin, a process known as ferritinophagy. Mechanistically, NCOA4-mediated ferritinophagy performs an increasingly vital role in the maintenance of intracellular iron homeostasis by promoting ferritin transport and iron release as needed. Ferritinophagy is not only involved in iron-dependent responses but also in the pathogenesis and progression of various human diseases, including metabolism-related, neurodegenerative, cardiovascular and infectious diseases. Therefore, ferritinophagy is of great importance in maintaining cell viability and function and represents a potential therapeutic target. Recent studies indicated that ferritinophagy regulates the signalling pathway associated with ferroptosis, a newly discovered type of cell death characterised by iron-dependent lipid peroxidation. Although accumulating evidence clearly demonstrates the importance of the interplay between dysfunction in iron metabolism and ferroptosis, a deeper understanding of the double-edged sword effect of ferritinophagy in ferroptosis has remained elusive. Details of the mechanisms underlying the ferritinophagy-ferroptosis axis in regulating relevant human diseases remain to be elucidated. In this review, we discuss the latest research findings regarding the mechanisms that regulate the biological function of NCOA4-mediated ferritinophagy and its contribution to the pathophysiology of ferroptosis. The important role of the ferritinophagy-ferroptosis axis in human diseases will be discussed in detail, highlighting the great potential of targeting ferritinophagy in the treatment of diseases.
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Autofagia , Ferritinas , Ferroptosis , Hierro , Coactivadores de Receptor Nuclear , Humanos , Ferroptosis/fisiología , Ferritinas/metabolismo , Coactivadores de Receptor Nuclear/metabolismo , Coactivadores de Receptor Nuclear/genética , Autofagia/fisiología , Hierro/metabolismo , Animales , Transducción de Señal , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patologíaRESUMEN
Mitochondria are the centers of energy and material metabolism, and they also serve as the storage and dispatch hubs of metal ions. Damage to mitochondrial structure and function can cause abnormal levels and distribution of metal ions, leading to cell dysfunction and even death. For a long time, mitochondrial quality control pathways such as mitochondrial dynamics and mitophagy have been considered to inhibit metal-induced cell death. However, with the discovery of new metal-dependent cell death including ferroptosis and cuproptosis, increasing evidence shows that there is a complex relationship between mitochondrial quality control and metal-dependent cell death. This article reviews the latest research results and mechanisms of crosstalk between mitochondrial quality control and metal-dependent cell death in recent years, as well as their involvement in neurodegenerative diseases, tumors and other diseases, in order to provide new ideas for the research and treatment of related diseases.
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Muerte Celular , Metales , Mitocondrias , Humanos , Mitocondrias/metabolismo , Metales/metabolismo , Animales , Mitofagia , Ferroptosis , Dinámicas Mitocondriales , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patologíaRESUMEN
Background: Ribophagy is a selective autophagic process that specifically degrades dysfunctional or superfluous ribosomes to maintain cellular homeostasis. Whether ribophagy can ameliorate the immunosuppression in sepsis similar to endoplasmic reticulum autophagy (ERphagy) and mitophagy remains unclear. This study was conducted to investigate the activity and regulation of ribophagy in sepsis and to further explore the potential mechanism underlying the involvement of ribophagy in T-lymphocyte apoptosis. Methods: The activity and regulation of nuclear fragile X mental retardation-interacting protein 1 (NUFIP1)-mediated ribophagy in T lymphocytes during sepsis were first investigated by western blotting, laser confocal microscopy and transmission electron microscopy. Then, we constructed lentivirally transfected cells and gene-defective mouse models to observe the impact of NUFIP1 deletion on T-lymphocyte apoptosis and finally explored the signaling pathway associated with T-cell mediated immune response following septic challenge. Results: Both cecal ligation and perforation-induced sepsis and lipopolysaccharide stimulation significantly induced the occurrence of ribophagy, which peaked at 24 h. When NUFIP1 was knocked down, T-lymphocyte apoptosis was noticeably increased. Conversely, the overexpression of NUFIP1 exerted a significant protective impact on T-lymphocyte apoptosis. Consistently, the apoptosis and immunosuppression of T lymphocytes and 1-week mortality rate in NUFIP1 gene-deficient mice were significantly increased compared with those in wild-type mice. In addition, the protective effect of NUFIP1-mediated ribophagy on T lymphocytes was identified to be closely related to the endoplasmic reticulum stress apoptosis pathway, and PERK-ATF4-CHOP signaling was obviously involved in downregulating T-lymphocyte apoptosis in the setting of sepsis. Conclusions: NUFIP1-mediated ribophagy can be significantly activated to alleviate T lymphocyte apoptosis through the PERK-ATF4-CHOP pathway in the context of sepsis. Thus, targeting NUFIP1-mediated ribophagy might be of importance in reversing the immunosuppression associated with septic complications.
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BACKGROUND: Sustained yet intractable immunosuppression is commonly observed in septic patients, resulting in aggravated clinical outcomes. However, due to the substantial heterogeneity within septic patients, precise indicators in deciphering clinical trajectories and immunological alterations for septic patients remain largely lacking. METHODS: We adopted cross-species, single-cell RNA sequencing (scRNA-seq) analysis based on two published datasets containing circulating immune cell profile of septic patients as well as immune cell atlas of murine model of sepsis. Flow cytometry, laser scanning confocal microscopy (LSCM) imaging and Western blotting were applied to identify the presence of S100A9+ monocytes at protein level. To interrogate the immunosuppressive function of this subset, splenic monocytes isolated from septic wild-type or S100a9-/- mice were co-cultured with naïve CD4+ T cells, followed by proliferative assay. Pharmacological inhibition of S100A9 was implemented using Paquinimod via oral gavage. RESULTS: ScRNA-seq analysis of human sepsis revealed substantial heterogeneity in monocyte compartments following the onset of sepsis, for which distinct monocyte subsets were enriched in disparate subclusters of septic patients. We identified a unique monocyte subset characterized by high expression of S100A family genes and low expression of human leukocyte antigen DR (HLA-DR), which were prominently enriched in septic patients and might exert immunosuppressive function. By combining single-cell transcriptomics of murine model of sepsis with in vivo experiments, we uncovered a similar subtype of monocyte significantly associated with late sepsis and immunocompromised status of septic mice, corresponding to HLA-DRlowS100Ahigh monocytes in human sepsis. Moreover, we found that S100A9+ monocytes exhibited profound immunosuppressive function on CD4+ T cell immune response and blockade of S100A9 using Paquinimod could partially reverse sepsis-induced immunosuppression. CONCLUSIONS: This study identifies HLA-DRlowS100Ahigh monocytes correlated with immunosuppressive state upon septic challenge, inhibition of which can markedly mitigate sepsis-induced immune depression, thereby providing a novel therapeutic strategy for the management of sepsis.
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Monocitos , Sepsis , Humanos , Animales , Ratones , Monocitos/química , Monocitos/metabolismo , Modelos Animales de Enfermedad , Antígenos HLA-DR/análisis , Antígenos HLA-DR/metabolismo , Sepsis/genéticaRESUMEN
Elevated serum cholesterol in humans is generally a risk factor correlated with the development of coronary heart disease (CHD). Reducing deoxycholic acid (DCA) content in the intestine can reduce serum cholesterol levels, which reduce the incidence of CHD. A total of 150 strains of lactic acid bacteria and bifidobacteria were isolated from human fecal samples. The DCA removal ability of these strains was evaluated. Results showed that 9 strains displayed above 10% DCA removal rate. The probiotic potentials of the 9 strains were evaluated. The strain Lactobacillus casei F0822 was screened out due to the stronger adhesion to HT-29 cells and tolerance to bile and acid. DCA removal for this strain resulted from that the S-layer protein locating the cell surface bound DCA. The FTIR spectra showed that the carboxyl group in DCA was the principal group by which DCA was bound to the S-layer protein of L. casei F0822. These findings suggested that L. casei F0822 is a better candidate probiotic strain, which has the potential to reduce human serum cholesterol levels.
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Bifidobacterium/metabolismo , Colesterol/metabolismo , Ácido Desoxicólico/metabolismo , Lactobacillales/metabolismo , Probióticos/aislamiento & purificación , Adulto , Bifidobacterium/aislamiento & purificación , Heces/microbiología , Humanos , Lactante , Lactobacillales/aislamiento & purificación , Lacticaseibacillus casei , Tamizaje Masivo/métodosRESUMEN
Background: Sepsis is considered an intractable dysfunction that results from the disordered host immune response to uncontrolled infection. Even though the precise mechanism of sepsis remains unclear, scientific advances have highlighted the key role of various programmed cell death processes in the pathophysiology of sepsis. The current study aims to explore the worldwide research trend on programmed cell death in the setting of sepsis and assesses the achievements of publications from various countries, institutions, journals, and authors globally. Material and methods: Associated publications during 2002-2022 with the topical subject of sepsis and programmed cell death were extracted from the Web of Science. VOSviewer was utilized to evaluate and map the published trend in the relevant fields. Results: All 2,037 relevant manuscripts with a total citation of 71,575 times were screened out by the end of 1 January 2022. China accounted for the largest number of publications (45.07%) and was accompanied by corporate citations (11,037) and H-index (48), which ranked second globally. The United States has been ranked first place with the highest citations (30,775) and H-index (88), despite a low publication number (29.95%), which was subsequent to China. The journal Shock accounted for the largest number of publications in this area. R. S. Hotchkiss, affiliated with Washington University, was considered to have published the most papers in the relevant fields (57) and achieved the highest citation frequencies (9,523). The primary keywords on the topic of programmed cell death in sepsis remarkably focused on "inflammation" "immunosuppression", and "oxidative stress", which were recognized as the core mechanisms of sepsis, eventually attributing to programmed cell death. The involved research on programmed cell death induced by immune dysregulation of sepsis was undoubtedly the hotspot in the pertinent areas. Conclusions: The United States has been academically outstanding in sepsis-related research. There appears to be an incompatible performance between publications and quantity with China. Frontier advances may be consulted in the journal Shock. The leading-edge research on the scope of programmed cell death in sepsis should preferably focus on immune dissonance-related studies in the future.
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Bibliometría , Sepsis , Apoptosis , China/epidemiología , Humanos , Terapia de Inmunosupresión , Estados UnidosRESUMEN
Doxorubicin (Dox) is a chemotherapeutic drug used to treat a wide range of cancers, but its clinical application is limited due to its cardiotoxicity. Protein kinase C-ζ (PKC-ζ) is a serine/threonine kinase belonging to atypical protein kinase C (PKC) subfamily, and is activated by its phosphorylation. We and others have reported that PKC-ζ induced cardiac hypertrophy by activating the inflammatory signaling pathway. This study focused on whether PKC-ζ played an important role in Dox-induced cardiotoxicity. We found that PKC-ζ phosphorylation was increased by Dox treatment in vivo and in vitro. PKC-ζ overexpression exacerbated Dox-induced cardiotoxicity. Conversely, knockdown of PKC-ζ by siRNA relieved Dox-induced cardiotoxicity. Similar results were observed when PKC-ζ enzyme activity was inhibited by its pseudosubstrate inhibitor, Myristoylated. PKC-ζ interacted with ß-catenin and inhibited Wnt/ß-catenin signaling pathway. Activation of Wnt/ß-catenin signaling by LiCl protected against Dox-induced cardiotoxicity. The Wnt/ß-catenin inhibitor XAV-939 aggravated Dox-caused decline of ß-catenin and cardiomyocyte apoptosis and mitochondrial damage. Moreover, activation of Wnt/ß-catenin suppressed aggravation of Dox-induced cardiotoxicity due to PKC-ζ overexpression. Taken together, our study revealed that inhibition of PKC-ζ activity was a potential cardioprotective approach to preventing Dox-induced cardiac injury.
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Cis-9, trans-11 conjugated linoleic acid (c9, t11 CLA) producing bacteria have attracted much attention as novel probiotics which have shown beneficial effects on host health. However, bile salts are able to inhibit bacterial growth and c9, t11 CLA production. For recovering growth and c9, t11 CLA production of Lactobacillus acidophilus F0221 in the presence of bile salts, Tween series (Tween 20, Tween 40, Tween 60 and Tween 80) were added in growth culture containing 0.3% oxgall. Results showed that the viable counts were significantly (P < 0.05) recovered to 8.58-8.75 log CFU/mL in the presence of all Tween treatments. However, recovery of c9, t11 CLA production was only demonstrated in the presence of Tween 80 (72.89 µg/mL). Stepwise increasing oxgall in a concentrations range from 0.1% to 0.9% according to human intestinal physiological environments, Tween 80 still showed significant (P < 0.05) recovery ability on growth (8.91-8.04 log CFU/mL) and c9, t11 CLA (69.22-34.27 µg/mL) production. The effect of Tween 80 on growth and production was also investigated in the presence of different types of bile salts (sodium salts of cholic acid (CA), deoxycholic acid (DCA), chendeoxycholic acid (CDCA), glycocholic acid (GCA) and taurocholic acid (TCA)). Results showed that Tween 80 could significantly (P < 0.05) recover c9, t11 CLA production in the presence of all types of bile salts, but the Tween 80 could only significantly (P < 0.05) recover viable counts of the strain in the presence of CA, DCA and CDCA. This recovery ability could be attributed to the protection of leakage of intracellular material. Additionally, although bile salts inhibited growth and c9, t11 CLA production by the growing cell, it promoted the c9, t11 CLA production by the resting cell.
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Ácidos y Sales Biliares/farmacología , Proliferación Celular/efectos de los fármacos , Lactobacillus acidophilus/efectos de los fármacos , Ácidos Linoleicos Conjugados/biosíntesis , Polisorbatos/farmacología , Lactobacillus acidophilus/metabolismo , Lactobacillus acidophilus/fisiologíaRESUMEN
Until recently, necrosis is generally regarded as traumatic cell death due to mechanical shear stress or other physicochemical factors, while apoptosis is commonly thought to be programmed cell death, which is silent to immunological response. Actually, multiple modalities of cell death are programmed to maintain systematic immunity. Programmed necrosis, such as necrosis, pyroptosis, and ferroptosis, are inherently more immunogenic than apoptosis. Programmed necrosis leads to the release of inflammatory cytokines, defined as danger-associated molecular patterns (DAMPs), resulting in a necroinflammatory response, which can drive the proinflammatory state under certain biological circumstances. Ferroptosis as a newly discovered non-apoptotic form of cell death, is characterized by excessive lipid peroxidation and overload iron, which occurs in cancer, neurodegeneration, immune and inflammatory diseases, as well as ischemia/reperfusion (I/R) injury. It is triggered by a surplus of reactive oxygen species (ROS) induced in an imbalanced redox reaction due to the decrease in glutathione synthesis and inaction of enzyme glutathione peroxidase 4 (GPX4). Ferroptosis is considered as a potential therapeutic and molecular target for the treatment of necroinflammatory disease, and further investigation into the underlying pathophysiological characteristics and molecular mechanisms implicated may lay the foundations for an interventional therapeutic strategy. This review aims to demonstrate the key roles of ferroptosis in the development of necroinflammatory diseases, the major regulatory mechanisms involved, and its potential as a therapeutic target.
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Ferroptosis/inmunología , Inflamación/inmunología , Necrosis/inmunología , Animales , HumanosRESUMEN
Ischemia-reperfusion injury (IRI), critically involved in the pathology of reperfusion therapy for myocardial infarction, is closely related to oxidative stress the inflammatory response, and disturbances in energy metabolism. Emerging evidence shows that metabolic imbalances of iron participate in the pathophysiological process of cardiomyocyte IRI [also termed as myocardial ischemia-reperfusion injury (MIRI)]. Iron is an essential mineral required for vital physiological functions, including cellular respiration, lipid and oxygen metabolism, and protein synthesis. Nevertheless, cardiomyocyte homeostasis and viability are inclined to be jeopardized by iron-induced toxicity under pathological conditions, which is defined as ferroptosis. Upon the occurrence of IRI, excessive iron is transported into cells that drive cardiomyocytes more vulnerable to ferroptosis by the accumulation of reactive oxygen species (ROS) through Fenton reaction and Haber-Weiss reaction. The increased ROS production in ferroptosis correspondingly leads cardiomyocytes to become more sensitive to oxidative stress under the exposure of excess iron. Therefore, ferroptosis might play an important role in the pathogenic progression of MIRI, and precisely targeting ferroptosis mechanisms may be a promising therapeutic option to revert myocardial remodeling. Notably, targeting inhibitors are expected to prevent MIRI deterioration by suppressing cardiomyocyte ferroptosis. Here, we review the pathophysiological alterations from iron homeostasis to ferroptosis together with potential pathways regarding ferroptosis secondary to cardiovascular IRI. We also provide a comprehensive analysis of ferroptosis inhibitors and initiators, as well as regulatory genes involved in the setting of MIRI.
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Ferroptosis is a nonapoptotic form of programmed cell death triggered by the accumulation of reactive oxygen species (ROS) depended on iron overload. Although most investigations focus on the relationship between ferroptosis and cancer, neurodegenerative diseases, and ischemia/reperfusion injury, research on ferroptosis induced by immune-related inflammatory diseases, especially sepsis, is scarce. Sestrin2 (Sesn2), a highly evolutionary and stress-responsive protein, is critically involved in defense against oxidative stress challenges. Upregulated expression of Sesn2 has been observed in preliminary experiments to have an antioxidative function in the context of an inflammatory response. Nevertheless, the underlying function of Sesn2 in inflammation-mediated ferroptosis in the immune system remains uncertain. The current study aimed to demonstrate the protective effect of Sesn2 on ferroptosis and even correlations with ferroptosis and the functions of ferroptotic-dendritic cells (DCs) stimulated with lipopolysaccharide (LPS). The mechanism underlying DCs protection from LPS-induced ferroptosis by Sesn2 was further explored in this study. We found that the immune response of DCs assessed by co-stimulatory phenotypes was gradually enhanced at the peak time of 12 h upon 1 µg/ml LPS stimulation while ferroptosis in DCs treated with LPS at 24 h was significantly detected. LPS-induced ferroptosis showed a suppressive impact on DCs in phenotypic maturation, which was conversely relieved by the ferroptotic inhibitor. Compared with wild-type (WT) mice, DCs in genetic defective mice of Sesn2 (Sesn2-/-) exhibited exacerbated ferroptosis. Furthermore, the protective effect of Sesn2 on ferroptosis was noticed to be associated with the ATF4-CHOP-CHAC1 pathway, eventually exacerbating ferroptosis by degrading of glutathione. These results indicate that Sesn2 can suppress the ferroptosis of DCs in sepsis by downregulating the ATF4-CHOP-CHAC1 signaling pathway, and it might play an antioxidative role.
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Células Dendríticas/metabolismo , Ferroptosis , Peroxidasas/metabolismo , Sustancias Protectoras/metabolismo , Sepsis/metabolismo , Sepsis/patología , Factor de Transcripción Activador 4 , Animales , Ciego/patología , Diferenciación Celular , Células Dendríticas/inmunología , Células Dendríticas/ultraestructura , Regulación hacia Abajo , Inmunidad , Ligadura , Lipopolisacáridos , Masculino , Ratones Endogámicos C57BL , Fenotipo , Punciones , Sepsis/inmunología , Transducción de Señal , Bazo/citología , Factor de Transcripción CHOP/metabolismo , gamma-Glutamilciclotransferasa/metabolismoRESUMEN
Background: Sepsis can cause unpredictable harm, and early identification of risk for mortality may be conducive to clinical diagnosis. The present study proposes to assess the efficacy of the monocyte/high-density lipoprotein cholesterol ratio (MHR) combined with the neutrophil/lymphocyte ratio (NLR) on the day of admission in predictive efficacy in the 28-day mortality risk in critical patients with sepsis. Material and Methods: We administered observational and retrospective cohort research from a single center. The correlation of the clinical variables, together with the system severity scores of APACHE II and SOFA, are displayed by correlation analysis, and a Cox regression model could be performed to screen the independent risk factors and estimate the capacity of multiple markers in predicting 28-day mortality. The receiver operating characteristic (ROC) curve served as an applied method to output cutoff values for the diagnosis and prognostic risk, and the area under the ROC curve and net reclassification improvement index (NRI), as well as integrated discrimination improvement index (IDI) were employed to assess the feasibility of multiple parameters for predictive value in 28-day mortality of septic patients. Results: The study enrolled 274 eligible patients with sepsis. The correlation analysis indicated NLR and MHR were related to the sepsis severity. A multivariate Cox regression analysis indicated that NLR together with MHR displayed a close relation to death rate after adjusting for other potential confounders (NLR, HR = 1.404 [95% CI 1.170-1.684], P < 0.001; MHR, HR = 1.217 [95% CI 1.112-1.331], P < 0.001). The AUC of NLR, MHR, NLR_MHR was 0.827, 0.876, and 0.934, respectively. The addition on the biomarker NLR_MHR to the prediction model improved IDI by 18.5% and NRI by 37.8%. Conclusions: Our findings suggest that NLR and MHR trend to an elevated level in non-surviving patients with sepsis. Evaluation of NLR_MHR, an independent risk factor for increased mortality, might improve the predictive efficacy for 28-day mortality risk in septic patients.
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At present, there are still no anti-Zika virus (ZIKV) drugs or vaccines approved by FDA with accurate targets and antiviral mechanisms. Considering the RNA G-quadruplex sequences in ZIKV genome, it is very meaningful to develop G-quadruplex binders as potential anti-ZIKV drugs with novel and accurate targets. In this paper, five classical G-quadruplex binders including Ber, Braco 19, NiL, 360A and PDS have been chosen to discuss their interaction with ZIKV RNA G-quadruplexes. PDS shows higher binding affinity and thermal stability than the other G-quadruplex binders. This property is further evidenced in cells by immunofluorescence microscopy. And PDS shows higher anti-ZIKV activity (EC50 = 4.2 ± 0.4 µM) than the other G-quadruplex binders as well as the positive control ribavirin, with a low cytotoxicity. By time-of-addition assay, PDS exerts antiviral activity at the post-entry process of ZIKV replication cycle, thus inhibiting ZIKV mRNA replication and protein expression. Furthermore, PDS combines with ZIKV NS2B-NS3 protease and reduces its catalytic activity. This study suggests that G-quadruplex binder PDS is an effective multi-target ZIKV inhibitor, which provides more guidance to design some novel anti-ZIKV drugs targeting ZIKV RNA G-quadruplexes.
Asunto(s)
Aminoquinolinas/farmacología , Antivirales/farmacología , G-Cuádruplex , Ácidos Picolínicos/farmacología , Virus Zika/fisiología , Aminoquinolinas/química , Animales , Chlorocebus aethiops , Cinética , Péptido Hidrolasas/metabolismo , Ácidos Picolínicos/química , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Viral/genética , Termodinámica , Células Vero , Proteínas Virales/metabolismo , Virus Zika/efectos de los fármacos , Virus Zika/genéticaRESUMEN
Photonic-crystal fibers (PCFs) are widely recognized as efficient sources of white-light supercontinuum. Here, we show that a combination of an ultrashort-pulse ytterbium PCF laser with a highly nonlinear PCF enables all-fiber generation of ultrashort pulses of coherent UV radiation in the black-light spectral region with all the key processes, such as lasing, amplification, and conversion of the amplified PCF-laser output to the UV range, taking place in specifically designed fiber components.