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1.
Proc Natl Acad Sci U S A ; 121(21): e2313797121, 2024 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-38709948

RESUMEN

During 2010 to 2020, Northeast Pacific (NEP) sea surface temperature (SST) experienced the warmest decade ever recorded, manifested in several extreme marine heatwaves, referred to as "warm blob" events, which severely affect marine ecosystems and extreme weather along the west coast of North America. While year-to-year internal climate variability has been suggested as a cause of individual events, the causes of the continuous dramatic NEP SST warming remain elusive. Here, we show that other than the greenhouse gas (GHG) forcing, rapid aerosol abatement in China over the period likely plays an important role. Anomalous tropospheric warming induced by declining aerosols in China generated atmospheric teleconnections from East Asia to the NEP, featuring an intensified and southward-shifted Aleutian Low. The associated atmospheric circulation anomaly weakens the climatological westerlies in the NEP and warms the SST there by suppressing the evaporative cooling. The aerosol-induced mean warming of the NEP SST, along with internal climate variability and the GHG-induced warming, made the warm blob events more frequent and intense during 2010 to 2020. As anthropogenic aerosol emissions continue to decrease, there is likely to be an increase in NEP warm blob events, disproportionately large beyond the direct radiative effects.

2.
Anim Genet ; 55(2): 249-256, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38194424

RESUMEN

The genetic foundation of chicken body plumage color has been extensively studied. However, little attention has been paid to the inheritance patterns and molecular mechanisms underlying the formation of distal feather colors (tail and wingtip). Differences in these colors are common; for example, the Chinese Huiyang Beard chicken has black tail feathers, but yellow body plumage. Here, the hybrid offspring of Huiyang Beard and White Leghorn chickens were used to study the inheritance patterns of tail-feather color. The expression levels of pigment genes in differently colored feather follicles were analyzed using quantitative real-time PCR. The results showed that genetic regulation of tail-feather color was independent of body-plumage color. The Dominant White locus inhibited eumelanin synthesis in tail feathers without affecting the formation of yellow body plumage, whereas the Silver locus had the opposite effect. The expression of agouti signaling protein (ASIP) gene class 1 transcripts was significantly lower in black tail-feather follicles than in yellow body follicles, whereas tyrosinase-related protein 1 (TYRP1) gene expression was significantly higher in black tail feathers. These differentially expressed genes were confirmed to exert an effect on eumelanin and pheomelanin formation in feathers, thus influencing the regulation of chicken tail-feather color. In conclusion, this study lays the foundation for further research on the genetic mechanisms of regional differences in feather color, contributing to a better understanding of plumage pigmentation in chickens.


Asunto(s)
Pollos , Cola (estructura animal) , Animales , Pollos/genética , Proteína de Señalización Agouti/genética , Plumas/fisiología , Expresión Génica , Pigmentación/genética
3.
Small ; 19(24): e2207252, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-36922734

RESUMEN

The abnormal pressure in tumor tissue is a significant limitation on the drug delivery efficiency of tumor therapy. This work reports a gradient-driven nanomotor as drug nanocarrier with the pressure-counterworking function. The dual-fuel nanomotors are formed by co-electrospinning of the photosensitive polymers with calcium peroxide (CaO2 ) and catalase (CAT), followed by ultraviolet (UV) irradiation and bovine serum albumin (BSA) incubation. The UV-responsive cleavage nanomotors can effectively release O2 molecules at the fractures as a driving force to increase the delivery speed and escape the phagocytosis of macrophage system in normal tissues. Furthermore, CAT catalyzes H2 O2 produced by CaO2 and the tumor interstitial fluids to provide stronger power for the nanomotors. Additionally, according to the analysis of directional motions of the nanomotors, the functional relationship between the rotational diffusion coefficient (DR ) and the physiological viscosity is constructed. The dual-fuel nanocarriers enable up to 13.25% of the injected dose (ID)/per gram tissue and significantly improve the penetration in deep tumor. It is of vital importance to design and obtain the adaptive pressure-gradient counterworking nanomotors, which can effectively improve the drug delivery efficiency in vitro and in vivo.


Asunto(s)
Sistemas de Liberación de Medicamentos , Líquido Extracelular , Preparaciones Farmacéuticas , Polímeros
4.
J Integr Neurosci ; 21(2): 71, 2022 Mar 23.
Artículo en Inglés | MEDLINE | ID: mdl-35364659

RESUMEN

As a catechol isoquinoline, salsolinol (Sal) is widely distributed in mammalian brains, and is increased in the cerebrospinal fluid (CSF) and urine of Parkinsonian patients. Sal can be metabolized to N-methyl-salsolinol (NM-Sal), an MPP+-like neurotoxin, and impairs the function of dopaminergic neurons, causing the clinical symptoms of Parkinson's disease (PD). Sal synthase, which catalyzes the production of Sal from dopamine and acetaldehyde, may be the important enzyme in the metabolism of catechol isoquinolines (CTIQs). Previously, our work demonstrated the existence of Sal synthase in rat brain and identified its amino acid sequence. However, the biological function of Sal synthase has not been thoroughly explored, especially its role in dopaminergic neuronal degeneration. In this study, we tried to clarify the catalytic role of Sal synthase in the formation of CTIQs which are endogenous neurotoxins in the mammalian brain. Furthermore, the cytotoxicity of Sal synthase was also observed in dopaminergic PC12 cells. The results demonstrated that Sal synthase overexpression can increase the level of Sal and NM-Sal, and ultimately cause mitochondria damage and apoptosis.


Asunto(s)
Dopamina , Tetrahidroisoquinolinas , Animales , Dopamina/química , Dopamina/metabolismo , Humanos , Isoquinolinas/química , Isoquinolinas/metabolismo , Mamíferos/metabolismo , Células PC12 , Ratas
5.
Appl Psychol ; 71(3): 935-958, 2022 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-34898803

RESUMEN

Although effective leaders are important for reducing employee stress during the COVID-19, limited studies have examined how follower behaviors can influence leader stress and well-being during the COVID-19. This study draws on defeat-entrapment theory to examine how followers' unclear demands during the COVID-19 consequently impact leaders' psychological states and well-being. We conducted a three-wave time-lagged investigation with a sample of 281 leaders in the United Kingdom and found that followers' unclear demands could generate feelings of entrapment in leaders, leading to decreased levels of well-being outcomes in leaders. Importantly, we found that leaders who have higher levels of leadership responsibility during the COVID-19 are likely to feel trapped by followers' unclear demands. They are also likely to face higher levels of feelings of entrapment and impaired well-being compared with leaders who have lower levels of leadership responsibility. We discuss the implications for theories and practices, as well as directions for future research.

6.
Appl Opt ; 57(12): 3031-3037, 2018 Apr 20.
Artículo en Inglés | MEDLINE | ID: mdl-29714333

RESUMEN

We introduce an alternative distribution to the gamma-gamma (GG) distribution, called inverse Gaussian gamma (IGG) distribution, which can efficiently describe moderate-to-strong irradiance fluctuations. The proposed stochastic model is based on a modulation process between small- and large-scale irradiance fluctuations, which are modeled by gamma and inverse Gaussian distributions, respectively. The model parameters of the IGG distribution are directly related to atmospheric parameters. The accuracy of the fit among the IGG, log-normal, and GG distributions with the experimental probability density functions in moderate-to-strong turbulence are compared, and results indicate that the newly proposed IGG model provides an excellent fit to the experimental data. As the receiving diameter is comparable with the atmospheric coherence radius, the proposed IGG model can reproduce the shape of the experimental data, whereas the GG and LN models fail to match the experimental data. The fundamental channel statistics of a free-space optical communication system are also investigated in an IGG-distributed turbulent atmosphere, and a closed-form expression for the outage probability of the system is derived with Meijer's G-function.

7.
J Mater Sci Mater Med ; 28(6): 83, 2017 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-28432501

RESUMEN

The aim of this study is to develop a simple, convenient and effective approach to synthesize nano-sized hydroxyapatite (nano-HA) at high-scale yield. Nano-HA was wet synthesized in the presence or absence of alendronate sodium (ALN), one of bisphosphonates for anti-osteoporotic. Then aged and washed nano-HA precipitate was directly treated by mechanical activation combined with the chemical dispersion of ALN to prevent the agglomeration of nano-HA. ALN acted not only as a chemical dispersant but also as an orthopedic drug. In vitro release showed that ALN was released slowly from nano-HA. Transmission electron microscopy (TEM) revealed that nano-HA with size less than 100 nm appeared as single particle after being treated by mechanical activation combined with the dispersion of ALN (AMA-HA and MA-HA). High resolution transmission electron microscopy (HRTEM) and X-ray diffraction (XRD) confirmed that as-prepared nanoparticles were HA with low crystallinity and crystallite size. Fourier transform infrared spectroscopy (FTIR) indicated that the phosphonate groups in ALN were introduced to bond with the Ca2+ of HA to impede the growth of HA crystal. Zeta potential illustrated that the absolute value of surface negative charge of nano-HA increased significantly with the addition of ALN, which inhibited the agglomeration of nano-HA. The present approach makes it feasible to produce nano-HA at high-scale yield, which provide the possibility to construct bone graft.


Asunto(s)
Materiales Biocompatibles , Durapatita/química , Ensayo de Materiales/métodos , Nanoestructuras/química , Microscopía Electrónica de Transmisión , Espectroscopía Infrarroja por Transformada de Fourier , Estrés Mecánico , Propiedades de Superficie
8.
Sheng Wu Yi Xue Gong Cheng Xue Za Zhi ; 34(4): 643-647, 2017 06 25.
Artículo en Zh | MEDLINE | ID: mdl-29745566

RESUMEN

1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (Sal) is a kind of catechol isoquinoline compound, which mainly exists in mammalian brain and performs a variety of biological functions. Through in vivo metabolism, Sal can be transformed into endogenous neurotoxins and can participate the occurrence of Parkinson's disease (PD). This has attracted widespread concern of researchers. Recently, many research works have shown that Sal may lead to alcohol addiction and regulate hormone release of the neuroendocrine system, which indicated that it is a potential regulator of dopaminergic neurons. In this paper, we discuss the neural functions of Sal on the above aspects, and wish to provide some theoretical supports for further research on its mechanism.

9.
Poult Sci ; 103(9): 103980, 2024 Jun 18.
Artículo en Inglés | MEDLINE | ID: mdl-38959666

RESUMEN

Utilizing publicly available RNA-seq data to screen for ideal reference genes is more efficient and accurate than traditional methods. Previous studies have identified optimal reference genes in various chicken tissues, but none have specifically focused on the oviduct (including the infundibulum, magnum, isthmus, uterus, and vagina), which is crucial for egg production. Identifying stable reference genes in the oviduct is essential for improving research on gene expression levels. This study investigated genes with consistent expression patterns in the chicken oviduct, encompassing both individual oviduct tract tissues and the entire oviduct, by utilizing multiple RNA-seq datasets. The screening results revealed the discovery of 100 novel reference genes in each segment of oviduct tissues, primarily associated with cell cycle regulation and RNA binding. Moreover, the majority of housekeeping genes (HKGs) showed inconsistent expression levels across distinct samples, suggesting their lack of stability under varying conditions. The stability of the newly identified reference genes was assessed in comparison to previously validated stable reference genes in chicken oviduct and commonly utilized HKGs, employing traditional reference gene screening methods. HERPUD2, CSDE1, VPS35, PBRM1, LSM14A, and YWHAB were identified to be suitable novel reference gene for different parts of the oviduct. HERPUD2 and YWHAB were reliable for gene expression normalization throughout the oviduct tract. Furthermore, overexpression and interference assays in DF1 cells showed LSM14A and YWHAB play a crucial role in cell proliferation, highlighting the importance of these newly reference genes for further research. Overall, this study has expanded the options for reference genes in RT-qPCR experiments in different segments of the chicken oviduct and the entire oviduct.

10.
Nat Commun ; 15(1): 1562, 2024 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-38378625

RESUMEN

The tropical Pacific warming pattern since the 1950s exhibits two warming centers in the western Pacific (WP) and eastern Pacific (EP), encompassing an equatorial central Pacific (CP) cooling and a hemispheric asymmetry in the subtropical EP. The underlying mechanisms of this warming pattern remain debated. Here, we conduct ocean heat decompositions of two coupled model large ensembles to unfold the role of wind-driven ocean circulation. When wind changes are suppressed, historical radiative forcing induces a subtropical northeastern Pacific warming, thus causing a hemispheric asymmetry that extends toward the tropical WP. The tropical EP warming is instead induced by the cross-equatorial winds associated with the hemispheric asymmetry, and its driving mechanism is southward warm Ekman advection due to the off-equatorial westerly wind anomalies around 5°N, not vertical thermocline adjustment. Climate models fail to capture the observed CP cooling, suggesting an urgent need to better simulate equatorial oceanic processes and thermal structures.

11.
Gene ; 918: 148479, 2024 Aug 05.
Artículo en Inglés | MEDLINE | ID: mdl-38636815

RESUMEN

The GHRL, LEAP2, and GHSR system have recently been identified as important regulators of feed intake in mammals and chickens. However, the complete cloning of the quail GHRL (qGHRL) and quail LEAP2 (qLEAP2) genes, as well as their association with feed intake, remains unclear. This study cloned the entire qGHRL and qLEAP2 cDNA sequence in Chinese yellow quail (Coturnix japonica), including the 5' and 3' untranslated regions. Sanger sequencing analysis revealed no missense mutations in the coding region of qGHRL and qLEAP2. Subsequently, phylogenetic analysis and protein homology alignment were conducted on the qGHRL and qLEAP2 in major poultry species. The findings of this research indicated that the qGHRL and qLEAP2 sequences exhibit a high degree of similarity with those of chicken and turkey. Specifically, the N-terminal 6 amino acids of GHRL mature peptides and all the mature peptide sequence of LEAP2 exhibited consistent patterns across all species examined. The analysis of tissue gene expression profiles indicated that qGHRL was primarily expressed in the proventriculus and brain tissue, whereas qLEAP2 exhibited higher expression levels in the intestinal tissue, kidney, and liver tissue, differing slightly from previous studies conducted on chicken. It is necessary to investigate the significance of elevated expression of qGHRL in brain and qLEAP2 in kidney in the future. Further research has shown that the expression of qLEAP2 can quickly respond to changes in different energy states, whereas qGHRL does not exhibit the same capability. Overall, this study successfully cloned the complete cDNA sequences of qGHRL and qLEAP2, and conducted a comprehensive examination of their tissue expression profiles and gene expression levels in the main expressing organs across different energy states. Our current findings suggested that qLEAP2 is highly expressed in the liver, intestine, and kidney, and its expression level is regulated by feed intake.


Asunto(s)
Clonación Molecular , Filogenia , Animales , Ghrelina/genética , Ghrelina/metabolismo , Proteínas Aviares/genética , Proteínas Aviares/metabolismo , Ingestión de Alimentos/genética , Secuencia de Aminoácidos , Perfilación de la Expresión Génica/métodos , Coturnix/genética , Coturnix/metabolismo , Pollos/genética , Pollos/metabolismo , Codorniz/genética , Polimorfismo Genético
12.
Nat Commun ; 15(1): 18, 2024 Jan 02.
Artículo en Inglés | MEDLINE | ID: mdl-38168125

RESUMEN

Observational evidence and climate model experiments suggest a slowdown of the Atlantic Meridional Overturning Circulation (AMOC) since the mid-1990s. Increased greenhouse gases and the declined anthropogenic aerosols (AAs) over North America and Europe are believed to contribute to the AMOC slowdown. Asian AAs continue to increase but the associated impact has been unclear. Using ensembles of climate simulations, here we show that the radiative cooling resulting from increased Asian AAs drives an AMOC reduction. The increased AAs over Asia generate circumglobal stationary Rossby waves in the northern midlatitudes, which shift the westerly jet stream southward and weaken the subpolar North Atlantic westerlies. Consequently, reduced transport of cold air from North America hinders water mass transformation in the Labrador Sea and thus contributes to the AMOC slowdown. The link between increased Asian AAs and an AMOC slowdown is supported by different models with different configurations. Thus, reducing emissions of Asian AAs will not only lower local air pollution, but also help stabilize the AMOC.

13.
Virology ; 594: 110050, 2024 06.
Artículo en Inglés | MEDLINE | ID: mdl-38479071

RESUMEN

The SARS-CoV-2 Omicron variant, which was classified as a variant of concern (VOC) by the World Health Organization on 26 November 2021, has attracted worldwide attention for its high transmissibility and immune evasion ability. The existing COVID-19 vaccine has been shown to be less effective in preventing Omicron variant infection and symptomatic infection, which brings new challenges to vaccine development and application. Here, we evaluated the immunogenicity and safety of an Omicron variant COVID-19 inactivated vaccine containing aluminum and CpG adjuvants in a variety of animal models. The results showed that the vaccine candidate could induce high levels of neutralizing antibodies against the Omicron variant virus and binding antibodies, and significantly promoted cellular immune response. Meanwhile, the vaccine candidate was safe. Therefore, it provided more foundation for the development of aluminum and CpG as a combination adjuvant in human vaccines.


Asunto(s)
Compuestos de Alumbre , Vacunas contra la COVID-19 , COVID-19 , Animales , Humanos , Aluminio , SARS-CoV-2 , COVID-19/prevención & control , Adyuvantes Inmunológicos , Inmunidad Celular , Anticuerpos Neutralizantes , Vacunas de Productos Inactivados , Anticuerpos Antivirales
14.
J Soc Psychol ; 163(5): 623-636, 2023 Sep 03.
Artículo en Inglés | MEDLINE | ID: mdl-35068359

RESUMEN

In accordance with the similarity attraction paradigm, this paper investigates when and how proactive employees can be rated as proactive performers by proposing supervisor-subordinate marital status similarity as a relational moderator and leader-member exchange as the mediator. It therefore advances understanding of performance evaluation of proactive employees. Data from a sample of 471 Chinese employees and their 161 supervisors are used to examine the models hypothesized. The results show that LMX mediates the interaction effect between a proactive personality and supervisor-subordinate marital status similarity on supervisors' evaluations of proactive performance. When proactive employees and their supervisors have similar (dissimilar) marital status, the indirect relationship between proactive personality and supervisor-rated proactive performance via LMX is stronger (weaker). Theoretical and practical implications are discussed.


Asunto(s)
Liderazgo , Personalidad , Humanos , Pueblo Asiatico , Relaciones Interpersonales , Grupos Profesionales/psicología , Estado Civil , Empleo
15.
Poult Sci ; 102(12): 103169, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37918133

RESUMEN

The application of reverse transcription quantitative real-time PCR technology for the production of gene tissue expression profiles is a widely employed approach in molecular biology research. It is imperative to ascertain internal reference genes that exhibit stable expression across diverse tissues to ensure the precision of tissue gene expression profiles. While there have been studies documenting the most suitable reference genes for various tissues in chickens, there is a dearth of research on the identification of reference genes in the gastrointestinal (GI) tract of chickens. This study utilized 4 different algorithms (Delta CT, BestKeeper, NormFinder, and Genorm) to assess the stability of 19 internal reference genes in various GI tract tissues, including individual GI tract tissues, the anterior and posterior GI tract, and the entire GI tissue. The RefFinder software was employed to comprehensively rank these genes. The research findings successfully identified the most appropriate internal reference genes for each type of GI tissue. Furthermore, TBP, DNAJC24, Polr2b, RPL13, andAp2m exhibited stable expression in the entire and posterior GI tract, whereas HMBS, TBP, Ap2m, GUSB, DNAJC24, and RPL13 demonstrated stable expression in the anterior GI tract. However, the internal reference genes commonly utilized, namely ß-Actin, 18s RNA, and ALB, exhibit poor stability and are not advised for future investigations concerning gene expression in the GI region. Consequently, MUC2 and CDX1, 2 genes that specifically express in the gut, were chosen for examination to ascertain the stability of the aforementioned internal reference genes in this particular study. In summary, this study presents a relatively stable set of internal reference genes that can be employed to enhance the precision of quantifying mRNA expression levels in functional genes within the chicken GI tract.


Asunto(s)
Pollos , Perfilación de la Expresión Génica , Animales , Pollos/genética , Perfilación de la Expresión Génica/veterinaria , Transcriptoma , Reacción en Cadena en Tiempo Real de la Polimerasa/veterinaria , Tracto Gastrointestinal
16.
Animals (Basel) ; 13(19)2023 Oct 05.
Artículo en Inglés | MEDLINE | ID: mdl-37835714

RESUMEN

Glycine, the most basic amino acid found in nature, is considered an essential amino acid for chicks. However, the precise understanding of high concentrations of glycine's significance in promoting the growth performance of chicks, as well as its impact on intestinal development, re-mains limited. Consequently, the objective of this study was to investigate the effects of glycine supplementation in drinking water on growth performance, intestine morphology, and development in newly hatched chicks. In this study, 200 newly born chicks were selected and pro-vided with a supplementation of 0.5%, 1%, and 2% glycine in their drinking water during their first week of life. The results revealed that glycine supplementation in drinking water could significantly increase the average daily gain of chicks from days 7 to 14. Furthermore, a significant difference was observed between the group supplemented with 1% glycine and the control group. Concurrently, this glycine supplementation increased the villus height and the ratio of the villus height to crypt depth in jejunum on both day 7 and day 14. Glycine supplementation in drinking water significantly affected the mRNA expression level of the ZO-1, GCLM, and rBAT genes in jejunum, which may have certain effects on the mucosal immune defense, cellular antioxidant stress capacity, and amino acid absorption. Overall, the findings of this study indicate that glycine supplementation in drinking water can enhance the growth performance of chicks and promote their intestine development.

17.
Poult Sci ; 102(10): 102971, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37562126

RESUMEN

The Huiyang beard chicken is a well-known Chinese local breed known for its elongated feathers gathered from both sides of the face (muffs) and below the beak (beard), as well as short wattles (SW). The muff and beard (Mb) mutation is caused by ectopic upregulation of the homeobox B8 (HOXB8) gene in the mandibular skin; and the chi-square test showed a significant correlation between SW and Mb genotypes. However, the underlying molecular mechanisms that regulate Mb and SW variations remain unclear. In this study, we investigated the transcriptomes of the mandibular skin and wattles of chickens with and without the Mb genotype to elucidate the molecular basis of these traits. Our results show that HOXB8 is expressed at significantly higher levels in both the mandibular skin and wattles of Mb chickens than in those of wild-type chickens, indicating that HOXB8 regulates both the Mb and SW phenotypes. Key genes for keratin synthesis were highly expressed in the mandibular skin of Mb chickens, suggesting that HOXB8 may play a role in feather development. In wattles, changes in the expression of extracellular matrix synthesis genes may contribute to SW traits. DNA-binding motif analyses revealed that differentially expressed genes were likely to be directly regulated by HOXB8 binding, indicating that HOXB8 may directly or indirectly regulate feather follicle development and wattle growth. Our study identified both known and novel targets, including several genes not previously implicated in feather development and mesenchymal formation. These findings provide insights into the molecular mechanisms of skin appendage variation in birds and offer potential applications in breeding poultry breeds with unique phenotypes.


Asunto(s)
Pollos , Genes Homeobox , Animales , Plumas , Genotipo , Análisis de Secuencia de ARN/veterinaria
18.
ACS Appl Mater Interfaces ; 15(1): 2030-2042, 2023 Jan 11.
Artículo en Inglés | MEDLINE | ID: mdl-36571106

RESUMEN

As the central cellular player in fibrogenesis, activated hepatic stellate cells (aHSCs) are the major target of antifibrotic nanomedicines. Based on our finding that activated HSCs increase the expression of folate receptor alpha (FRα), we tried to apply folic acid (FA) decoration to generate an active drug-targeting at aHSCs and suppress hepato-fibrogenesis. FA-conjugated poly(ethylene glycol)-poly(ε-caprolactone) copolymers (PEG-PCL) were synthesized and self-assembled into the spherical micelles that owned a uniform size distribution averaging at 60 nm, excellent hemo- and cyto-compatibility, and pH-sensitive stability. These FA-modified micelles were preferentially ingested by aHSCs as expected and accumulated more in acutely CCl4 injured mouse livers compared to nondecorated counterparts. Such an aHSC targetability facilitated the loaded medicinal camptothecin (CPT) to achieve a greater therapeutic efficacy and inhibition of MF phenotypic genes in aHSCs. Encouragingly, though free CPT and nontargeting CPT micelles produced negligible curative outcomes, FA-decorated CPT micelles yielded effectively remedial effects in chronically CCl4-induced fibrotic mice, as represented by a significant shrinkage of aHSC population, suppression of fibrogenesis, and recovery of liver structure and function, clearly indicating the success of the folate decoration-supported aHSC-targeted strategy for antifibrotic nanomedicines in fibrosis resolution.


Asunto(s)
Ácido Fólico , Micelas , Ratones , Animales , Ácido Fólico/química , Células Estrelladas Hepáticas , Sistemas de Liberación de Medicamentos , Polietilenglicoles/química , Camptotecina/farmacología , Camptotecina/química , Portadores de Fármacos
19.
Acta Biomater ; 168: 497-514, 2023 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-37507035

RESUMEN

The persistent transformation of quiescent hepatic stellate cells (HSCs) into myofibroblasts (MFs) and the excessive proliferation of MF-HSCs in the liver contribute to the pathogenesis of liver fibrosis, cirrhosis, and liver cancer. Glycolysis inhibition of MF-HSCs can reverse their MF phenotype and suppress their abnormal expansion. Here, we have developed vitamin A-derivative (VA) decorated PEG-PCL polymeric micelles to encapsulate the labile and hydrophobic camptothecin (CPT) and direct its active attack on HSCs, selectively inhibiting of HIF-1α and cellular glycolysis, ultimately repressing hepatic fibrogenesis. The obtained micelles exhibited a good stability, biocompatibility, pH sensitivity, and exceptional HSC-targetability, allowing an efficient accumulation of their carried CPT in acutely and chronically injured livers. On their intracellular release of CPT specifically in MF-HSCs, these CPT micelles nicely inhibited the HIF-1α and a series of glycolytic players in MF-HSCs and prominently suppressed their proliferation and MF phenotypic characteristics. Accordingly, on in vitro administration to the mice challenged by CCl4 or subjected to bile duct ligation, these VA-decorated CPT micelles ameliorated the pathological symptoms of the livers, as evidenced by the significant reduction in serum levels of ALT and AST, infiltration of inflammatory cells, and collagen accumulation, the drastic down-regulation of multiple fibrotic genes, and the good recovery of attenuated hepatocyte CYP2E1 and lipogenesis regulator PPARγ. Overall, the CPT carried by VA-decorated PEG-PCL polymeric micelles can selectively inhibit the glycolysis and expansion of HSCs and thus suppress fibrogenesis, providing an original and effective approach for anti-fibrotic therapy. STATEMENT OF SIGNIFICANCE: Our work introduces an innovative antifibrotic drug system that is developed upon the active targeting of CPT and aims for the fate reversal of HSCs. Through HSC-targeted delivery achieved by PEG-PCL polymeric micelles decorated with vitamin A-derivatives, CPT significantly suppressed the expressions of HIF-1α and glycolytic enzymes in MF-HSCs, as well as their pathologic expansion in mouse livers. It effectively ameliorated chronic liver fibrosis in mice induced by CCl4 injection or BDL and restored the damaged liver structure and function. These compelling findings demonstrate the therapeutic potential of glycolytic HSC-targeting in combating fibrosis and related disorders and thus provide new promise for future clinical management of such prevalent and life-threatening conditions.


Asunto(s)
Células Estrelladas Hepáticas , Vitamina A , Ratones , Animales , Vitamina A/efectos adversos , Vitamina A/metabolismo , Células Estrelladas Hepáticas/metabolismo , Micelas , Células Cultivadas , Hígado/patología , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/metabolismo , Glucólisis , Camptotecina/farmacología
20.
Toxicon ; 231: 107177, 2023 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-37276986

RESUMEN

Aflatoxin B1 (AFB1) is widely distributed in crops and feeds, and ingestion of AFB1-contaminated crops is harmful to human/animal health. This study was designed to investigate hepatoprotective effects of chlorogenic acid (CGA), due to its excellent antioxidant and anti-inflammatory activities, on mice exposed to AFB1. Male Kunming mice were orally fed with CGA prior to daily AFB1 exposure for 18 consecutive days. The results showed that CGA treatment reduced the serum activity of aspartate aminotransferase, hepatic malondialdehyde content and pro-inflammatory cytokines synthesis, prevented histopathological changes of the liver, increased hepatic glutathione level, catalase activity and IL10 mRNA expression in mice subjected to AFB1. Taken together, CGA exerted the protective effect on AFB1-induced hepatic damage by modulating redox status and inflammation, suggesting that CGA may be a candidate compound for the treatment of aflatoxicosis.


Asunto(s)
Aflatoxina B1 , Ácido Clorogénico , Ratones , Masculino , Humanos , Animales , Aflatoxina B1/toxicidad , Aflatoxina B1/metabolismo , Ácido Clorogénico/farmacología , Ácido Clorogénico/uso terapéutico , Estrés Oxidativo , Antioxidantes/farmacología , Antioxidantes/metabolismo , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Hígado
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