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1.
Proc Natl Acad Sci U S A ; 121(25): e2316615121, 2024 Jun 18.
Artículo en Inglés | MEDLINE | ID: mdl-38861602

RESUMEN

Many cancer-driving protein targets remain undruggable due to a lack of binding molecular scaffolds. In this regard, octahedral metal complexes with unique and versatile three-dimensional structures have rarely been explored as inhibitors of undruggable protein targets. Here, we describe antitumor iridium(III) pyridinium-N-heterocyclic carbene complex 1a, which profoundly reduces the viability of lung and breast cancer cells as well as cancer patient-derived organoids at low micromolar concentrations. Compound 1a effectively inhibits the growth of non-small-cell lung cancer and triple-negative breast cancer xenograft tumors, impedes the metastatic spread of breast cancer cells, and can be modified into an antibody-drug conjugate payload to achieve precise tumor delivery in mice. Identified by thermal proteome profiling, an important molecular target of 1a in cellulo is Girdin, a multifunctional adaptor protein that is overexpressed in cancer cells and unequivocally serves as a signaling hub for multiple pivotal oncogenic pathways. However, specific small-molecule inhibitors of Girdin have not yet been developed. Notably, 1a exhibits high binding affinity to Girdin with a Kd of 1.3 µM and targets the Girdin-linked EGFR/AKT/mTOR/STAT3 cancer-driving pathway, inhibiting cancer cell proliferation and metastatic activity. Our study reveals a potent Girdin-targeting anticancer compound and demonstrates that octahedral metal complexes constitute an untapped library of small-molecule inhibitors that can fit into the ligand-binding pockets of key oncoproteins.


Asunto(s)
Antineoplásicos , Iridio , Metano , Animales , Humanos , Ratones , Antineoplásicos/farmacología , Antineoplásicos/química , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Iridio/química , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/secundario , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Metano/análogos & derivados , Metano/química , Metano/farmacología , Proteínas de Microfilamentos/metabolismo , Metástasis de la Neoplasia , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Masculino
2.
J Biol Chem ; 300(4): 107199, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38508309

RESUMEN

Porcine reproductive and respiratory syndrome virus (PRRSV), a highly infectious virus, causes severe losses in the swine industry by regulating the inflammatory response, inducing tissue damage, suppressing the innate immune response, and promoting persistent infection in hosts. Interleukin-13 (IL-13) is a cytokine that plays a critical role in regulating immune responses and inflammation, particularly in immune-related disorders, certain types of cancer, and numerous bacterial and viral infections; however, the underlying mechanisms of IL-13 regulation during PRRSV infection are not well understood. In this study, we demonstrated that PRRSV infection elevates IL-13 levels in porcine alveolar macrophages. PRRSV enhances m6A-methylated RNA levels while reducing the expression of fat mass and obesity associated protein (FTO, an m6A demethylase), thereby augmenting IL-13 production. PRRSV nonstructural protein 9 (nsp9) was a key factor for this modulation. Furthermore, we found that the residues Asp567, Tyr586, Leu593, and Asp595 were essential for nsp9 to induce IL-13 production via attenuation of FTO expression. These insights delineate PRRSV nsp9's role in FTO-mediated IL-13 release, advancing our understanding of PRRSV's impact on host immune and inflammatory responses.


Asunto(s)
Interleucina-13 , Macrófagos Alveolares , Síndrome Respiratorio y de la Reproducción Porcina , Virus del Síndrome Respiratorio y Reproductivo Porcino , Proteínas no Estructurales Virales , Animales , Virus del Síndrome Respiratorio y Reproductivo Porcino/genética , Porcinos , Interleucina-13/metabolismo , Interleucina-13/genética , Proteínas no Estructurales Virales/metabolismo , Proteínas no Estructurales Virales/genética , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/virología , Macrófagos Alveolares/inmunología , Síndrome Respiratorio y de la Reproducción Porcina/metabolismo , Síndrome Respiratorio y de la Reproducción Porcina/virología , Síndrome Respiratorio y de la Reproducción Porcina/inmunología , Síndrome Respiratorio y de la Reproducción Porcina/genética , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/metabolismo , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/genética , Regulación hacia Arriba
3.
BMC Genomics ; 25(1): 634, 2024 Jun 25.
Artículo en Inglés | MEDLINE | ID: mdl-38918701

RESUMEN

BACKGROUND: Previous studies have demonstrated the role of N6-methyladenosine (m6A) RNA methylation in various biological processes, our research is the first to elucidate its specific impact on LCAT mRNA stability and adipogenesis in poultry. RESULTS: The 6 100-day-old female chickens were categorized into high (n = 3) and low-fat chickens (n = 3) based on their abdominal fat ratios, and their abdominal fat tissues were processed for MeRIP-seq and RNA-seq. An integrated analysis of MeRIP-seq and RNA-seq omics data revealed 16 differentially expressed genes associated with to differential m6A modifications. Among them, ELOVL fatty acid elongase 2 (ELOVL2), pyruvate dehydrogenase kinase 4 (PDK4), fatty acid binding protein 9 (PMP2), fatty acid binding protein 1 (FABP1), lysosomal associated membrane protein 3 (LAMP3), lecithin-cholesterol acyltransferase (LCAT) and solute carrier family 2 member 1 (SLC2A1) have ever been reported to be associated with adipogenesis. Interestingly, LCAT was down-regulated and expressed along with decreased levels of mRNA methylation methylation in the low-fat group. Mechanistically, the highly expressed ALKBH5 gene regulates LCAT RNA demethylation and affects LCAT mRNA stability. In addition, LCAT inhibits preadipocyte proliferation and promotes preadipocyte differentiation, and plays a key role in adipogenesis. CONCLUSIONS: In conclusion, ALKBH5 mediates RNA stability of LCAT through demethylation and affects chicken adipogenesis. This study provides a theoretical basis for further understanding of RNA methylation regulation in chicken adipogenesis.


Asunto(s)
Adenosina , Adipogénesis , Desmetilasa de ARN, Homólogo 5 de AlkB , Pollos , Fosfatidilcolina-Esterol O-Aciltransferasa , Estabilidad del ARN , Animales , Adipogénesis/genética , Pollos/genética , Pollos/metabolismo , Fosfatidilcolina-Esterol O-Aciltransferasa/genética , Fosfatidilcolina-Esterol O-Aciltransferasa/metabolismo , Desmetilasa de ARN, Homólogo 5 de AlkB/metabolismo , Desmetilasa de ARN, Homólogo 5 de AlkB/genética , Femenino , Adenosina/análogos & derivados , Adenosina/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Metilación
4.
J Am Chem Soc ; 146(19): 13391-13398, 2024 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-38691098

RESUMEN

Inverted p-i-n perovskite solar cells (PSCs) are easy to process but need improved interface characteristics with reduced energy loss to prevent efficiency drops when increasing the active photovoltaic area. Here, we report a series of poly ferrocenyl molecules that can modulate the perovskite surface enabling the construction of small- and large-area PSCs. We found that the perovskite-ferrocenyl interaction forms a hybrid complex with enhanced surface coordination strength and activated electronic states, leading to lower interfacial nonradiative recombination and charge transport resistance losses. The resulting PSCs achieve an enhanced efficiency of up to 26.08% for small-area devices and 24.51% for large-area devices (1.0208 cm2). Moreover, the large-area PSCs maintain >92% of the initial efficiency after 2000 h of continuous operation at the maximum power point under 1-sun illumination and 65 °C.

5.
J Neuroinflammation ; 21(1): 116, 2024 May 03.
Artículo en Inglés | MEDLINE | ID: mdl-38702778

RESUMEN

BACKGROUND: Subarachnoid hemorrhage (SAH), a severe subtype of stroke, is characterized by notably high mortality and morbidity, largely due to the lack of effective therapeutic options. Although the neuroprotective potential of PPARg and Nrf2 has been recognized, investigative efforts into oroxin A (OA), remain limited in preclinical studies. METHODS: SAH was modeled in vivo through filament perforation in male C57BL/6 mice and in vitro by exposing HT22 cells to hemin to induce neuronal damage. Following the administration of OA, a series of methods were employed to assess neurological behaviors, brain water content, neuronal damage, cell ferroptosis, and the extent of neuroinflammation. RESULTS: The findings indicated that OA treatment markedly improved survival rates, enhanced neurological functions, mitigated neuronal death and brain edema, and attenuated the inflammatory response. These effects of OA were linked to the suppression of microglial activation. Moreover, OA administration was found to diminish ferroptosis in neuronal cells, a critical factor in early brain injury (EBI) following SAH. Further mechanistic investigations uncovered that OA facilitated the translocation of nuclear factor erythroid 2-related factor 2 (Nrf-2) from the cytoplasm to the nucleus, thereby activating the Nrf2/GPX4 pathway. Importantly, OA also upregulated the expression of FSP1, suggesting a significant and parallel protective effect against ferroptosis in EBI following SAH in synergy with GPX4. CONCLUSION: In summary, this research indicated that the PPARg activator OA augmented the neurological results in rodent models and diminished neuronal death. This neuroprotection was achieved primarily by suppressing neuronal ferroptosis. The underlying mechanism was associated with the alleviation of cellular death through the Nrf2/GPX4 and FSP1/CoQ10 pathways.


Asunto(s)
Ferroptosis , Ratones Endogámicos C57BL , Enfermedades Neuroinflamatorias , Hemorragia Subaracnoidea , Animales , Hemorragia Subaracnoidea/metabolismo , Hemorragia Subaracnoidea/patología , Hemorragia Subaracnoidea/complicaciones , Ferroptosis/efectos de los fármacos , Ferroptosis/fisiología , Ratones , Masculino , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/etiología , Lesiones Encefálicas/metabolismo , Lesiones Encefálicas/patología , Lesiones Encefálicas/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Neuronas/patología
6.
Br J Dermatol ; 2024 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-38366639

RESUMEN

BACKGROUND: Xeligekimab is a fully human monoclonal antibody that selectively neutralizes IL-17A and had shown potential efficacy in preliminary trials. OBJECTIVE: To evaluate the efficacy and safety of Xeligekimab in Chinese patients with moderate-to-severe psoriasis. METHODS: A total of 420 Chinese patients were randomized to 200 mg Xeligekimab every 2 weeks (n = 281) or placebo (n = 139) for the first 12 weeks, followed by extending the treatment schedule to GR1501 every 4 weeks for further 40 weeks. Efficacy was assessed by evaluating the Physician's Global Assessment (PGA) 0/1 and Psoriasis Area and Severity Index (PASI) 75/90/100 improvement. The safety profile was also evaluated. RESULTS: At week 12, The PASI 75/90/100 were achieved in 90.7%/74.4%/30.2%% patients in GR1501 group compared with 8.6%/1.4%/0% patients in placebo group, respectively. The PGA 0/1 were achieved in 74.4% patients of GR1501 group and 3.6% patients in placebo group, respectively. The PASI 75 and PGA 0/1 maintained until week 52. No unexpected adverse events were observed. CONCLUSION: Xeligekimab showed high efficacy and is well tolerated in Chinese patients with moderate-to-severe plaque psoriasis.

7.
Artículo en Inglés | MEDLINE | ID: mdl-38948962

RESUMEN

BACKGROUND: FMX101 4%, as a topical foam formulation of minocycline, has been approved by US Food and Drug Administration for the treatment of moderate-to-severe acne vulgaris (AV). OBJECTIVE: To evaluate the efficacy and safety of FMX101 4% in treating Chinese subjects with moderate-to-severe facial AV. METHODS: This was a multi-centre, randomized, double-blind, vehicle-controlled phase 3 study in Chinese subjects with moderate-to-severe AV. Eligible subjects were randomized 2:1 to receive either FMX101 4% or vehicle foam treatment for 12 weeks. The primary efficacy endpoint was the change in inflammation lesion count (ILC) from baseline at week 12. The key secondary endpoint was the treatment success rate according to Investigator's Global Assessment (IGA) at week 12. RESULTS: In total, 372 subjects were randomized into two groups (FMX101 4% group, n = 248; vehicle group, n = 124). After 12 weeks treatment, the reduction in ILC from baseline was statistically significant in favour of FMX101 4%, compared with vehicle foam (-21.0 [0.08] vs. -12.3 [1.14]; LSM [SE] difference, -8.7 [1.34]; 95% CI [-11.3, -6.0]; p < 0.001). FMX101 4% treatment yielded significantly higher IGA treatment success rate at week 12 as compared to the control treatment (8.06% vs. 0%). Applying FMX101 4% also resulted in significant reduction in noninflammatory lesion count (nILC) versus vehicle foam at week 12 (-19.4 [1.03] vs. -14.9 [1.47]; LSM [SE] difference, -4.5 [1.74]; 95% CI [-8.0, -1.1]; p = 0.009). Most treatment-emergent adverse events (TEAEs) were mild-to-moderate in severity, and no treatment-related treatment-emergent serious adverse event (TESAE) occurred. Thus, FMX101 4% was considered to be a safe and well-tolerated product during the 12-week treatment period. CONCLUSION: FMX101 4% treatment for 12 weeks could lead to significantly reduced ILC and nILC, and improved IGA treatment success rate in Chinese subjects with moderate-to-severe facial AV. It also showed a well acceptable safe and tolerability profile.

8.
Artículo en Inglés | MEDLINE | ID: mdl-38619440

RESUMEN

BACKGROUND: Lupus erythematosus (LE) is a spectrum of autoimmune diseases. Due to the complexity of cutaneous LE (CLE), clinical skin image-based artificial intelligence is still experiencing difficulties in distinguishing subtypes of LE. OBJECTIVES: We aim to develop a multimodal deep learning system (MMDLS) for human-AI collaboration in diagnosis of LE subtypes. METHODS: This is a multi-centre study based on 25 institutions across China to assist in diagnosis of LE subtypes, other eight similar skin diseases and healthy subjects. In total, 446 cases with 800 clinical skin images, 3786 multicolor-immunohistochemistry (multi-IHC) images and clinical data were collected, and EfficientNet-B3 and ResNet-18 were utilized in this study. RESULTS: In the multi-classification task, the overall performance of MMDLS on 13 skin conditions is much higher than single or dual modals (Sen = 0.8288, Spe = 0.9852, Pre = 0.8518, AUC = 0.9844). Further, the MMDLS-based diagnostic-support help improves the accuracy of dermatologists from 66.88% ± 6.94% to 81.25% ± 4.23% (p = 0.0004). CONCLUSIONS: These results highlight the benefit of human-MMDLS collaborated framework in telemedicine by assisting dermatologists and rheumatologists in the differential diagnosis of LE subtypes and similar skin diseases.

9.
Proc Natl Acad Sci U S A ; 118(17)2021 04 27.
Artículo en Inglés | MEDLINE | ID: mdl-33883283

RESUMEN

Vimentin is a cytoskeletal intermediate filament protein that plays pivotal roles in tumor initiation, progression, and metastasis, and its overexpression in aggressive cancers predicted poor prognosis. Herein described is a highly effective antitumor and antimetastatic metal complex [PtII(C^N^N)(NHC2Bu)]PF6 (Pt1a; HC^N^N = 6-phenyl-2,2'-bipyridine; NHC= N-heterocyclic carbene) that engages vimentin via noncovalent binding interactions with a distinct orthogonal structural scaffold. Pt1a displays vimentin-binding affinity with a dissociation constant of 1.06 µM from surface plasmon resonance measurements and fits into a pocket between the coiled coils of the rod domain of vimentin with multiple hydrophobic interactions. It engages vimentin in cellulo, disrupts vimentin cytoskeleton, reduces vimentin expression in tumors, suppresses xenograft growth and metastasis in different mouse models, and is well tolerated, attributable to biotransformation to less toxic and renal-clearable platinum(II) species. Our studies uncovered the practical therapeutic potential of platinum(II)‒NHC complexes as effective targeted chemotherapy for combating metastatic and cisplatin-resistant cancers.


Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Compuestos Organoplatinos/uso terapéutico , Vimentina/efectos de los fármacos , Animales , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Femenino , Células HCT116 , Humanos , Neoplasias Pulmonares/secundario , Ratones , Ratones Desnudos , Simulación de Dinámica Molecular , Compuestos Organoplatinos/metabolismo , Compuestos Organoplatinos/farmacología , Ratas , Vimentina/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
10.
J Asian Nat Prod Res ; 26(2): 248-258, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37905564

RESUMEN

Four new alkaloids (1 - 4), together with five known ones (5 - 9), were isolated from the bulbs of Dactylicapnos scandens. The structures were determined by analysis of their spectroscopic data and quantum-chemical calculations. All the isolates were tested for their ability to modulate neuronal Ca2+ mobilization in primary cultured neocortical neurons. Compound 8 inhibited spontaneous Ca2+ oscillations at low micromolar concentrations.


Asunto(s)
Alcaloides , Alcaloides/química , Raíces de Plantas/química , Neuronas
11.
J Environ Sci (China) ; 138: 697-708, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38135432

RESUMEN

Ca-type todorokite catalysts were designed and prepared by a simple redox method and applied to the selective reduction of NOx by NH3 (NH3-SCR) for the first time. Compared with the Na-type manjiroite prepared by the same method, the todorokite catalysts with different Mn/Ca ratios showed greatly improved catalytic activity for NOx reduction. Among them, Mn8Ca4 catalyst exhibited the best NH3-SCR performance, achieving 90% NOx conversion within temperature range of 70-275°C and having a high sulphur resistance. Compared to the Na-type manjiroite sample, Ca-type todorokite catalysts possessed an increased size of tunnel, resulting in a larger specific surface area. As increased the amounts of Ca doping, the Na content in Ca-type todorokite catalysts significantly decreased, providing larger amounts of Brønsted acid sites for NH3 adsorption to produce NH4+. The NH4+ species were highly active for reaction with NO + O2, playing a determining role in NH3-SCR process at low temperatures. Meanwhile, larger amounts of surface adsorbed oxygen contained over the Ca-doping samples than that over Na-type manjiroite, promoting the oxidation of NO and fast SCR processes. Over the Ca-type todorokite catalysts, furthermore, nitrates produced during the flow of NO + O2, were more active for reaction with NH3 than that over Na-type manjiroite, benefiting the occurrence of NH3-SCR process. This study provides novel insights into the design of NH3-SCR catalysts with high performance.


Asunto(s)
Amoníaco , Frío , Temperatura , Oxidación-Reducción , Nitratos , Oxígeno , Catálisis
12.
BMC Genomics ; 24(1): 68, 2023 Feb 09.
Artículo en Inglés | MEDLINE | ID: mdl-36759768

RESUMEN

BACKGROUND: The early craniofacial development is a highly coordinated process involving neural crest cell migration, proliferation, epithelial apoptosis, and epithelial-mesenchymal transition (EMT). Both genetic defects and environmental factors can affect these processes and result in orofacial clefts. Mutations in MID1 gene cause X-linked Opitz Syndrome (OS), which is a congenital malformation characterized by craniofacial defects including cleft lip/palate (CLP). Previous studies demonstrated impaired neurological structure and function in Mid1 knockout mice, while no CLP was observed. However, given the highly variable severities of the facial manifestations observed in OS patients within the same family carrying identical genetic defects, subtle craniofacial malformations in Mid1 knockout mice could be overlooked in these studies. Therefore, we propose that a detailed morphometric analysis should be necessary to reveal mild craniofacial dysmorphologies that reflect the similar developmental defects seen in OS patients. RESULTS: In this research, morphometric study of the P0 male Mid1-cKO mice were performed using Procrustes superimposition as well as EMDA analysis of the size-adjusted three-dimensional coordinates of 105 skull landmarks, which were collected on the bone surface reconstructed using microcomputed tomographic images. Our results revealed the craniofacial deformation such as the increased dimension of the frontal and nasal bone in Mid1-cKO mice, in line with the most prominent facial features such as hypertelorism, prominent forehead, broad and/or high nasal bridge seen in OS patients. CONCLUSION:  While been extensively used in evolutionary biology and anthropology in the last decades, geometric morphometric analysis was much less used in developmental biology. Given the high interspecies variances in facial anatomy, the work presented in this research suggested the advantages of morphometric analysis in characterizing animal models of craniofacial developmental defects to reveal phenotypic variations and the underlining pathogenesis.


Asunto(s)
Labio Leporino , Fisura del Paladar , Masculino , Ratones , Animales , Fisura del Paladar/genética , Labio Leporino/genética , Cráneo/diagnóstico por imagen , Ubiquitina-Proteína Ligasas , Ratones Noqueados
13.
Small ; : e2309827, 2023 Dec 12.
Artículo en Inglés | MEDLINE | ID: mdl-38084461

RESUMEN

Solution-processed photodetectors have emerged as promising candidates for next-generation of visible-near infrared (vis-NIR) photodetectors. This is attributed to their ease of processing, compatibility with flexible substrates, and the ability to tune their detection properties by integrating complementary photoresponsive semiconductors. However, the limited performance continues to hinder their further development, primarily influenced by the difference of charge transport properties between perovskite and organic semiconductors. In this work, a perovskite-organic bipolar photodetectors (PDs) is introduced with multispectral responsivity, achieved by effectively managing charges in perovskite and a ternary organic heterojunction. The ternary heterojunction, incorporating a designed NIR guest acceptor, exhibits a faster charge transfer rate and longer carrier diffusion length than the binary heterojunction. By achieving a more balanced carrier dynamic between the perovskite and organic components, the PD achieves a low dark current of 3.74 nA cm-2 at -0.2 V, a fast response speed of <10 µs, and a detectivity of exceeding 1012 Jones. Furthermore, a bioinspired retinotopic system for spontaneous chromatic adaptation is achieved without any optical filter. This charge management strategy opens up possibilities for surpassing the limitations of photodetection and enables the realization of high-purity, compact image sensors with exceptional spatial resolution and accurate color reproduction.

14.
Microb Pathog ; 184: 106345, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37714310

RESUMEN

Porcine reproductive and respiratory syndrome virus (PRRSV) is a highly infectious and pathogenic agent that causes considerable economic damage in the swine industry. It regulates the inflammatory response, triggers inflammation-induced tissue damage, suppresses the innate immune response, and leads to persistent infection. Interleukin-8 (IL-8), a pro-inflammatory chemokine, plays a crucial role in inflammatory response during numerous bacteria and virus infections. However, the underlying mechanisms of IL-8 regulation during PRRSV infection are not well understood. In this study, we demonstrate that PRRSV-infected PAMs and Marc-145 cells release higher levels of IL-8. We screened the nucleocapsid protein, non-structural protein (nsp) 9, and nsp11 of PRRSV to enhance IL-8 promoter activity via the C/EBPα pathway. Furthermore, we identified that the amino acids Q35A, S36A, R113A, and I115A of the nucleocapsid protein play a crucial role in the induction of IL-8. Through reverse genetics, we generated two mutant viruses (rQ35-2A and rR113A), which showed lower induction of IL-8 in PAMs during infection. This finding uncovers a previously unrecognized role of the PRRSV nucleocapsid protein in modulating IL-8 production and provides insight into an additional mechanism by which PRRSV modulates immune responses and inflammation.


Asunto(s)
Síndrome Respiratorio y de la Reproducción Porcina , Virus del Síndrome Respiratorio y Reproductivo Porcino , Animales , Porcinos , Virus del Síndrome Respiratorio y Reproductivo Porcino/metabolismo , Interleucina-8/genética , Proteínas de la Nucleocápside/genética , Proteínas de la Nucleocápside/metabolismo , Inflamación , Macrófagos Alveolares/metabolismo
15.
Anim Biotechnol ; 34(4): 1406-1412, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-35075975

RESUMEN

Intramuscular fat content is closely related to meat quality traits and has high heritability. miRNAs are a class of small non-coding RNA, which are highly conserved in animals and play important regulatory roles in adipogenesis. Therefore, they can be used as molecular markers for meat quality traits. Herein, we used in vitro model of myoblasts adipogenic differentiation to screen differential miRNAs by RNA-seq. A total of 71 differentially miRNAs were filtered, including 31 up-regulated miRNAs and 40 down-regulated miRNAs. Since, we selected 18 miRNAs for RT-qPCR validation, including some miRNAs likely miR-146a-5p, miR-210-3p, miR-199a, miR-224, and miR-214-3p that play important regulatory roles in adipogenesis. In addition, functional enrichment analysis results revealed that members of miRNA target genes were enriched into insulin signaling pathway and MAPK signaling pathway, which are closely related to adipogenesis. Taken together, these data will contribute to further investigate the function of miRNAs in intramuscular fat deposition. These differentially miRNAs can be developed as biomarkers for animal breeding.


Asunto(s)
MicroARNs , Animales , MicroARNs/genética , MicroARNs/metabolismo , Adipogénesis/genética , Perfilación de la Expresión Génica , Transducción de Señal , Mioblastos/metabolismo , Transcriptoma
16.
Anim Biotechnol ; 34(7): 2514-2526, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-35875894

RESUMEN

MiR-424-5p was found to be a potential regulator in the proliferation, migration, and invasion of various cancer cells. However, the effects and functional mechanism of miR-424-5p in the process of myogenesis are still unclear. Previously, using microRNA (miRNA) sequencing and expression analysis, we discovered that miR-424-5p was expressed differentially in the different skeletal muscle growth periods of Xuhuai goats. We hypothesized that miR-424-5p might play an important role in skeletal muscle myogenesis. Then, we found that the proliferation ability of the mouse myoblast cell (C2C12 myoblast cell line) was significantly augmented, whereas the C2C12 differentiation was repressed after increasing the expression of miR-424-5p. Mechanistically, HSP90AA1 presented a close interrelation with miR-424-5p, which was predicted as a target gene in the progression of skeletal muscle myogenesis, using transcriptome sequencing, dual luciferase reporter gene detection, and qRT-PCR. The silencing of HSP90AA1 obviously increased C2C12 proliferation and diminished differentiation, which is consistent with the ability of miR-424-5p in C2C12. Altogether, our findings indicated the role of miR-424-5p as a novel potential regulator via HSP90AA1 during muscle myogenesis progression.


Asunto(s)
MicroARNs , Animales , Ratones , MicroARNs/genética , MicroARNs/metabolismo , Proliferación Celular/genética , Diferenciación Celular/genética , Línea Celular , Desarrollo de Músculos/genética , Cabras/genética , Músculo Esquelético/metabolismo
17.
Anim Biotechnol ; 34(7): 2617-2625, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-35951546

RESUMEN

MircoRNAs (miRNAs) play an important role in skeletal muscle development. Previous study had found that miR-495-3p was differentially expressed in fetal and adult goat skeletal muscle, but its function in myogenic proliferation and differentiation are unclear. Herein, we found the expression of miR-495-3p in C2C12 was downregulated during proliferation stage and upregulated during differentiation stage. Functionally, overexpression of miR-495-3p in C2C12 inhibited proliferation, and promoted myogenic differentiation. Mechanistically, the luciferase reporter assay demonstrated that cadherin 2 (CDH2) was a potential target gene of miR-495-3p. Importantly, overexpression of miR-495-3p inhibited CDH2 expression. Furthermore, knockdown of CDH2 in C2C12 inhibited proliferation and promoted myogenic differentiation. Together, the results showed that miR-495-3p inhibits C2C12 proliferation and promotes myogenic differentiation through targeting CDH2.


Asunto(s)
MicroARNs , Animales , MicroARNs/genética , MicroARNs/metabolismo , Mioblastos/fisiología , Proliferación Celular/genética , Cadherinas/genética , Cadherinas/metabolismo , Desarrollo de Músculos/genética , Diferenciación Celular/genética
18.
Int J Mol Sci ; 25(1)2023 Dec 19.
Artículo en Inglés | MEDLINE | ID: mdl-38203196

RESUMEN

In pig production, pigs often show more aggressive behavior after mixing, which adversely affects animal welfare and growth performance. The Jumonji and structural domain-rich AT interaction domain 2 (JARID2) gene plays an important role in neurodevelopment in mice and various psychiatric disorders in humans. The JARID2 gene may impact the aggressive behavior of pigs. By observing the behavior of 500 weaned pigs during the first 72 h after mixing, the ear tissue samples of the 12 most aggressive and 12 least aggressive pigs were selected for DNA resequencing based on the intensity of their aggressive behavior. Large group correlation analysis indicated that the rs3262221458 site located in the 3'-UTR region of the porcine JARID2 gene has a strong relationship with the aggressive behavior of weaned pigs. Pigs with the mutant TT genotype of rs3262221458 have more aggressive behavior than those pigs with the GG and GT genotypes. The dual luciferase assay indicated that the luciferase activity of the plasmids containing the G allele of rs326221458 was significantly less than that of plasmids containing the T allele of rs326221458 and control groups. The binding ability of miR-9828-3p to sequences containing the T allele was less than that of sequences containing the G allele. The overexpression of miR-9828-3p in porcine neuroglial cells (PNGCs) and PK15 cells significantly decreased the mRNA and protein levels of the JARID2 gene. In addition, miR-9828-3p inhibited the proliferation of PNGCs. After inhibiting miR-9828-3p, the mRNA and protein expression levels of JARID2 increased, and the proliferation of PNGCs showed an opposite trend to the cells that forced the expression of miR-9828-3p. In addition, interference with the JARID2 gene by siRNA can effectively inhibit the proliferation of PNGCs. In summary, we found that the rs326221458 locus regulates the expression of the JARID2 gene by affecting the binding of miR-9828-3p and the JARID2 gene, thereby affecting the aggressive behavior of weaned pigs after mixing.


Asunto(s)
MicroARNs , Polimorfismo de Nucleótido Simple , Humanos , Porcinos/genética , Animales , Ratones , Regiones no Traducidas 3' , ARN Mensajero , Luciferasas , MicroARNs/genética , Complejo Represivo Polycomb 2
19.
Int Wound J ; 20(8): 2964-2972, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-36965159

RESUMEN

A meta-analysis study to assess the influence of instant surgery (IS) compared with conservative therapy (CT) on paediatric complicated acute appendicitis (CAA) post-surgery wounds. A comprehensive literature examination until January 2023 was implemented, and 2098 linked studies were appraised. The picked studies contained 66 674 subjects with paediatric CAA post-surgery wounds in the picked studies' baseline; 64 643 of them were using IS, and 2031 were using CT. The odds ratio (OR) in addition to 95% confidence intervals (CIs) were used to calculate the consequence of the IS compared with the CT on paediatric CAA post-surgery wounds using the dichotomous and continuous styles and a fixed or random model. The IS had a significantly higher wound infection (OR, 4.97; 95% CI, 2.35-10.54, P < .001) with moderate heterogeneity (I2  = 57%) compared with the CT in a paediatric CAA post-surgery wound. However, no significant difference was found between IS and CT in total antibiotic duration (MD, -5.34; 95% CI,-12.67 to -1.98, P = .15) with high heterogeneity (I2  = 95%) in paediatric CAA post-surgery wounds. The IS had a significantly higher wound infection; however, no significant difference was found in total antibiotic duration compared with the CT in paediatric CAA post-surgery wounds. Although precautions should be taken when commerce with the consequences because most of the studies picked for this meta-analysis had low sample sizes.


Asunto(s)
Apendicitis , Infección de Heridas , Humanos , Niño , Apendicitis/cirugía , Tratamiento Conservador , Antibacterianos/uso terapéutico , Oportunidad Relativa , Infección de la Herida Quirúrgica/etiología , Infección de la Herida Quirúrgica/terapia
20.
J Environ Sci (China) ; 125: 82-94, 2023 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-36375963

RESUMEN

The performance of catalysts used in after-treatment systems is the key factor for the removal of diesel soot, which is an important component of atmospheric fine particle emissions. Herein, three-dimensionally ordered macroporous-mesoporous TixSi1-xO2 (3DOM-m TixSi1-xO2) and its supported MnOx catalysts doped with different alkali/alkaline-earth metals (AMnOx/3DOM-m Ti0.7Si0.3O2 (A: Li, Na, K, Ru, Cs, Mg, Ca, Sr, Ba)) were prepared by mesoporous template (P123)-assisted colloidal crystal template (CCT) and incipient wetness impregnation methods, respectively. Physicochemical characterizations of the catalysts were performed using scanning electron microscopy, X-ray diffraction, N2 adsorption-desorption, H2 temperature-programmed reduction, O2 temperature-programmed desorption, NO temperature-programmed oxidation, and Raman spectroscopy techniques; then, we evaluated their catalytic performances for the removal of diesel soot particles. The results show that the 3DOM-m Ti0.7Si0.3O2 supports exhibited a well-defined 3DOM-m nanostructure, and AMnOx nanoparticles with 10-50 nm were evenly dispersed on the inner walls of the uniform macropores. In addition, the as-prepared catalysts exhibited good catalytic performance for soot combustion. Among the prepared catalysts, CsMnOx/3DOM-m Ti0.7Si0.3O2 had the highest catalytic activity for soot combustion, with T10, T50, and T90 (the temperatures corresponding to soot conversion rates of 10%, 50%, and 90%) values of 285, 355, and 393°C, respectively. The high catalytic activity of the CsMnOx/3DOM-m Ti0.7Si0.3O2 catalysts was attributed to their excellent low-temperature reducibility and homogeneous macroporous-mesoporous structure, as well as to the synergistic effects between Cs and Mn species and between CsMnOx and the Ti0.7Si0.3O2 support.

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