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The incidence of myopia, particularly high myopia, is increasing annually. Myopia has gradually become one of the leading causes of global blindness and is a considerable public-health concern. However, the pathogenesis of myopia remains unclear, and exploring the mechanism underlying myopia has become an urgent scientific priority. Creating animal models of myopia is important for studying the pathogenesis of refractive errors. This approach allows researchers to study and analyze the pathogenesis of myopia from aspects such as changes in refractive development, pathological changes in eye tissue, and molecular pathways related to myopia. This review summarizes the examples of animal models, methods of inducing myopia experimentally, and molecular signaling pathways involved in developing myopia-induced animal models. This review provides solid literature for researchers in the field of myopia prevention and control. It offers guidance in selecting appropriate animal models and research methods to fit their research objectives. By providing new insights and a theoretical basis for studying mechanisms of myopia, we detail how elucidated molecular pathways can be exploited to translate into safe and effective measures for myopia prevention and control.
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Liquid biopsy provides a convenient and safer procedure for the diagnosis and genomic profiling of tumors that are inaccessible to biopsy by analyzing exfoliated tumor cells (ETCs) or tumor-derived cell-free DNA (cfDNA). However, its primary challenge lies in its limited accuracy in comparison to tissue-based approaches. We report a parallel single-ETC genomic sequencing (Past-Seq) method for the accurate diagnosis and genomic profiling of hard-to-biopsy tumors such as cholangiocarcinoma (CCA) and upper tract urothelial carcinoma (UTUC). For CCA, a prospective cohort of patients with suspicious biliary strictures (n = 36) was studied. Parallel single-cell whole genome sequencing and whole exome sequencing were performed on bile ETCs for CCA diagnosis and resolving mutational profiles, respectively, along with bile cfDNA sequenced for comparison. Concordant single-cell copy number alteration (CNA) profiles in multiple ETCs provided compelling evidence for generating a malignant diagnosis. Past-Seq yielded bile-based accurate CCA diagnosis (96% sensitivity, 100% specificity, and positive predictive value), surpassing pathological evaluation (56% sensitivity) and bile cfDNA CNA analysis (13% sensitivity), and generated the best performance in the retrieval tissue mutations. To further explore the applicability of Past-Seq, 10 suspicious UTUC patients were investigated with urine specimens, and Past-Seq exhibited 90% sensitivity in diagnosing UTUC, demonstrating its broad applicability across various liquid biopsies and cancer types.
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Análisis de la Célula Individual , Humanos , Biopsia Líquida , Colangiocarcinoma/diagnóstico , Colangiocarcinoma/genética , Colangiocarcinoma/patología , Neoplasias de los Conductos Biliares/diagnóstico , Neoplasias de los Conductos Biliares/genética , Neoplasias de los Conductos Biliares/patología , Genómica , Femenino , Masculino , Anciano , Persona de Mediana Edad , MutaciónRESUMEN
OBJECTIVE: To investigate the effects of astragaloside IV (AS-IV) on podocyte injury of diabetic nephropathy (DN) and reveal its potential mechanism. METHODS: In in vitro experiment, podocytes were divided into 4 groups, normal, high glucose (HG), inositol-requiring enzyme 1 (IRE-1) α activator (HG+thapsigargin 1 µmol/L), and IRE-1α inhibitor (HG+STF-083010, 20 µmol/L) groups. Additionally, podocytes were divided into 4 groups, including normal, HG, AS-IV (HG+AS-IV 20 µmol/L), and IRE-1α inhibitor (HG+STF-083010, 20 µmol/L) groups, respectively. After 24 h treatment, the morphology of podocytes and endoplasmic reticulum (ER) was observed by electron microscopy. The expressions of glucose-regulated protein 78 (GRP78) and IRE-1α were detected by cellular immunofluorescence. In in vivo experiment, DN rat model was established via a consecutive 3-day intraperitoneal streptozotocin (STZ) injections. A total of 40 rats were assigned into the normal, DN, AS-IV [AS-IV 40 mg/(kg·d)], and IRE-1α inhibitor [STF-083010, 10 mg/(kg·d)] groups (n=10), respectively. The general condition, 24-h urine volume, random blood glucose, urinary protein excretion rate (UAER), urea nitrogen (BUN), and serum creatinine (SCr) levels of rats were measured after 8 weeks of intervention. Pathological changes in the renal tissue were observed by hematoxylin and eosin (HE) staining. Quantitative reverse transcription-polymerase chain reaction (RT-PCR) and Western blot were used to detect the expressions of GRP78, IRE-1α, nuclear factor kappa Bp65 (NF-κBp65), interleukin (IL)-1ß, NLR family pyrin domain containing 3 (NLRP3), caspase-1, gasdermin D-N (GSDMD-N), and nephrin at the mRNA and protein levels in vivo and in vitro, respectively. RESULTS: Cytoplasmic vacuolation and ER swelling were observed in the HG and IRE-1α activator groups. Podocyte morphology and ER expansion were improved in AS-IV and IRE-1α inhibitor groups compared with HG group. Cellular immunofluorescence showed that compared with the normal group, the fluorescence intensity of GRP78 and IRE-1α in the HG and IRE-1α activator groups were significantly increased whereas decreased in AS-IV and IRE-1α inhibitor groups (P<0.05). Compared with the normal group, the mRNA and protein expressions of GRP78, IRE-1α, NF-κ Bp65, IL-1ß, NLRP3, caspase-1 and GSDMD-N in the HG group was increased (P<0.05). Compared with HG group, the expression of above indices was decreased in the AS-IV and IRE-1α inhibitor groups, and the expression in the IRE-1α activator group was increased (P<0.05). The expression of nephrin was decreased in the HG group, and increased in AS-IV and IRE-1α inhibitor groups (P<0.05). The in vivo experiment results revealed that compared to the normal group, the levels of blood glucose, triglyceride, total cholesterol, BUN, blood creatinine and urinary protein in the DN group were higher (P<0.05). Compared with DN group, the above indices in AS-IV and IRE-1α inhibitor groups were decreased (P<0.05). HE staining revealed glomerular hypertrophy, mesangial widening and mesangial cell proliferation in the renal tissue of the DN group. Compared with the DN group, the above pathological changes in renal tissue of AS-IV and IRE-1α inhibitor groups were alleviated. Quantitative RT-PCR and Western blot results of GRP78, IRE-1α, NF-κ Bp65, IL-1ß, NLRP3, caspase-1 and GSDMD-N were consistent with immunofluorescence analysis. CONCLUSION: AS-IV could reduce ERS and inflammation, improve podocyte pyroptosis, thus exerting a podocyte-protective effect in DN, through regulating IRE-1α/NF-κ B/NLRP3 signaling pathway.
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Mitophagy is critical for mitochondrial quality control and function to clear damaged mitochondria. Here, we found that Burkholderia pseudomallei maneuvered host mitophagy for its intracellular survival through the type III secretion system needle tip protein BipD. We identified BipD, interacting with BTB-containing proteins KLHL9 and KLHL13 by binding to the Back and Kelch domains, recruited NEDD8 family RING E3 ligase CUL3 in response to B. pseudomallei infection. Although evidently not involved in regulation of infectious diseases, KLHL9/KLHL13/CUL3 E3 ligase complex was essential for BipD-dependent ubiquitination of mitochondria in mouse macrophages. Mechanistically, we discovered the inner mitochondrial membrane IMMT via host ubiquitome profiling as a substrate of KLHL9/KLHL13/CUL3 complex. Notably, K63-linked ubiquitination of IMMT K211 was required for initiating host mitophagy, thereby reducing mitochondrial ROS production. Here, we show a unique mechanism used by bacterial pathogens that hijacks host mitophagy for their survival.
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Proteínas Bacterianas , Burkholderia pseudomallei , Macrófagos , Mitocondrias , Mitofagia , Burkholderia pseudomallei/metabolismo , Burkholderia pseudomallei/patogenicidad , Burkholderia pseudomallei/fisiología , Burkholderia pseudomallei/genética , Animales , Ratones , Mitocondrias/metabolismo , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/genética , Humanos , Macrófagos/microbiología , Macrófagos/metabolismo , Ubiquitinación , Melioidosis/microbiología , Melioidosis/metabolismo , Interacciones Huésped-Patógeno , Especies Reactivas de Oxígeno/metabolismo , Sistemas de Secreción Tipo III/metabolismo , Sistemas de Secreción Tipo III/genética , Ratones Endogámicos C57BL , Membranas Mitocondriales/metabolismo , Células HEK293 , Células RAW 264.7RESUMEN
Photobiomodulation (PBM) therapy uses light of different wavelengths to treat various retinal degeneration diseases, but the potential damage to the retina caused by long-term light irradiation is still unclear. This study were designed to detect the difference between long- and short-wavelength light (650-nm red light and 450-nm blue light, 2.55 mW/cm2, reference intensity in PBM)-induced injury. In addition, a comparative study was conducted to investigate the differences in retinal light damage induced by different irradiation protocols (short periods of repeated irradiation and a long period of constant irradiation). Furthermore, the protective role of PARP-1 inhibition on the molecular mechanism of blue light-induced injury was confirmed by a gene knockdown technique or a specific inhibitor through in vitro and in vivo experiments. The results showed that the susceptibility to retinal damage caused by irradiation with long- and short-wavelength light is different. Shorter wavelength lights, such as blue light, induce more severe retinal damage, while the retina exhibits better resistance to longer wavelength lights, such as red light. In addition, repeated irradiation for short periods induces less retinal damage than constant exposure over a long period. PARP-1 plays a critical role in the molecular mechanism of blue light-induced damage in photoreceptors and retina, and inhibiting PARP-1 can significantly protect the retina against blue light damage. This study lays an experimental foundation for assessing the safety of phototherapy products and for developing target drugs to protect the retina from light damage.
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Luz , Poli(ADP-Ribosa) Polimerasa-1 , Retina , Degeneración Retiniana , Animales , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Ratones , Luz/efectos adversos , Retina/efectos de la radiación , Retina/patología , Degeneración Retiniana/etiología , Degeneración Retiniana/metabolismo , Degeneración Retiniana/patología , Degeneración Retiniana/prevención & control , Ratones Endogámicos C57BL , Traumatismos Experimentales por Radiación/patología , Traumatismos Experimentales por Radiación/metabolismo , Modelos Animales de Enfermedad , Western Blotting , Masculino , Terapia por Luz de Baja Intensidad , Luz AzulRESUMEN
OBJECTIVE: To explore the molecular mechanism of Astragaloside IV (AS-IV) in alleviating renal fibrosis by inhibiting Urotensin II-induced pyroptosis and epithelial-mesenchymal transition of renal tubular epithelial cells. METHODS: Forty SD rats were randomly divided into control group without operation: gavage with 5ml/kg/d water for injection and UUO model group: gavage with 5ml/kg/d water for injection; UUO+ AS-IV group (gavage with AS-IV 20mg/kg/d; and UUO+ losartan potassium group (gavage with losartan potassium 10.3mg/kg/d, with 10 rats in each group. After 2 weeks, Kidney pathology, serum Urotensin II, and cAMP concentration were detected, and the expressions of NLRP3, GSDMD-N, Caspase-1, and IL-1ß were detected by immunohistochemistry. Rat renal tubular epithelial cells were cultured in vitro, and different concentrations of Urotensin II were used to intervene for 24h and 48h. Cell proliferation activity was detected using the CCK8 assay. Suitable concentrations of Urotensin II and intervention time were selected, and Urotensin II receptor antagonist (SB-611812), inhibitor of PKA(H-89), and AS-IV (15ug/ml) were simultaneously administered. After 24 hours, cells and cell supernatants from each group were collected. The cAMP concentration was detected using the ELISA kit, and the expression of PKA, α-SMA, FN, IL-1ß, NLRP3, GSDMD-N, and Caspase-1 was detected using cell immunofluorescence, Western blotting, and RT-PCR. RESULTS: Renal tissue of UUO rats showed renal interstitial infiltration, tubule dilation and atrophy, renal interstitial collagen fiber hyperplasia, and serum Urotensin II and cAMP concentrations were significantly higher than those in the sham operation group (p <0.05). AS-IV and losartan potassium intervention could alleviate renal pathological changes, and decrease serum Urotensin II, cAMP concentration levels, and the expressions of NLRP3, GSDMD-N, Caspase-1, and IL-1ß in renal tissues (p <0.05). Urotensin II at a concentration of 10-8 mol/L could lead to the decrease of cell proliferation, (p<0.05). Compared with the normal group, the cAMP level and the PKA expression were significantly increased (p<0.05). After intervention with AS-IV and Urotensin II receptor antagonist, the cAMP level and the expression of PKA were remarkably decreased (p<0.05). Compared with the normal group, the expression of IL-1ß, NLRP3, GSDMD-N, and Caspase-1 in the Urotensin II group was increased (p<0.05), which decreased in the AS-IV and H-89 groups. CONCLUSION: AS-IV can alleviate renal fibrosis by inhibiting Urotensin II-induced pyroptosis of renal tubular epithelial cells by regulating the cAMP/PKA signaling pathway.
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Proteínas Quinasas Dependientes de AMP Cíclico , AMP Cíclico , Células Epiteliales , Túbulos Renales , Piroptosis , Saponinas , Transducción de Señal , Triterpenos , Urotensinas , Animales , Masculino , Ratas , AMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Células Epiteliales/metabolismo , Células Epiteliales/efectos de los fármacos , Células Epiteliales/patología , Transición Epitelial-Mesenquimal/efectos de los fármacos , Fibrosis , Enfermedades Renales/metabolismo , Enfermedades Renales/tratamiento farmacológico , Enfermedades Renales/patología , Enfermedades Renales/etiología , Túbulos Renales/patología , Túbulos Renales/metabolismo , Túbulos Renales/efectos de los fármacos , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Piroptosis/efectos de los fármacos , Ratas Sprague-Dawley , Saponinas/farmacología , Transducción de Señal/efectos de los fármacos , Triterpenos/farmacología , Urotensinas/metabolismoRESUMEN
BACKGROUND: The preservation of retinal ganglion cells (RGCs) and the facilitation of axon regeneration are crucial considerations in the management of various vision-threatening disorders. Therefore, we investigate the efficacy of interleukin-4 (IL-4), a potential therapeutic agent, in promoting neuroprotection and axon regeneration of retinal ganglion cells (RGCs) as identified through whole transcriptome sequencing in an in vitro axon growth model. METHODS: A low concentration of staurosporine (STS) was employed to induce in vitro axon growth. Whole transcriptome sequencing was utilized to identify key target factors involved in the molecular mechanism underlying axon growth. The efficacy of recombinant IL-4 protein on promoting RGC axon growth was validated through in vitro experiments. The protective effect of recombinant IL-4 protein on somas of RGCs was assessed using RBPMS-specific immunofluorescent staining in mouse models with optic nerve crush (ONC) and N-methyl-D-aspartic acid (NMDA) injury. The protective effect on RGC axons was evaluated by anterograde labeling of cholera toxin subunit B (CTB), while the promotion of RGC axon regeneration was assessed through both anterograde labeling of CTB and immunofluorescent staining for growth associated protein-43 (GAP43). RESULTS: Whole-transcriptome sequencing of staurosporine-treated 661 W cells revealed a significant upregulation in intracellular IL-4 transcription levels during the process of axon regeneration. In vitro experiments demonstrated that recombinant IL-4 protein effectively stimulated axon outgrowth. Subsequent immunostaining with RBPMS revealed a significantly higher survival rate of RGCs in the rIL-4 group compared to the vehicle group in both NMDA and ONC injury models. Axonal tracing with CTB confirmed that recombinant IL-4 protein preserved long-distance projection of RGC axons, and there was a notably higher number of surviving axons in the rIL-4 group compared to the vehicle group following NMDA-induced injury. Moreover, intravitreal delivery of recombinant IL-4 protein substantially facilitated RGC axon regeneration after ONC injury. CONCLUSION: The recombinant IL-4 protein exhibits the potential to enhance the survival rate of RGCs, protect RGC axons against NMDA-induced injury, and facilitate axon regeneration following ONC. This study provides an experimental foundation for further investigation and development of therapeutic agents aimed at protecting the optic nerve and promoting axon regeneration.
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Axones , Interleucina-4 , Regeneración Nerviosa , Células Ganglionares de la Retina , Células Ganglionares de la Retina/efectos de los fármacos , Células Ganglionares de la Retina/metabolismo , Animales , Interleucina-4/farmacología , Axones/efectos de los fármacos , Axones/metabolismo , Regeneración Nerviosa/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Traumatismos del Nervio Óptico/patología , Traumatismos del Nervio Óptico/tratamiento farmacológico , N-Metilaspartato/farmacología , Estaurosporina/farmacología , Fármacos Neuroprotectores/farmacología , Proteínas Recombinantes/farmacologíaRESUMEN
BACKGROUND: MDR Staphylococcus aureus infections, along with the severity of biofilm-associated infections, continue to threaten human health to a great extent. It necessitates the urgent development of novel antimicrobial and antibiofilm agents. OBJECTIVES: To reveal the mechanism and target of cinacalcet as an antibacterial and antimicrobial agent for S. aureus. METHODS: Screening of non-antibiotic drugs for antibacterial and antibiofilm properties was conducted using a small-molecule drug library. In vivo efficacy was assessed through animal models, and the antibacterial mechanism was studied using quantitative proteomics, biochemical assays, LiP-SMap, BLI detection and gene knockout techniques. RESULTS: Cinacalcet, an FDA-approved drug, demonstrated antibacterial and antibiofilm activity against S. aureus, with less observed development of bacterial resistance. Importantly, cinacalcet significantly improved survival in a pneumonia model and bacterial clearance in a biofilm infection model. Moreover, the antibacterial mechanism of cinacalcet mainly involves the destruction of membrane-targeted structures, alteration of energy metabolism, and production of reactive oxygen species (ROS). Cinacalcet was found to target IcaR, inhibiting biofilm formation through the negative regulation of IcaADBC. CONCLUSIONS: The findings suggest that cinacalcet has potential for repurposing as a therapeutic agent for MDR S. aureus infections and associated biofilms, warranting further investigation.
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Antiinfecciosos , Staphylococcus aureus Resistente a Meticilina , Infecciones Estafilocócicas , Animales , Humanos , Staphylococcus aureus , Cinacalcet/farmacología , Cinacalcet/uso terapéutico , Complejo Hierro-Dextran/uso terapéutico , Reposicionamiento de Medicamentos , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Antiinfecciosos/uso terapéutico , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/microbiología , Membrana Celular , Biopelículas , Pruebas de Sensibilidad MicrobianaRESUMEN
Zearalenone (ZEA), one of the usual mycotoxins, has been recognized in many areas and crops, posing a significant threat to the living organisms even to human beings. However, the mechanisms of locomotive defects remain unknown. Herein, zebrafish larvae was employed to investigate ZEA effects on developmental indexes, muscle and neural toxicity, apoptosis, transcriptome and motor behaviors of zebrafish larvae. Zebrafish larvae exposed to ZEA (0, 0.5, 1, 2 and 4 µM) showed no change in survival rate, but the malformation rate of zebrafish larvae increased dramatically manifesting with severe body bending and accomplished with adverse effects on hatching rate and body length. Moreover, the larvae manifested with defective muscle and abnormal neural development, resulting in decreased swimming ability, which probably due to the abnormal overactivation of apoptosis. And this was confirmed by enriched caspase 8-mediated apoptosis signaling pathway in the following transcriptome analysis. Meanwhile, there was a recovery in swimming behaviors in the larvae co-exposed in ZEA and caspase 8 inhibitor. These findings provide an important evidence for risk assessment and potential treatment target of ZEA exposure.
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Discinesias , Zearalenona , Animales , Humanos , Apoptosis , Caspasa 8/genética , Caspasa 8/metabolismo , Larva , Músculos/metabolismo , Zearalenona/toxicidad , Zearalenona/metabolismo , Pez Cebra , Micotoxinas/química , Micotoxinas/metabolismoRESUMEN
Soil moisture (SM) directly controls the land surface energy partition which plays an important role in the formation of extreme weather events. However, its dependence on specific climatic conditions is not thoroughly understood due to the complexity of soil moisture effects. Here, we examine the relationship between SM and surface energy partitioning under different climate conditions, and identify the influence paradigms of soil moisture on surface energy partition. We find that temperature changes can explicitly determine the impact paradigm of different physical processes, i.e. evapotranspiration, soil freezing and thawing, and such influence paradigms are also affected by atmospheric aridity (VPD). Globally, there are five paradigms that effects on surface energy partitioning, including the warm-wet paradigm (WW), transitional paradigm (TP), warm-dry paradigm (WD), cool-wet paradigm (CW) and cold paradigm (CP). Since 1981, the global area proportion for TP is observed to increase pronouncedly. We also find that the critical SM threshold exhibits regional variations and the global average is 0.45 m3/m3. The identified paradigms and their long-term change trends provide new insights into the global intensification of land-atmosphere interaction, which has important implications for global warming and the formation of heatwaves.
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Ciprofloxacin (CIP) is a prevalent environmental contaminant that poses a high risk of antibiotic resistance. High concentrations of antibiotics can lead to the development of resistant bacteria with high fitness costs, which often face a competitive disadvantage. However, it is unclear whether low-cost resistant bacteria formed by exposure to sub-MIC CIP in the environment can evolve competitive mechanisms against sensitive Escherichia coli (SEN) other than stronger resistance to CIP. Our study exposed E. coli to sub-MIC CIP levels, resulting in the development of CIP-resistant E. coli (CIPr). In antibiotic-free co-culture assays, CIPr outcompeted SEN. This indicates that CIPr is very likely to continue to develop and spread in antibiotic-free environments such as drinking water and affect human health. Further mechanism investigation revealed that bacterial membrane vesicles (BMVs) in CIPr, functioning as substance delivery couriers, mediated a cleavage effect on SEN. Proteomic analysis identified Entericidin B (EcnB) within CIPr-BMVs as a key factor in this competitive interaction. RT-qPCR analysis showed that the transcription of its negative regulator ompR/envZ was down-regulated. Moreover, EcnB plays a crucial role in the development of CIP resistance, and some resistance-related proteins and pathways have also been discovered. Metabolomics analysis highlighted the ability of CIPr-BMVs to acidify SEN, increasing the lytic efficiency of EcnB through cationization. Overall, our study reveals the importance of BMVs in mediating bacterial resistance and competition, suggesting that regulating BMVs production may be a new strategy for controlling the spread of drug-resistant bacteria.
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Ciprofloxacina , Escherichia coli , Humanos , Ciprofloxacina/farmacología , Escherichia coli/genética , Proteómica , Pruebas de Sensibilidad Microbiana , Antibacterianos/farmacología , BacteriasRESUMEN
Working memory training (WMT) has shown potential benefits in emotion regulation (ER), mainly in terms of improved ability to downregulate negative emotions in cognitive reappraisal. However, the goal of cognitive reappraisal can be not only to reduce negative emotion but also to increase negative emotion. It is not clear what effect WMT has on the upregulation of negative emotion. In the current study, we conducted a 20-day WMT with participants to explore the effects of training on the down- and upregulation of negative emotion and followed participants for 3 months after training to examine the persistent effects of training. Our results suggest that participants in the training group improved their ability to regulate negative emotions in both the down- and upregulation conditions. Notably, benefits from training were also observed in the look negative condition, suggesting that WMT may elicit general cognitive enhancement that is broadly transferable to any kind of negative situation to help individuals regulate the effects of negative emotions. In addition, our study also showed that the improvement in negative ER by training could last even over 3 months. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
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Emociones , Objetivos , Humanos , Emociones/fisiología , Cognición/fisiología , Entrenamiento Cognitivo , Memoria a Corto Plazo/fisiologíaRESUMEN
To investigate the effect of isoliquiritigenin (ISL) on high glucose (HG)-induced glomerular mesangial cells (GMCs) proliferation, extracellular matrix (ECM) deposition and inflammation, and the underlying mechanisms. Mouse GMCs (SV40-MES-13) were cultured in HG medium, with or without ISL. The proliferation of GMCs was determined by MTT assay. The production of proinflammatory cytokines was detected by qRT-PCR and ELISA. The expression of connective tissue growth factor (CTGF), TGF-ß1, collagen IV, and fibronectin was measured by qRT-PCR and western blot. The phosphorylation of JAK2 and STAT3 was examined by western blot. Next, JAK2 inhibitor AG490 was applied to HG-exposed GMCs. The levels of JAK2/STAT3 phosphorylation and pro-fibrotic markers were analyzed by western blot, and the secretion of TNF-α and IL-1ß was evaluated by ELISA. GMCs were treated with HG, HG plus ISL or HG plus ISL, and recombinant IL-6 (rIL-6) which is a JAK2 activator. The levels of JAK2/STAT3 activation, ECM formation, and proinflammatory cytokines secretion were determined by western blot and ELISA, respectively. In mouse GMCs, ISL successfully repressed HG-induced hyperproliferation; production of TNF-α and IL-1ß; expression of CTGF, TGF-ß1, collagen IV, and fibronectin; and activation of JAK2/STAT3. Similar to ISL, AG490 was able to reverse the inflammation and ECM generation caused by HG. Moreover, rIL-6 impeded the amelioration of ISL on HG-induced adverse effects. Our study demonstrated that ISL displayed preventive effects on HG-exposed GMCs through inhibiting JAK2/STAT3 pathway and provided an insight into the application of ISL for diabetic nephropathy (DN) treatment.
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Células Mesangiales , Factor de Crecimiento Transformador beta1 , Ratones , Animales , Factor de Crecimiento Transformador beta1/metabolismo , Fibronectinas , Factor de Necrosis Tumoral alfa/metabolismo , Glucosa/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Citocinas/metabolismo , Proliferación Celular , Matriz Extracelular/metabolismo , Colágeno/metabolismoRESUMEN
Background: Child sexual abuse is a major public health problem with adverse consequences for victims' physical, mental, and reproductive health. This cross-sectional study aimed to determine the prevalence of child sexual abuse and its associated factors among 15- to 17-year-old adolescents in mainland China. Methods: From September 8, 2019 to January 17, 2020, a total of 48,660 participants were recruited by 58 colleges and universities across the whole country to complete the self-administered, structured, online questionnaire. This analysis was restricted to 3,215 adolescents aged between 15 and 17 years in mainland China. Chi-square tests and multivariate Logistic regression analyses were performed to identify individual, relationship, and community factors associated with child sexual abuse. Results: The overall prevalence of child sexual abuse was 12.0%. More specifically, 13.0% of girls and 10.6% of boys reported that they were sexually abused prior to 18 years of age. At the individual level, being female, sexual minority identity, younger age, and higher levels of knowledge, skills and self-efficacy regarding condom use were significantly related to increased odds of reporting sexual abuse. At the relationship and community level, adolescents from disrupted families and those entering into a marriage, having casual sexual partners, and having first intercourse at a younger age were more likely to report sexual abuse. On the contrary, those who had never discussed sex-related topics with their family members at home and were offered school-based sexuality education later (vs. earlier) were less likely to report sexual abuse. Conclusion: Multilevel prevention programs and strategies, including targeting adolescents with high-risk characteristics, educating young children and their parents about child sexual abuse prevention and optimizing the involvement of parents, school, community, society and government in comprehensive sexuality education, should be taken to reduce child sexual abuse among 15- to 17-year-old adolescents.
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Abuso Sexual Infantil , Masculino , Humanos , Adolescente , Femenino , Niño , Preescolar , Estudios Transversales , Conducta Sexual , Encuestas y Cuestionarios , China/epidemiologíaRESUMEN
Axonal degeneration is a pathologic change common to multiple retinopathies and optic neuropathies. Various pathologic factors, such as mechanical injury, inflammation, and ischemia, can damage retinal ganglion cell (RGC) somas and axons, eventually triggering axonal degeneration and RGC death. The molecular mechanisms of somal and axonal degeneration are distinct but also overlap, and axonal degeneration can result in retrograde somal degeneration. While the mitogen-activated protein kinase pathway acts as a central node in RGC axon degeneration, several newly discovered molecules, such as sterile alpha and Toll/interleukin-1 receptor motif-containing protein 1 and nicotinamide mononucleotide adenylyltransferase 2, also play a critical role in this pathological process following different types of injury. Therefore, we summarize the types of injury that cause RGC axon degeneration and retrograde RGC death and important underlying molecular mechanisms, providing a reference for the identification of targets for protecting axons and RGCs.
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Axones , Células Ganglionares de la Retina , Células Ganglionares de la Retina/metabolismo , Células Ganglionares de la Retina/patología , Axones/metabolismo , Axones/patologíaRESUMEN
To investigate the effect of astragaloside IV (AS) on podocytes pyroptosis in diabetic kidney disease (DKD). Forty male Sprague-Dawley rats were randomly divided into normal group (n = 10) and model group (n = 30). Rats in model group were intraperitoneally injected streptozotocin (60 mg/kg) for 3 days to induce DKD. Then rats were divided into DKD group, AS group, and UBCS group. The AS group was given 40 mg/kg/d of AS by gavage, and UBCS group was given 50 mg/kg/d of UBCS039 by gavage, and normal group and DKD group were given the same amount saline for 8 weeks, once a day. Hematoxylin-eosin and masson staining were used to observe pathology of kidney. Rat podocytes were divided into normal group, mannitol hypertonic group, high-glucose group, UBCS group, OSS group, and AS group. Western blotting, quantitative real-time polymerase chain reaction, immunofluorescence, and flow cytometry were used to analyze pyroptosis-related markers and reactive oxygen species (ROS) levels. Results showed that AS inhibited ROS and alleviated podocytes pyroptosis in rats by increasing expression of sirtuin 6 (SIRT6) and decreasing expression of hypoxia inducible factor 1 subunit alpha (HIF-1α). UBCS039 and AS enhanced SIRT6 level, decreased HIF-1α level, and finally improved pyroptosis of podocytes in vitro, whereas OSS-128167 showed the opposite effect for podocytes pyroptosis. AS improved podocytes pyroptosis in DKD by regulating SIRT6/HIF-1α pathway, thereby alleviating injury of DKD.
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Nefropatías Diabéticas , Podocitos , Piroptosis , Saponinas , Sirtuinas , Triterpenos , Animales , Masculino , Ratas , Nefropatías Diabéticas/tratamiento farmacológico , Podocitos/efectos de los fármacos , Podocitos/metabolismo , Piroptosis/efectos de los fármacos , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Sirtuinas/metabolismo , Saponinas/farmacología , Saponinas/uso terapéutico , Triterpenos/farmacología , Triterpenos/uso terapéuticoRESUMEN
OBJECTIVES: Because buprenorphine treatment of opioid use disorder reduces opioid overdose deaths (OODs), expanding access to care is an important policy and clinical care goal. Policymakers must choose within capacity limitations whether to expand the number of people with opioid use disorder who are treated or extend duration for existing patients. This inherent tradeoff could be made less acute with expanded buprenorphine treatment capacity. METHODS: To inform such decisions, we used a validated simulation model to project the effects of increasing buprenorphine treatment-seeking, average episode duration, and capacity (patients per provider) on OODs in the United States from 2023 to 2033, varying the start time to assess the effects of implementation delays. RESULTS: Results show that increasing treatment duration alone could cost lives in the short term by reducing capacity for new admissions yet save more lives in the long term than accomplished by only increasing treatment seeking. Increasing provider capacity had negligible effects. The most effective 2-policy combination was increasing capacity and duration simultaneously, which would reduce OODs up to 18.6% over a decade. By 2033, the greatest reduction in OODs (≥20%) was achieved when capacity was doubled and average duration reached 2 years, but only if the policy changes started in 2023. Delaying even a year diminishes the benefits. Treatment-seeking increases were equally beneficial whether they began in 2023 or 2025 but of only marginal benefit beyond what capacity and duration achieved. CONCLUSIONS: If policymakers only target 2 policies to reduce OODs, they should be to increase capacity and duration, enacted quickly and aggressively.
Asunto(s)
Buprenorfina , Sobredosis de Droga , Sobredosis de Opiáceos , Trastornos Relacionados con Opioides , Humanos , Estados Unidos , Buprenorfina/uso terapéutico , Antagonistas de Narcóticos/uso terapéutico , Sobredosis de Opiáceos/tratamiento farmacológico , Tratamiento de Sustitución de Opiáceos/métodos , Trastornos Relacionados con Opioides/tratamiento farmacológico , Sobredosis de Droga/tratamiento farmacológico , Analgésicos Opioides/uso terapéuticoRESUMEN
Bisabolene is a bioactive sesquiterpene with a wide range of applications in food, cosmetics, medicine, and aviation fuels. Microbial production offers a green, efficient, and sustainable alternative. In this study, we focused on improving the titers of α-bisabolene in Yarrowia lipolytica by applying two strategies, (i) optimizing the metabolic flux of α-bisabolene biosynthetic pathway and (ii) sequestering α-bisabolene in lipid droplet, thus alleviating its inherent toxicity to host cells. We showed that overexpression of DGA1 and OLE1 to increase lipid content and unsaturated fatty acid levels was essential for boosting the α-bisabolene synthesis when supplemented with auxiliary carbon sources. The final engineered strain Po1gαB10 produced 1954.3 mg/L α-bisabolene from the waste cooking oil under shake flask fermentation, which was 96-fold higher than the control strain Po1gαB0. At the time of writing, our study represents the highest reported α-bisabolene titer in the engineered Y. lipolytica cell factory. This work describes novel strategies to improve the bioproduction of α-bisabolene that potentially may be applicable for other high-value terpene products.
Asunto(s)
Sesquiterpenos , Yarrowia , Yarrowia/genética , Yarrowia/metabolismo , Ingeniería Metabólica , Gotas Lipídicas/metabolismo , Terpenos/metabolismo , Sesquiterpenos/metabolismoRESUMEN
Dysregulation of nucleocytoplasmic shuttling impairs cellular homeostasis and promotes cancer development. KPNB1 is a member of karyopherin ß family, mediating the transportation of proteins from the cytoplasm to the nucleus. In a variety of cancers, the expression of KPNB1 is upregulated to facilitate tumor growth and progression. Both downregulation of KPNB1 level and inhibition of KPNB1 activity prevent the entry of cancer-related transcription factors into the nucleus, subsequently suppressing the proliferation and metastasis of cancer cells. Currently, five KPNB1 inhibitors have been reported and exhibited good efficacy against cancer. This paper provides an overview of the role and mechanism of KPNB1 in different cancers and KPNB1-targeted anticancer compounds which hold promise for the future.