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1.
J Adv Res ; 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38621622

RESUMO

INTRODUCTION: Necroptosis triggered by H2O2 is hypothesized to be a critical factor in the rupture of atherosclerotic plaques, which may precipitate acute cardiovascular events. Nevertheless, the specific regulatory molecules of this development remain unclear. We aims to elucidate a mechanism from the perspective of circular RNA. OBJECTIVES: There are few studies on circRNA in VSMCs necroptosis. The objective of our research is to shed light on the intricate roles that circHIPK3 plays in the process of necroptosis in VSMCs and the development of atherosclerotic plaques that are prone to rupture. Our study elucidates the specific molecular mechanisms by which circHIPK3 regulates necroptosis and atherosclerotic vulnerable plaque formation through targeted proteins. Identifying this mechanism at the cellular level offers a molecular framework for understanding plaque progression and stability regulation, as well as a potential biomarker for the prognosis of susceptible atherosclerotic plaques. METHODS: We collected clinical vascular tissue for HE staining and Masson staining to determine the presence and stability of plaques. Then, NCBI database was used to screen out circRNA with elevated expression level in plaque tissue, and the up-regulated circRNA, circHIPK3, was verified by qRT-PCR and FISH. Further, we synthesized circHIPK3's small interference sequence and overexpressed plasmid in vitro, and verified its regulation effect on necroptosis of VSMCs under physiological and pathological conditions by WB, qRT-PCR and PI staining. Through RNA pull down, mass spectrometry and RNA immunoprecipitation, DRP1 was identified as circHIPK3 binding protein and was positively regulated by circHIPK3. Meanwhile, on the basis of silencing of DRP1, the regulation of circHIPK3 on necroptosis is verified to be mediated by DRP1. Finally, we validated the regulation of circHIPK3 on vulnerable plaque formation in ApoE-/- mice. RESULTS: We investigated that circHIPK3 was highly expressed in vulnerable plaques, and the increase in expression level promoted H2O2 induced necroptosis of VSMCs. CircHIPK3 targeted the protein DRP1, leading to an elevation in mitochondrial division rate, resulting in increased reactive oxygen species and impaired mitochondrial function, ultimately leading to necroptosis of VSMCs and vulnerable plaque formation. CONCLUSION: CircHIPK3 interact with DRP1 involve in H2O2 induced Mitochondrial damage and necroptosis of VSMCs, and Silencing circHIPK3 in vivo can reduce atherosclerotic vulnerable plaque formation. Our research findings may have applications in providing diagnostic biomarkers for vulnerable plaques.

2.
iScience ; 27(4): 109502, 2024 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-38591009

RESUMO

Constitutive explorations indicate a correlation between circular RNAs (circRNAs) and cardiovascular diseases. However, the involvement of circRNAs in endothelial recuperation and in-stent restenosis (ISR) remains underexplored. CircTMEM165 has first been reported to be highly expressed in hypoxic human umbilical vein endothelial cells (HUVECs). Here, we identified that circTMEM165 was downregulated in ISR patients, inversely correlating with ISR severity. Functionally, circTMEM165 was found to be abundant in endothelial cells, inhibiting inflammation, and adhesion. Particularly, we first observed that circTMEM165 could alleviate HUVECs apoptosis and mitochondrial fission induced by lipopolysaccharide (LPS). Mechanistically, circTMEM165, as a miR-192-3p sponge, enhancing SCP2 expression, which serves as a critical regulator of HUVECs biological functions. Moreover, in vivo, circTMEM165 attenuated intimal hyperplasia and facilitated repair following classic rat carotid artery balloon injury model. These findings investigated the circTMEM165-miR-192-3p-SCP2 axis as a critical determinant of endothelial health and a potential biomarker and therapeutic target for vascular disorders.

3.
Soft Matter ; 2024 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-38595302

RESUMO

The decellularized tilapia skin (dTS) has gained significant attention as a promising material for tissue regeneration due to its ability to provide unique structural and functional components that support cell growth, adhesion, and proliferation. However, the clinical application of dTS is limited by its low mechanical strength and rapid biodegradability. Herein, we prepare a novel RGD (arginine-glycine-aspartic acid) functionalized dTS scaffold (dTS/RGD) by using transglutaminase (TGase) crosslinking. The developed dTS/RGD scaffold possesses excellent properties, including a medium porosity of ∼59.2%, a suitable degradation rate of approximately 80% over a period of two weeks, and appropriate mechanical strength with a maximum tensile stress of ∼46.36 MPa which is much higher than that of dTS (∼32.23 MPa). These properties make the dTS/RGD scaffold ideal for promoting cell adhesion and proliferation, thereby accelerating skin wound healing in a full-thickness skin defect model. Such an enzymatic cross-linking strategy provides a favorable microenvironment for wound healing and holds great potential for application in skin regeneration engineering.

4.
Front Microbiol ; 15: 1355028, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38435699

RESUMO

This study investigated the spatiotemporal distribution of the phytoplankton in the coral habitat of Dongshan Bay (China), along with critical factors affecting the distribution, during June, August, and December 2022. Phytoplankton abundance in Dongshan Bay exhibited considerably temporal variation, peaking in June 2022, gradually decreasing thereafter, and reaching its lowest point in December 2022. The abundance of bottom-layer phytoplankton consistently exceeded that of the surface layer throughout all seasons. The average phytoplankton abundance in the coral habitat of Dongshan Bay was lower than that in non-coral habitat areas. Fluctuations in the Zhangjiang River and coastal upwelling influenced the diversity and community structure of the phytoplankton. Critical factors causing spatiotemporal variability in phytoplankton community structure included nutrient concentrations and seawater temperature. Nutrients played key roles in influencing various phytoplankton groups. Dominant diatom species, such as Thalassionema nitzschioides and Thalassiosira diporocyclus, were positively correlated with ammonia nitrogen, seawater salinity, coral cover, and the number of coral species present. In winter, Calanus sinicus exhibited a negative correlation with harmful algal bloom species. Additionally, it was found that both in the coral habitat and surrounding open sea, currents, nutrients, and zooplankton may play crucial roles in determining the spatiotemporal variability in the phytoplankton community structure.

5.
Sci Total Environ ; 927: 172002, 2024 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-38547986

RESUMO

The Yellow River, renowned as the most sediment-laden river globally, grapples with sediment deposition issues compromising reservoir functionality and elevating downstream riverbeds, posing threats to human life and property safety. In response, the Water-Sediment Regulation Scheme (WSRS) has been innovatively implemented to address these challenges. While effectively mitigating sediment deposition, WSRS has concurrently disrupted the equilibrium of the estuarine ecosystem. This paper addresses the understudied but crucial topic of the interannual impact of WSRS on the estuarine ecosystem. Drawing upon physical, chemical, and biological data gathered through field surveys conducted before, during, and after WSRS from 2011 to 2022, the analysis delves into the interannual changes in the estuarine environment, fish eggs and larvae abundance, and species diversity under the influence of WSRS. The findings reveal an interannual decreasing trend in terrestrial material input due to WSRS, juxtaposed with an interannual increasing trend in fish eggs and larvae around the estuary, as well as the species diversity index. Notably, these trends became more pronounced post-2014. Compared to pre-2014, nutrient concentrations experienced a ~20 % decrease, chlorophyll-a concentration increased by 44 %, fish eggs proliferated approximately 1 time, and the species diversity index transitioned from a declining trend to an ascending trajectory. After 12 years of continuous WSRS implementation, the impact on the estuarine ecosystem has demonstrably diminished. This research aims to furnish reference experience and scientific basis for water and sediment regulation in major rivers around the world in terms of estuarine ecology.

6.
Mol Immunol ; 169: 50-65, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38493581

RESUMO

Macrophages play a crucial role in the inflammatory response following sciatic nerve injury. Studies have demonstrated that C-X-C motif chemokine (CXCL) 1 recruit macrophages by binding to C-X-C chemokine receptor (CXCR) 2 and participates in the inflammatory response of various diseases. Based on these findings, we aimed to explore the role of the CXCL1-CXCR2 axis in the repair process after peripheral nerve injury. Initially, we simulated sciatic nerve injury and observed an increased expression of CXCL1 and CXCR2 in the nerves of the injury group. Both in vivo and in vitro experiments confirmed that the heightened CXCL1 expression occurs in Schwann cells and is secreted, while the elevated CXCR2 is expressed by recruited macrophages. In addition, in vitro experiments demonstrated that the binding of CXCL1 to CXCR2 can activate the NLRP3 inflammasome and promote the production of interleukin-1 beta (IL-1ß) in macrophages. However, after mice were subjected to sciatic nerve injury, the number of macrophages and the expression of inflammatory factors in the sciatic nerve were reduced following treatment with the CXCR2 inhibitor SB225002. Simultaneously, we evaluated the sciatic nerve function index, the expression of p75 neurotrophic factor receptor (p75NTR), and myelin proteins, and all of these results were improved with the use of SB225002. Thus, our results suggest that after sciatic nerve injury, the CXCL1-CXCR2 axis mediates the inflammatory response by promoting the recruitment and activation of macrophages, which is detrimental to the repair of the injured nerves. In contrast, treatment with SB225002 promotes the repair of injured sciatic nerves.


Assuntos
Traumatismos dos Nervos Periféricos , Camundongos , Animais , Quimiocina CXCL1/metabolismo , Compostos de Fenilureia/farmacologia , Macrófagos/metabolismo , Nervo Isquiático
7.
Animals (Basel) ; 14(5)2024 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-38473062

RESUMO

The number of vertebrae is a crucial economic trait that can significantly impact the carcass length and meat production in animals. However, our understanding of the quantitative trait loci (QTLs) and candidate genes associated with the vertebral number in sheep (Ovis aries) remains limited. To identify these candidate genes and QTLs, we collected 73 Ujimqin sheep with increased numbers of vertebrae (T13L7, T14L6, and T14L7) and 23 sheep with normal numbers of vertebrae (T13L6). Through high-throughput genome resequencing, we obtained a total of 24,130,801 effective single-nucleotide polymorphisms (SNPs). By conducting a selective-sweep analysis, we discovered that the most significantly selective region was located on chromosome 7. Within this region, we identified several genes, including VRTN, SYNDIG1L, LTBP2, and ABCD4, known to regulate the spinal development and morphology. Further, a genome-wide association study (GWAS) performed on sheep with increased and normal vertebral numbers confirmed that ABCD4 is a candidate gene for determining the number of vertebrae in sheep. Additionally, the most significant SNP on chromosome 7 was identified as a candidate QTL. Moreover, we detected two missense mutations in the ABCD4 gene; one of these mutations (Chr7: 89393414, C > T) at position 22 leads to the conversion of arginine (Arg) to glutamine (Gln), which is expected to negatively affect the protein's function. Notably, a transcriptome expression profile in mouse embryonic development revealed that ABCD4 is highly expressed during the critical period of vertebral formation (4.5-7.5 days). Our study highlights ABCD4 as a potential major gene influencing the number of vertebrae in Ujimqin sheep, with promising prospects for future genome-assisted breeding improvements in sheep.

8.
Eye (Lond) ; 2024 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-38555400

RESUMO

BACKGROUND/OBJECTIVES: Tessellated fundus can exist in normal healthy eyes. This study aims to evaluate the occurrence and influencing factors of tessellated fundus in preschool children aged 3-6 years. SUBJECTS/METHODS: This kindergarten-based cross-sectional study included 1716 children with an age range of 3-6 years. All participants underwent a comprehensive eye examination and a questionnaire. According to the number of quadrants occupied by tessellated fundus around the optic disc in fundus photographs, it was divided into four grades. RESULTS: 600 (35.0%) children had peripapillary tessellation. According to the spherical equivalent (SE), the subjects were divided into three groups: Hyperopia group (SE > + 0.75D, n = 1194);Pre-myopia group (-0.50D < SE ≤ + 0.75D, n = 455); Myopia group (SE ≤ -0.50D, n = 67). The proportion of peripapillary tessellated fundus was 33.0%, 38.0%, 50.7% respectively. According to the regression analysis, in the non-myopia group (Pre-myopia group and Hyperopia group), the occurrence of peripapillary tessellated fundus was associated with longer axial length (OR, 1.566; 95% CI: 1.229-1.996, p < 0.001) and larger corneal radius of curvature (OR, 1.837; 95% CI: 1.006-3.354, p = 0.048). However, in Pre-myopia group, the corneal radius of curvature was not associated with the occurrence of peripapillary tessellated fundus (p = 0.830). In Hyperopia group, the corneal radius of curvature was associated with the occurrence of peripapillary tessellated fundus (OR, 2.438; 95% CI: 1.160-5.122, p = 0.019). CONCLUSIONS: The occurrence of peripapillary tessellated fundus is more than 30% in 3-6 year old preschool children. Tessellated fundus can also occur in non-myopic children, and is related to the length of axial length and large radius of corneal curvature.

9.
Plant Biotechnol J ; 2024 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-38548388

RESUMO

Carotenoids are indispensable to plants and critical components of the human diet. The carotenoid metabolic pathway is conserved across plant species, but our understanding of the genetic basis of carotenoid variation remains limited for the seeds of most cereal crops. To address this issue, we systematically performed linkage and association mapping for eight carotenoid traits using six recombinant inbred line (RIL) populations. Single linkage mapping (SLM) and joint linkage mapping (JLM) identified 77 unique additive QTLs and 104 pairs of epistatic QTLs. Among these QTLs, we identified 22 overlapping hotspots of additive and epistatic loci, highlighting the important contributions of some QTLs to carotenoid levels through additive or epistatic mechanisms. A genome-wide association study based on all RILs detected 244 candidate genes significantly associated with carotenoid traits, 23 of which were annotated as carotenoid pathway genes. Effect comparisons suggested that a small number of loci linked to pathway genes have substantial effects on carotenoid variation in our tested populations, but many loci not associated with pathway genes also make important contributions to carotenoid variation. We identified ZmPTOX as the causal gene for a QTL hotspot (Q10/JLM10/GWAS019); this gene encodes a putative plastid terminal oxidase that produces plastoquinone-9 used by two enzymes in the carotenoid pathway. Natural variants in the promoter and second exon of ZmPTOX were found to alter carotenoid levels. This comprehensive assessment of the genetic mechanisms underlying carotenoid variation establishes a foundation for rewiring carotenoid metabolism and accumulation for efficient carotenoid biofortification.

10.
Occup Ther Int ; 2024: 1088666, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38528963

RESUMO

Occupational therapy is a profession with origins rooted in Western values. As culture plays an important role in shaping theory and practice, the curriculum design of academic programs that train future rehabilitation professionals should reflect the local context. As part of an international partnership, a dual-degree graduate program in occupational therapy was established between a Chinese and an American university. A team composed of members from both institutions collaborated on culturally adapting an entry-level master's program in occupational therapy for China, based on a U.S. program, which welcomed its first cohort in September 2019. This article details the timeline and process of program design and adaptation from conception, through implementation to evaluation and revision, with the aim of offering a framework for curriculum adaptation of other academic programs in the U.S. and internationally. The adapted curriculum includes the program mission, vision, and philosophy; the curriculum model with program outcomes and threads; the program scope and sequence; materials and resources; and course-specific objectives, learning activities, and assessments. The authors also share lessons learned through this experience of international collaboration as well as next steps for program evaluation and sustainability. The detailed overview of this international collaboration offers suggestions for individuals and institutions seeking to develop global partnerships and adapt curricula across cultural contexts.


Assuntos
Terapia Ocupacional , Humanos , Terapia Ocupacional/educação , Currículo , Avaliação de Programas e Projetos de Saúde , China
11.
Proc Natl Acad Sci U S A ; 121(7): e2315476121, 2024 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-38319970

RESUMO

Marine photosynthetic dinoflagellates are a group of successful phytoplankton that can form red tides in the ocean and also symbiosis with corals. These features are closely related to the photosynthetic properties of dinoflagellates. We report here three structures of photosystem I (PSI)-chlorophylls (Chls) a/c-peridinin protein complex (PSI-AcpPCI) from two species of dinoflagellates by single-particle cryoelectron microscopy. The crucial PsaA/B subunits of a red tidal dinoflagellate Amphidinium carterae are remarkably smaller and hence losing over 20 pigment-binding sites, whereas its PsaD/F/I/J/L/M/R subunits are larger and coordinate some additional pigment sites compared to other eukaryotic photosynthetic organisms, which may compensate for the smaller PsaA/B subunits. Similar modifications are observed in a coral symbiotic dinoflagellate Symbiodinium species, where two additional core proteins and fewer AcpPCIs are identified in the PSI-AcpPCI supercomplex. The antenna proteins AcpPCIs in dinoflagellates developed some loops and pigment sites as a result to accommodate the changed PSI core, therefore the structures of PSI-AcpPCI supercomplex of dinoflagellates reveal an unusual protein assembly pattern. A huge pigment network comprising Chls a and c and various carotenoids is revealed from the structural analysis, which provides the basis for our deeper understanding of the energy transfer and dissipation within the PSI-AcpPCI supercomplex, as well as the evolution of photosynthetic organisms.


Assuntos
Antozoários , Dinoflagelados , Animais , Antozoários/metabolismo , Complexos de Proteínas Captadores de Luz/metabolismo , Dinoflagelados/metabolismo , Proliferação Nociva de Algas , Simbiose , Microscopia Crioeletrônica , Complexo de Proteína do Fotossistema I/metabolismo , Clorofila/metabolismo
12.
J Clin Monit Comput ; 2024 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-38368302

RESUMO

Lung recruitment manoeuvres (RMs) during mechanical ventilation may reduce atelectasis, however, the optimal recruitment strategy for patients undergoing thoracic surgery remains unknown. Our study was designed to investigate whether ultrasound-guided lung RMs is superior to conventional RMs in reducing perioperative atelectasis during thoracic surgery with one-lung ventilation. We conducted a randomised controlled clinical trial from August 2022 to September 2022. Sixty patients scheduled for video-assisted thoracoscopic surgery (VATS) under general anaesthesia were enrolled. Subjects were randomly divided into the ultrasound-guided RMs group (manual inflation guided by lung ultrasound) or conventional RMs group (manual inflation with 30 cmH2O pressure). Lung ultrasound were performed at three predefined time points (1 min after anaesthetic induction; after RMs at the end of surgery; before discharge from postanesthesia care unit [PACU]). The primary outcome was lung ultrasound score before discharge from the PACU after extubation. In the early postoperative period, lung aeration deteriorated in both groups even after lung RMs. However, ultrasound-guided lung RMs had significantly lower lung ultrasound scores when compared with conventional RMs in bilateral lungs (2.0 [0.8-4.0] vs. 8.0 [3.8-10.3], P < 0.01) at the end of surgery, which remained before patients discharged from the PACU. Accordingly, the lower incidence of atelectasis was found in ultrasound-guided RMs group than in conventional RMs group (7% vs. 53%; P < 0.01) at the end of surgery. Ultrasound-guided RMs is superior to conventional RMs in improving lung aeration and reducing the incidence of lung atelectasis at early postoperative period in patients undergoing VATS. The study protocol was approved by the Institutional Review Board of the Fudan University Shanghai Cancer Center (No. 220,825,810; date of approval: August 5, 2022) and registered on Chinese Clinical Trial Registry (registration number: ChiCTR2200062761).

13.
Heliyon ; 10(2): e24378, 2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-38298673

RESUMO

Background: Epidermal growth factor receptor (EGFR) mutations have been identified as promising therapeutic targets for non-small cell lung cancer. Osimertinib, a third-generation EGFR-tyrosine kinase inhibitor-targeting drug, has good anti-tumor ability and excellent intracranial effects. However, management of osimertinib resistance is a clinical challenge. The clinical benefit of osimertinib combined with the antiangiogenic drug, bevacizumab, remains to be determined. Case presentation: A 40-year-old female with right lung adenocarcinoma (cT2aN3M1c, IVb) was confirmed positive for EGFR exon 19 deletion mutation (c.2235_2249del, 1.3%). After receiving 5 months of osimertinib (80 mg, qd) therapy, the patient's disease progressed and she subsequently accepted treatment with osimertinib (80 mg, qd) plus bevacizumab (15 mg/kg, q21d) and achieved notable clinical remission for 23 months until renal impairment occurred, after which bevacizumab was discontinued. The patient had 6 months of remission before progression, after which bevacizumab was added again. To date, the disease has been under control. The brain lesion showed partial response again, and the side effects of bevacizumab were tolerable. The overall survival time exceeded 4 years. Conclusion: This case report describes a treatment strategy for osimertinib-resistant patients with EGFR exon 19 deletion mutations. Metronomic treatment with osimertinib plus bevacizumab was achieved for more than 4 years.

14.
Int Immunopharmacol ; 129: 111601, 2024 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-38350354

RESUMO

Understanding the mechanisms of resistance of hepatocellular carcinoma (HCC) to targeted therapies and immune checkpoint blockade is critical for the development of new combination therapies and improving patient survival. Here, we found that in HCC, anti-programmed cell death 1 ligand 1 (PD-L1) therapy reduces liver cancer growth, but the tumors eventually become resistant to continued therapy. Experimental analyses shows that the infiltration of pathogenic T helper 17 (pTh17) cells increases in drug-resistant HCC, and pTh17 cells secrete interleukin-17A (IL-17A), which promotes the expression of PD-L1 on the surface of HCC cells and produces resistance to anti-PD-L1 therapy. Anti-IL-17A combined with PD-L1 blockade significantly increased the infiltration of cytotoxic CD8+ T cells expressing high levels of interferon-γ and reduced treatment resistance in HCC. These results support the combination of anti-PD-L1 and anti-IL-17A as a novel strategy to induce effective T cell-mediated anti-tumor immune responses.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Linfócitos T CD8-Positivos , Antígeno B7-H1/metabolismo , Células Th17/metabolismo , Imunoterapia/métodos , Anticorpos Monoclonais/metabolismo , Microambiente Tumoral
15.
Proc Natl Acad Sci U S A ; 121(8): e2316731121, 2024 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-38359290

RESUMO

One important goal of circadian medicine is to apply time-of-day dosing to improve the efficacy of chemotherapy. However, limited knowledge of how the circadian clock regulates DNA repair presents a challenge to mechanism-based clinical application. We studied time-series genome-wide nucleotide excision repair in liver and kidney of wild type and three different clock mutant genotypes (Cry1-/-Cry2-/-, Per1-/-Per2-/-, and Bmal1-/-). Rhythmic repair on the nontranscribed strand was lost in all three clock mutants. Conversely, rhythmic repair of hundreds of genes on the transcribed strand (TSs) persisted in the livers of Cry1-/-Cry2-/- and Per1-/-Per2-/- mice. We identified a tissue-specific, promoter element-driven repair mode on TSs of collagen and angiogenesis genes in the absence of clock activators or repressors. Furthermore, repair on TSs of thousands of genes was altered when the circadian clock is disrupted. These data contribute to a better understanding of the regulatory role of the circadian clock on nucleotide excision repair in mammals and may be invaluable toward the design of time-aware platinum-based interventions in cancer.


Assuntos
Relógios Circadianos , Animais , Camundongos , Relógios Circadianos/genética , Ritmo Circadiano/genética , Proteínas CLOCK/genética , Mutação , Nucleotídeos , Criptocromos/genética , Fatores de Transcrição ARNTL/genética , Mamíferos
16.
Gene ; 910: 148310, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38401832

RESUMO

With the change in diet structure, individuals prefer to consume mutton with less fat. However, sheep tail has a lot of fat. We identified a breed of low-fat short-tailed sheep (i.e., Hulunbuir short-tailed sheep). It is necessary to develop an animal model that can promote research on the potential mechanisms of the short-tail phenotype in sheep, which results from the TBXT gene c.G334T mutation. To create animal models, we selected mice as experimental animals. Mouse embryos lacking the TBXT protein, which crucially regulates mouse embryonic development, cannot develop normally. We utilized CRISPR/Cas9 gene editing technology to generate site-specific mutation (c.G334T) in the TBXT gene of mice, and found that the mouse TBXT mutation (c.G334T) leads to a short-tail phenotype. Furthermore, we investigated the interaction between TBXT and Wnt signaling pathways. The expressions of TBXT, Axin2, Dkk1, Wnt3, Wnt3a, and Wnt5a were discovered to be significantly different between mutant embryos and wild embryos by obtaining mouse embryos at various developmental stages and examining the expression relationship between the TBXT and Wnt signaling pathway-related components in all of these embryos. Therefore, as a transcription factor, TBXT regulates the expression of the aforementioned Wnt signaling pathway components by forming a regulatory network for the normal development of mouse embryos. This study enriches the research on the functional role of the TBXT in the development of mouse embryos and the mechanism by which the short-tailed phenotype in sheep develops.


Assuntos
Sistemas CRISPR-Cas , Cauda , Gravidez , Feminino , Camundongos , Animais , Ovinos/genética , Desenvolvimento Embrionário/genética , Fenótipo , Edição de Genes/métodos
17.
RSC Adv ; 14(6): 3834-3840, 2024 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-38274160

RESUMO

Polymeric membrane sensors based on molecular imprinted polymers (MIPs) have been attractive analytical tools for detecting organic species. However, the MIPs in electrochemical sensors developed so far are usually prepared by in situ polymerization of pre-polymers and non-covalent adsorption on the surface of the working electrode. Meanwhile, the MIPs in the electrochemical sensors developed are typically made of a non-conductive polymer film. This results in a relatively low current due to the lack of electron transfer. Additionally, the smoothness of the traditional electrochemical substrate results in a low specific surface area, which reduces the sensitivity of the electrochemical sensor. Here, we describe a novel electrochemical sensor with a conductive interface and MIPs modification. The electrochemical sensor was modified by covalent coupled layer by layer self-assembly with the imprinted polymer film. The incorporation of these two conductive functional materials improves the conductivity of the electrodes and provides interface support materials to obtain high specific surface area. By using 2,4,6-trichlorophenol as the model, the sensitivity of the developed conductive sensor was greatly improved compared to that of the traditional MIPs sensor. We believe that the proposed MIPs-based sensing strategy provides a general and convenient method for making sensitive and selective electrochemical sensors.

18.
Discov Med ; 36(180): 140-149, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38273754

RESUMO

BACKGROUND: Endometritis is a condition usually resulted from the bacterial infection of uterus, causing pelvic disease, sepsis, shock, uterine necrosis and even death if it is inappropriately treated. The aim of this study is to explore the pathogenesis of endometritis, and investigate whether the combination of doxycycline and metronidazole offers stronger protection against lipopolysaccharide (LPS)-induced endometritis, and decipher more about the mechanisms underlying endometritis-related pyroptosis. METHODS: Sprague-Dawley (SD) rats were divided into five groups (n = 8 per group): control, model, metronidazole, doxycycline, and combination groups. In control group, the rats were injected with saline, while in other groups, lipopolysaccharide was injected into uterus of the rats to establish endometritis. Hematoxylin-eosin (H&E) staining was performed as part of the histopathological examination of endometrium. The integrity of chromatin and pyroptosis were evaluated by terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) assay. Western blot and quantitative real-time reverse-transcription polymerase chain reaction (qRT-PCR) were performed to ascertain the activation of toll-like receptors (TLR4)/nuclear factor-kappa B (NF-κB) pathway by detecting protein levels of phosphorylated p50 (p-p50)/p50, phosphorylated nuclear factor-kappa B (p-NF-κB)/NF-κB, phosphorylated IkappaB (p-IκB), and TLR4 protein and mRNA. Development of pyroptosis was also detected by determining the levels of caspase-1 and caspase-5 through Western blot and qRT-PCR. Enzyme-linked immunosorbent assay (ELISA) was used to detect levels of interleukin (IL)-1ß, IL-18, IL-2, IL-4, IL-6 and tumor necrosis factor alpha (TNF-α), and flow cytometry was adopted to determine T-helper (Th)1 and Th2 cell percentage to assess the extent of pyroptosis and Th1/Th2 imbalance. RESULTS: The uterine of the model group exhibited pathological alterations and higher degree of cell apoptosis. Compared with the control rats, model group showed lower protein levels of p-p50/p50 (p < 0.001), p-NF-κB/NF-κB (p < 0.001), p-IκB (p < 0.001), and TLR4 protein (p < 0.001) and mRNA (p < 0.001). Elevated levels of caspase-1 (p < 0.001), caspase-5 (p < 0.001), IL-1ß (p < 0.001), IL-18 (p < 0.001), IL-2 (p < 0.01), TNF-α (p < 0.05) and Th1/Th2 (p < 0.001) as well as reduced levels of IL-4 (p < 0.05) and IL-6 (p < 0.01) were observed in the model group, which could however be reversed by metronidazole (p < 0.01) or doxycycline (p < 0.01), with a more significant effect detected if a combination of the two drugs was administered (p < 0.01). CONCLUSIONS: The combination of doxycycline and metronidazole protects against rat endometritis by inhibiting TLR4/NF-κB pathway-mediated inflammation and suppressing pyroptosis.


Assuntos
Endometrite , NF-kappa B , Humanos , Feminino , Ratos , Animais , NF-kappa B/metabolismo , NF-kappa B/farmacologia , Endometrite/tratamento farmacológico , Interleucina-18/farmacologia , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Metronidazol/uso terapêutico , Metronidazol/farmacologia , Doxiciclina/farmacologia , Transdução de Sinais , Fator de Necrose Tumoral alfa/farmacologia , Lipopolissacarídeos/farmacologia , Interleucina-6/metabolismo , Piroptose , Interleucina-2/farmacologia , Interleucina-4/farmacologia , Ratos Sprague-Dawley , Caspases/metabolismo , Caspases/farmacologia , RNA Mensageiro/genética
19.
Ann Hum Biol ; 51(1): 1-6, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38251837

RESUMO

BACKGROUND: At present, there are no available genetic data on the AGCU EX22 Kit from the Wuhu Han population. AIM: This study investigates the applicability of the AGCU EX22 kit, designed for the Chinese population for forensic analysis and population genetics of the Wuhu Han population. SUBJECTS AND METHODS: Bloodstains from 1565 unrelated healthy individuals in Wuhu city, Anhui Province, were collected for analysis. The AGCU EX22 kit was used for amplification, and capillary electrophoresis was used to separate the amplification products. Allele frequencies and forensic parameters were determined. The Wuhu Han population was compared to 10 reference populations through genetic distance, a phylogenetic neighbor-joining tree and principal component analysis. RESULTS: In total, 281 alleles and 1187 genotypes were observed. No significant deviations from Hardy-Weinberg equilibrium at any locus were found after Bonferroni's correction. The 21 autosomal short tandem repeat (STR) genetic markers exhibited high informativeness and polymorphism. The cumulative power of discrimination and power of exclusion were 0.999999999999999999999999913380 and 0.999999996752339, respectively. Population comparisons revealed a genetic affinity between Wuhu Han and southern Han populations, except for the Guangdong Han population, which aligned with the traditional geographical division in China. CONCLUSION: The AGCU EX22 Kit, containing 21 STR loci, is suitable for forensic application and population genetics studies in the Wuhu Han population.


Assuntos
População do Leste Asiático , Repetições de Microssatélites , Humanos , Alelos , China , População do Leste Asiático/genética , Genética Forense , Frequência do Gene , Genética Populacional , Voluntários Saudáveis , Filogenia , Sangue
20.
Comb Chem High Throughput Screen ; 27(1): 148-156, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-37282650

RESUMO

AIM: In this study, the protective effects of atorvastatin calcium (AC) on nerve cells and cognitive improvement in vivo and in vitro were investigated by establishing cell models and vascular dementia (VD) rat models. BACKGROUND: VD is a neurodegenerative disease characterized by cognitive deficits caused by chronic cerebral hypoperfusion. AC has been studied for its potential to cure VD but its efficacy and underlying mechanism are still unclear. OBJECTIVE: The mechanism of action of AC on cognitive deficits in the early stages of VD is unclear. Here, the 2-vessel occlusion (2-VO) model in vivo and the hypoxia/reoxygenation (H/R) cell model in vitro was established to investigate the function of AC in VD. METHODS: The spatial learning and memory abilities of rats were detected by the Morris method. The IL-6, tumour necrosis factor-α (TNF-α), malondialdehyde (MDA) and superoxide dismutase (SOD) in cell supernatant was tested by ELISA kits. After behavioural experiments, rats were anaesthetized and sacrificed, and their brains were extracted. One part was immediately fixed in 4% paraformaldehyde for H&E, Nissl, and immunohistochemical analyses, and the other was stored in liquid nitrogen. All data were shown as mean ± SD. Statistical comparison between the two groups was performed by Student's t-test. A two-way ANOVA test using GraphPad Prism 7 was applied for escape latency analysis and the swimming speed test. The difference was considered statistically significant at p < 0.05. RESULTS: AC decreased apoptosis, increased autophagy, and alleviated oxidative stress in primary hippocampal neurons. AC regulated autophagy-related proteins in vitro by western blotting. VD mice improved cognitively in the Morris water maze. Spatial probing tests showed that VD animals administered AC had considerably longer swimming times to the platform than VD rats. H&E and Nissl staining showed that AC reduces neuronal damage in VD rats. Western blot and qRT-PCR indicated that AC in VD rats inhibited Bax and promoted LC3-II, Beclin-1, and Bcl-2 in the hippocampus region. AC also improves cognition via the AMPK/mTOR pathway. CONCLUSION: This study found that AC may relieve learning and memory deficits as well as neuronal damage in VD rats by changing the expression of apoptosis/autophagy-related genes and activating the AMPK/mTOR signalling pathway in neurons.


Assuntos
Demência Vascular , Doenças Neurodegenerativas , Ratos , Animais , Camundongos , Demência Vascular/tratamento farmacológico , Demência Vascular/metabolismo , Demência Vascular/patologia , Ratos Sprague-Dawley , Atorvastatina/farmacologia , Atorvastatina/uso terapêutico , Proteínas Quinases Ativadas por AMP , Cognição , Serina-Treonina Quinases TOR
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