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1.
J Phys Chem B ; 128(25): 6071-6081, 2024 Jun 27.
Article in English | MEDLINE | ID: mdl-38877985

ABSTRACT

The G protein-coupled receptors (GPCRs) play a pivotal role in numerous biological processes as crucial cell membrane receptors. However, the dynamic mechanisms underlying the activation of GPR183, a specific GPCR, remain largely elusive. To address this, we employed computational simulation techniques to elucidate the activation process and key events associated with GPR183, including conformational changes from inactive to active state, binding interactions with the Gi protein complex, and GDP release. Our findings demonstrate that the association between GPR183 and the Gi protein involves the formation of receptor-specific conformations, the gradual proximity of the Gi protein to the binding pocket, and fine adjustments of the protein conformation, ultimately leading to a stable GPR183-Gi complex characterized by a high energy barrier. The presence of Gi protein partially promotes GPR183 activation, which is consistent with the observation of GPCR constitutive activity test experiments, thus illustrating the reliability of our calculations. Moreover, our study suggests the existence of a stable partially activated state preceding complete activation, providing novel avenues for future investigations. In addition, the relevance of GPR183 for various diseases, such as colitis, the response of eosinophils to Mycobacterium tuberculosis infection, antiviral properties, and pulmonary inflammation, has been emphasized, underscoring its therapeutic potential. Consequently, understanding the activation process of GPR183 through molecular dynamic simulations offers valuable kinetic insights that can aid in the development of targeted therapies.


Subject(s)
Molecular Dynamics Simulation , Receptors, G-Protein-Coupled , Receptors, G-Protein-Coupled/metabolism , Receptors, G-Protein-Coupled/chemistry , Humans , Protein Conformation , Guanosine Diphosphate/metabolism , Guanosine Diphosphate/chemistry , Protein Binding , Binding Sites , GTP-Binding Protein alpha Subunits, Gi-Go/metabolism , GTP-Binding Protein alpha Subunits, Gi-Go/chemistry
2.
Breast Cancer Res ; 26(1): 94, 2024 Jun 06.
Article in English | MEDLINE | ID: mdl-38844963

ABSTRACT

BACKGROUND: RNA m5C methylation has been extensively implicated in the occurrence and development of tumors. As the main methyltransferase, NSUN2 plays a crucial regulatory role across diverse tumor types. However, the precise impact of NSUN2-mediated m5C modification on breast cancer (BC) remains unclear. Our study aims to elucidate the molecular mechanism underlying how NSUN2 regulates the target gene HGH1 (also known as FAM203) through m5C modification, thereby promoting BC progression. Additionally, this study targets at preliminarily clarifying the biological roles of NSUN2 and HGH1 in BC. METHODS: Tumor and adjacent tissues from 5 BC patients were collected, and the m5C modification target HGH1 in BC was screened through RNA sequencing (RNA-seq) and single-base resolution m5C methylation sequencing (RNA-BisSeq). Methylation RNA immunoprecipitation-qPCR (MeRIP-qPCR) and RNA-binding protein immunoprecipitation-qPCR (RIP-qPCR) confirmed that the methylation molecules NSUN2 and YBX1 specifically recognized and bound to HGH1 through m5C modification. In addition, proteomics, co-immunoprecipitation (co-IP), and Ribosome sequencing (Ribo-Seq) were used to explore the biological role of HGH1 in BC. RESULTS: As the main m5C methylation molecule, NSUN2 is abnormally overexpressed in BC and increases the overall level of RNA m5C. Knocking down NSUN2 can inhibit BC progression in vitro or in vivo. Combined RNA-seq and RNA-BisSeq analysis identified HGH1 as a potential target of abnormal m5C modifications. We clarified the mechanism by which NSUN2 regulates HGH1 expression through m5C modification, a process that involves interactions with the YBX1 protein, which collectively impacts mRNA stability and protein synthesis. Furthermore, this study is the first to reveal the binding interaction between HGH1 and the translation elongation factor EEF2, providing a comprehensive understanding of its ability to regulate transcript translation efficiency and protein synthesis in BC cells. CONCLUSIONS: This study preliminarily clarifies the regulatory role of the NSUN2-YBX1-m5C-HGH1 axis from post-transcriptional modification to protein translation, revealing the key role of abnormal RNA m5C modification in BC and suggesting that HGH1 may be a new epigenetic biomarker and potential therapeutic target for BC.


Subject(s)
Breast Neoplasms , Disease Progression , Gene Expression Regulation, Neoplastic , Methyltransferases , RNA Stability , Y-Box-Binding Protein 1 , Animals , Female , Humans , Mice , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Breast Neoplasms/metabolism , Cell Line, Tumor , Cell Proliferation , Methylation , Methyltransferases/metabolism , Methyltransferases/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Y-Box-Binding Protein 1/metabolism , Y-Box-Binding Protein 1/genetics , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/metabolism
4.
Proc Natl Acad Sci U S A ; 121(21): e2401079121, 2024 May 21.
Article in English | MEDLINE | ID: mdl-38739800

ABSTRACT

Homomeric dimerization of metabotropic glutamate receptors (mGlus) is essential for the modulation of their functions and represents a promising avenue for the development of novel therapeutic approaches to address central nervous system diseases. Yet, the scarcity of detailed molecular and energetic data on mGlu2 impedes our in-depth comprehension of their activation process. Here, we employ computational simulation methods to elucidate the activation process and key events associated with the mGlu2, including a detailed analysis of its conformational transitions, the binding of agonists, Gi protein coupling, and the guanosine diphosphate (GDP) release. Our results demonstrate that the activation of mGlu2 is a stepwise process and several energy barriers need to be overcome. Moreover, we also identify the rate-determining step of the mGlu2's transition from the agonist-bound state to its active state. From the perspective of free-energy analysis, we find that the conformational dynamics of mGlu2's subunit follow coupled rather than discrete, independent actions. Asymmetric dimerization is critical for receptor activation. Our calculation results are consistent with the observation of cross-linking and fluorescent-labeled blot experiments, thus illustrating the reliability of our calculations. Besides, we also identify potential key residues in the Gi protein binding position on mGlu2, mGlu2 dimer's TM6-TM6 interface, and Gi α5 helix by the change of energy barriers after mutation. The implications of our findings could lead to a more comprehensive grasp of class C G protein-coupled receptor activation.


Subject(s)
Receptors, Metabotropic Glutamate , Receptors, Metabotropic Glutamate/metabolism , Receptors, Metabotropic Glutamate/chemistry , Humans , Protein Multimerization , Molecular Dynamics Simulation , Protein Conformation , Protein Binding
5.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 55(2): 469-474, 2024 Mar 20.
Article in Chinese | MEDLINE | ID: mdl-38645865

ABSTRACT

Craniomaxillofacial development involves a series of highly ordered temporal-spatial cellular differentiation processes in which a variety of cell signaling factors, such as fibroblast growth factors, play important regulatory roles. As a classic fibroblast growth factor, fibroblast growth factor 7 (FGF7) serves a wide range of regulatory functions. Previous studies have demonstrated that FGF7 regulates the proliferation and migration of epithelial cells, protects them, and promotes their repair. Furthermore, recent findings indicate that epithelial cells are not the only ones subjected to the broad and powerful regulatory capacity of FGF7. It has potential effects on skeletal system development as well. In addition, FGF7 plays an important role in the development of craniomaxillofacial organs, such as the palate, the eyes, and the teeth. Nonetheless, the role of FGF7 in oral craniomaxillofacial development needs to be further elucidated. In this paper, we summarized the published research on the role of FGF7 in oral craniomaxillofacial development to demonstrate the overall understanding of FGF7 and its potential functions in oral craniomaxillofacial development.


Subject(s)
Fibroblast Growth Factor 7 , Humans , Fibroblast Growth Factor 7/metabolism , Fibroblast Growth Factor 7/genetics , Animals , Skull/growth & development , Skull/metabolism , Maxillofacial Development/physiology , Tooth/metabolism , Tooth/growth & development
6.
Spectrochim Acta A Mol Biomol Spectrosc ; 316: 124316, 2024 Aug 05.
Article in English | MEDLINE | ID: mdl-38669982

ABSTRACT

Lysosomes, as crucial acidic organelles in cells, play a significant role in cellular functions. The levels and distribution of hypochlorous acid (HOCl) within lysosomes can profoundly impact their biological functionality. Hence, real-time monitoring of the concentration of HOCl in lysosomes holds paramount importance for further understanding various physiological and pathological processes associated with lysosomes. In this study, we developed a bodipy-based fluorescent probe derived from pyridine and phenyl selenide for the specific detection of HOCl in aqueous solutions. Leveraging the probe's sensitive photoinduced electron transfer effect from phenyl selenide to the fluorophore, the probe exhibited satisfactory high sensitivity (with a limit of detection of 5.2 nM and a response time of 15 s) to hypochlorous acid. Further biological experiments confirmed that the introduction of the pyridine moiety enabled the probe molecule to selectively target lysosomes. Moreover, the probe successfully facilitated real-time monitoring of HOCl in cell models stimulated by N-acetylcysteine (NAC) and lipopolysaccharide (LPS), as well as in a normal zebrafish model. This provides a universal method for dynamically sensing HOCl in lysosomes.


Subject(s)
Fluorescent Dyes , Hypochlorous Acid , Lysosomes , Optical Imaging , Zebrafish , Hypochlorous Acid/analysis , Hypochlorous Acid/metabolism , Lysosomes/metabolism , Lysosomes/chemistry , Fluorescent Dyes/chemistry , Fluorescent Dyes/chemical synthesis , Animals , Humans , RAW 264.7 Cells , Mice , Boron Compounds/chemistry , Spectrometry, Fluorescence , Pyridines/chemistry , Limit of Detection
7.
Nat Commun ; 15(1): 2252, 2024 Mar 13.
Article in English | MEDLINE | ID: mdl-38480744

ABSTRACT

Zero thermal expansion (ZTE) alloys with high mechanical response are crucial for their practical usage. Yet, unifying the ZTE behavior and mechanical response in one material is a grand obstacle, especially in multicomponent ZTE alloys. Herein, we report a near isotropic zero thermal expansion (αl = 1.10 × 10-6 K-1, 260-310 K) in the natural heterogeneous LaFe54Co3.5Si3.35 alloy, which exhibits a super-high toughness of 277.8 ± 14.7 J cm-3. Chemical partition, in the dual-phase structure, assumes the role of not only modulating thermal expansion through magnetic interaction but also enhancing mechanical properties via interface bonding. The comprehensive analysis reveals that the hierarchically synergistic enhancement among lattice, phase interface, and heterogeneous structure is significant for strong toughness. Our findings pave the way to tailor thermal expansion and obtain prominent mechanical properties in multicomponent alloys, which is essential to ultra-stable functional materials.

8.
Transplantation ; 2024 Mar 19.
Article in English | MEDLINE | ID: mdl-38499504

ABSTRACT

BACKGROUND: Uterus transplantation (UTx) is an emerging treatment for uterine factor infertility. Determining the maximum tolerable cold ischemia time is crucial for successful UTx. However, the limit for cold ischemia in the uterus is unclear. This study aimed to examine cold ischemia's effects on mouse uteri and identify the maximum cold ischemia duration that uteri can endure. METHODS: We systematically assessed the tolerance of mouse uteri to extended cold ischemia, 24 h, 36 h, and 48 h, using the cervical heterotopic UTx model. Multiple indicators were used to evaluate ischemia-reperfusion injury, including reperfusion duration, macroscopic examination, oxidative stress, inflammation, and histopathology. The function of transplants was evaluated through estrous cycle monitoring and embryo transfer. RESULTS: Mouse uteri subjected to 48 h of cold ischemia exhibited significant delays and insufficiencies in reperfusion, substantial tissue necrosis, and loss of the estrous cycle. Conversely, uteri that underwent cold ischemia within 36 h showed long survival, regular estrous cycles, and fertility. CONCLUSIONS: Our study demonstrated that mouse uteri can endure at least 36 h of cold ischemia, extending the known limits for cold ischemia and providing a pivotal reference for research on the prevention and treatment of cold ischemic injury in UTx.

9.
Zhongguo Zhong Yao Za Zhi ; 49(1): 88-99, 2024 Jan.
Article in Chinese | MEDLINE | ID: mdl-38403342

ABSTRACT

Anemarrhena asphodeloides is a common medicinal material used in clinical prescriptions and Chinese patent medicine. In this study, the Illumina platform was used to obtain the chloroplast genome sequences of seven kinds of A. asphodeloides from different areas. The specific DNA barcodes were screened by comparative genomics analysis, and the DNA barcodes were used to identify the germplasm resources and analyze the genetic diversity of A. asphodeloides samples from different areas in China. All the seven chloroplast genomes had a ring structure. The total length was 156 801-156 930 bp, and 113 genes were annotated, including 79 protein-coding genes, 30 tRNA genes, and four rRNA genes. The comparative genomics analysis showed that rps16, trnG-GCC, atpF, rpoB, ycf3, rpl16, ndhF, trnS-GCU_trnG-GCC, petN-psbM, and ndhF-rpl32 were potential candidates for specific DNA barcodes of A. asphodeloides. In this study, the second intron of ycf3 and atpF intron sequences with a sequence length of 700-800 bp and easy amplification were selected for polymerase chain reaction(PCR) amplification and sequencing of 594 samples from 26 areas. The sequence analysis showed that six and eight haplotypes of ycf3 and atpF sequences could be identified, respectively, and 17 haplotypes could be identified by combined analysis of the two sequences, which were named Hap1-Hap17. The haplotype diversity(H_d), nucleotide diversity(P_i), and genetic distance of A. asphodeloides in 26 populations were 0.68, 0.93×10~(-3), and 0-0.003 1, respectively, indicating that the genetic diversity within the species of A. asphodeloides is rich. The intermediary adjacent network analysis showed that Hap5 was the oldest haplotype, which was mainly distributed in Yixian county of Baoding, Hebei province, Hequ county of Xinzhou, Shanxi province, and Xiangfen county of Linfen, Shanxi province. This study has important guiding significance for the identification of A. asphodeloides species, the protection and development of germplasm resources, and the identification of production areas, and it provides a research basis for further revealing the genetic evolution law of A. asphodeloides.


Subject(s)
Anemarrhena , Anemarrhena/chemistry , DNA Barcoding, Taxonomic , Genetic Variation , China , Phylogeny
10.
Proteins ; 92(6): 705-719, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38183172

ABSTRACT

The omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) characterized by 30 mutations in its spike protein, has rapidly spread worldwide since November 2021, significantly exacerbating the ongoing COVID-19 pandemic. In order to investigate the relationship between these mutations and the variant's high transmissibility, we conducted a systematic analysis of the mutational effect on spike-angiotensin-converting enzyme-2 (ACE2) interactions and explored the structural/energy correlation of key mutations, utilizing a reliable coarse-grained model. Our study extended beyond the receptor-binding domain (RBD) of spike trimer through comprehensive modeling of the full-length spike trimer rather than just the RBD. Our free-energy calculation revealed that the enhanced binding affinity between the spike protein and the ACE2 receptor is correlated with the increased structural stability of the isolated spike protein, thus explaining the omicron variant's heightened transmissibility. The conclusion was supported by our experimental analyses involving the expression and purification of the full-length spike trimer. Furthermore, the energy decomposition analysis established those electrostatic interactions make major contributions to this effect. We categorized the mutations into four groups and established an analytical framework that can be employed in studying future mutations. Additionally, our calculations rationalized the reduced affinity of the omicron variant towards most available therapeutic neutralizing antibodies, when compared with the wild type. By providing concrete experimental data and offering a solid explanation, this study contributes to a better understanding of the relationship between theories and observations and lays the foundation for future investigations.


Subject(s)
Angiotensin-Converting Enzyme 2 , COVID-19 , Mutation , Protein Binding , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , SARS-CoV-2/genetics , SARS-CoV-2/metabolism , SARS-CoV-2/chemistry , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , COVID-19/virology , COVID-19/transmission , Humans , Angiotensin-Converting Enzyme 2/metabolism , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/genetics , Antibodies, Neutralizing/immunology , Antibodies, Neutralizing/chemistry , Molecular Dynamics Simulation , Thermodynamics , Models, Molecular
11.
Cancer Med ; 13(1): e6720, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38111983

ABSTRACT

BACKGROUND: Although adjuvant chemotherapy (ACT) is widely used to treat patients with Stage II/III colorectal cancer (CRC), administering ACT to specific patients remains a challenge. The decision to ACT requires an accurate assessment of recurrence risk and absolute treatment benefit. However, the traditional TNM staging system does not accurately assess a patient's individual risk of recurrence. METHODS: To identify recurrence risk-related genetic factors for Stage II/III CRC patients after radical surgery, we conducted an analysis of whole-exome sequencing of 47 patients with Stage II/III CRC who underwent radical surgery at five institutions. Patients were grouped into non-recurrence group (NR, n = 24, recurrence-free survival [RFS] > 5 years) and recurrence group (R, n = 23, RFS <2 years). The TCGA-COAD/READ cohort was employed as the validation dataset. RESULTS: A recurrence-predictive model (G8plus score) based on eight gene (CUL9, PCDHA12, HECTD3, DCX, SMARCA2, FAM193A, AATK, and SORCS2) mutations and tumor mutation burden/microsatellite instability (TMB/MSI) status was constructed, with 97.87% accuracy in our data and 100% negative predictive value in the TCGA-COAD/READ cohort. For the TCGA-COAD/READ cohort, the G8plus-high group had better RFS (HR = 0.22, p = 0.024); the G8plus-high tumors had significantly more infiltrated immune cell types, higher tertiary lymphoid structure signature scores, and higher immunological signature scores. The G8plus score was also a predict biomarker for immunotherapeutic in advanced CRC in the PUCH cohort. CONCLUSIONS: In conclusion, the G8plus score is a powerful biomarker for predicting the risk of recurrence in patients with stage II/III CRC. It can be used to stratify patients who benefit from ACT and immunotherapy.


Subject(s)
Colorectal Neoplasms , Microsatellite Instability , Humans , Prognosis , Colorectal Neoplasms/therapy , Colorectal Neoplasms/drug therapy , Neoplasm Staging , Biomarkers, Tumor/genetics
12.
Sheng Li Xue Bao ; 75(6): 918-926, 2023 Dec 25.
Article in Chinese | MEDLINE | ID: mdl-38151353

ABSTRACT

Aging is a crucial factor influencing postural stability control and contributing to frequent falls, yet its underlying mechanisms remain incompletely understood. This study aims to explore the effects of aging on postural stability control by comparing differences in postural stability and node strength of electroencephalogram (EEG) brain network between elderly and young people under the conditions of congruent and incongruent visual-vestibular sensory inputs. Eighteen elderly volunteers without neuromuscular disorders and eighteen young individuals participated in the present study. Virtual reality (VR) technology was employed to manipulate visual rotation stimuli (clockwise and counterclockwise), and a horizontal rotating platform was used for vestibular rotation stimuli (clockwise). Based on the directional disparity of sensory input in the horizontal plane, visual-vestibular input consistency was categorized as congruent and incongruent. Postural stability was assessed by the center of pressure (COP) trajectory, and EEG signals were collected and analyzed using directed network analysis to observe EEG brain network node connectivity strength. The results revealed that, under conditions of incongruent visual-vestibular sensory inputs, the elderly exhibited significantly inferior postural stability performance in terms of COP anterior-posterior (Y-axial) sway speed, total path length, anterior-posterior and medial-lateral sample entropy, compared to the young adults. Moreover, the node connectivity strength of visual cortex in the elderly was notably higher, while node connectivity strength of superior temporal cortex was significantly lower than that in the young adults. These findings suggest that the elderly have a heightened reliance on visual information in postural control and an impaired ability to cope with sensory conflicts arising from incongruent visual-vestibular sensory inputs, leading to compromised postural stability. The outcomes of this study hold significant implications for future assessments of balance function in the elder and fall prevention trainings.


Subject(s)
Postural Balance , Posture , Young Adult , Humans , Aged , Adolescent , Aging , Brain
13.
Transpl Immunol ; 81: 101952, 2023 12.
Article in English | MEDLINE | ID: mdl-37918580

ABSTRACT

BACKGROUND: Identifying effective immunosuppressive strategies is critical for addressing immunological rejection following organ transplantation. This study explores the potential immunosuppressive effects and mechanisms of temsirolimus, a rapamycin derivative, in organ transplantation. METHODS: A mouse cardiac allograft model was established using a cervical cannula technique with BALB/c donors and C57BL/6 recipients. Mice were administered temsirolimus intragastrically and graft survival was evaluated. Histological staining was used to assess pathological changes. The BrdU assay was used to measure splenic T cell proliferation. Flow cytometry was used to quantify regulatory T cells (Tregs), CD4+ T cells, and CD8+ T cells. ELISA and qPCR assays were used to determine Foxp3, IL-4, IFN-γ, and TGF-ß expression. RESULTS: Temsirolimus displayed potent immunosuppressive effects at 20 mg/kg/day, significantly inhibiting T cell proliferation (84.6%, P < 0.0001) and prolonging graft survival (median 49 days vs. 8.5 days in controls, P < 0.0001). However, median survival decreased to 34.5 days upon withdrawal. Temsirolimus also reduced splenic CD4+ and CD8+ T cells (2.85% and 2.92%, P < 0.001) and antibody levels (IgM, IgG1, IgG2) by 11.85-29.09% (P < 0.0001) and increased Tregs, Foxp3, IL-4 (P < 0.01), and TGF-ß (P < 0.05), while decreasing IFN-γ (P < 0.001). CONCLUSIONS: Temsirolimus exhibited potent immunosuppressive effects, emerging as a strong candidate to mitigate organ transplant rejection.


Subject(s)
Interleukin-4 , Sirolimus , Mice , Animals , Mice, Inbred C57BL , Sirolimus/therapeutic use , Sirolimus/pharmacology , T-Lymphocytes, Regulatory , Graft Survival , Transforming Growth Factor beta , Forkhead Transcription Factors/metabolism , Graft Rejection/drug therapy , Graft Rejection/prevention & control , Mice, Inbred BALB C
14.
Front Aging Neurosci ; 15: 1250685, 2023.
Article in English | MEDLINE | ID: mdl-38020765

ABSTRACT

Background: Parkinson's disease (PD), which is associated to autoimmune disorders, is characterized by the pathological deposition of alpha-synuclein (α-Syn) and loss of dopaminergic (DA) neurons. Th17 cells are thought to be responsible for the direct loss of DA neurons. C-C chemokine ligand 5 (CCL5) specifically induces Th17 cell infiltration into the SN. However, the specific effect of CCL5 on Th17 cells in PD and the relationship between CCL5 and lymphocyte function-associated antigen-1 (LFA-1) expression in Th17 cells are unknown. Methods: We evaluated the effects of CCL5 on LFA-1 expression in Th17 cells in mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and examined Th17 cell differentiation upon CCL5 stimulation in vitro. Furthermore, we assessed the effects of CCL5 on tyrosine kinase zeta-chain-associated protein kinase 70 (ZAP70) and lymphocyte-specific protein tyrosine kinase (LCK) activity in CCL5-stimulated Th17 cells in vivo and in vitro. Results: CCL5 increased the proportion of peripheral Th17 cells in MPTP-treated mice, LFA-1 expression on Th17 cells, and Th17 cell levels in the SN of MPTP-treated mice. CCL5 promoted Th17 cell differentiation and LFA-1 expression in naive T cells in vitro. Moreover, CCL5 increased Th17 cell differentiation and LFA-1 expression by stimulating LCK and ZAP70 activation in naive CD4+ T cells. Inhibiting LCK and ZAP70 activation reduced the proportion of peripheral Th17 cells and LFA-1 surface expression in MPTP-treated mice, and Th17 cell levels in the SN also significantly decreased. Conclusion: CCL5, which increased Th17 cell differentiation and LFA-1 protein expression by activating LCK and ZAP70, could increase the Th17 cell number in the SN, induce DA neuron death and aggravate PD.

15.
J Anesth ; 37(6): 896-904, 2023 12.
Article in English | MEDLINE | ID: mdl-37707572

ABSTRACT

PURPOSE: Patients with robot-assisted laparoscopic radical prostatectomy (RALP) need to be placed in Trendelenburg position, which results in cranial displacement of the diaphragm and decreases functional residual capacity and pulmonary compliance. Positive end-expiratory pressure (PEEP) can increase ventilation in the dorsal area, reduce the occurrence of atelectasis and improve oxygenation. However, due to individual differences, inappropriate PEEP will cause lung injury and even hemodynamic instability. Therefore, our study is to evaluate the efficacy of individualized PEEP in RALP. METHODS: We randomly recruited 48 patients and divided them into driving pressure-guided individualized PEEP group (P group, individualized PEEP) or traditional lung-protective ventilation strategy group (C group, tidal volume 8 mL/kg combined with PEEP of 5cmH2O). The primary outcome was the PaO2/FiO2 before extubation. The secondary outcomes included individualized PEEP values in the P group, the results of arterial blood gas analysis, respiratory mechanics parameters and vital sign parameters. Other measurements included intraoperative vasoactive drug dosage, length of stay, postoperative SpO2, leukocyte count, temperature, serum inflammatory factors and soluble receptor for advanced glycation end products (sRAGE). RESULTS: Individualized PEEP improved the PaO2/FiO2 before extubation (P = 0.034) and decreased driving pressure (P = 0.011). The PEEP valued in the P group was 14 [10-14] cmH2O. The lung compliance of the P group was significantly higher than that in the C group (P = 0.013). There was no significant difference in other measurements. CONCLUSIONS: Individualized PEEP could improve PaO2/FiO2 in patients who underwent RALP and do not increase the dosage of intraoperative vasoactive drug and the release of inflammatory factors. TRIAL REGISTRATION: www.chictr.org.cn (registration no. ChiCTR2100047271).


Subject(s)
Laparoscopy , Robotics , Male , Humans , Positive-Pressure Respiration/methods , Lung , Prostatectomy/methods , Laparoscopy/methods
16.
Science ; 382(6667): 185-190, 2023 Oct 13.
Article in English | MEDLINE | ID: mdl-37708297

ABSTRACT

Coarse-grained materials are widely accepted to display the highest strain hardening and the best tensile ductility. We experimentally report an attractive strain hardening rate throughout the deformation stage at 77 kelvin in a stable single-phase alloy with gradient dislocation cells that even surpasses its coarse-grained counterparts. Contrary to conventional understanding, the exceptional strain hardening arises from a distinctive dynamic structural refinement mechanism facilitated by the emission and motion of massive multiorientational tiny stacking faults (planar defects), which are fundamentally distinct from the traditional linear dislocation-mediated deformation. The dominance of atomic-scale planar deformation faulting in plastic deformation introduces a different approach for strengthening and hardening metallic materials, offering promising properties and potential applications.

17.
World J Gastrointest Surg ; 15(8): 1600-1614, 2023 Aug 27.
Article in English | MEDLINE | ID: mdl-37701707

ABSTRACT

BACKGROUND: Spindle and kinetochore-associated complex subunit 3 (SKA3) is a malignancy-associated gene that plays a critical role in the regulation of chromosome separation and cell division. However, the molecular mechanism through which SKA3 regulates tumor cell proliferation in hepatocellular carcinoma (HCC) has not been fully elucidated. AIM: To investigate the molecular mechanisms underlying the role of SKA3 in HCC. METHODS: SKA3 expression, clinicopathological, and survival analyses were performed using multiple public database platforms, and the results were verified by Western blot and immunohistochemistry staining using collected clinical samples. Functional enrichment analyses were performed to evaluate the biological functions and molecular mechanisms of SKA3 in HCC. Furthermore, the Tumor Immune Estimation Resource and single-sample Gene Set Enrichment Analysis (ssGSEA) algorithms were utilized to investigate the abundance of tumor-infiltrating immune cells in HCC. The response to chemotherapeutic drugs was evaluated by the R package "pRRophetic". RESULTS: We found that upregulated SKA3 expression was significantly correlated with poor prognosis in patients with HCC. Multivariable Cox regression analysis indicated that SKA3 was an independent risk factor for survival. GSEA revealed that SKA3 expression may facilitate proliferation and migratory processes by regulating the cell cycle and DNA repair. Moreover, patients with high SKA3 expression had significantly decreased ratios of CD8+ T cells, natural killer cells, and dendritic cells. Drug sensitivity analysis showed that the high SKA3 group was more sensitive to sorafenib, sunitinib, paclitaxel, doxorubicin, gemcitabine, and vx-680. CONCLUSION: High SKA3 expression led to poor prognosis in patients with HCC by enhancing HCC proliferation and repressing immune cell infiltration surrounding HCC. SKA3 may be used as a biomarker for poor prognosis and as a therapeutic target in HCC.

18.
Sleep Breath ; 2023 Sep 29.
Article in English | MEDLINE | ID: mdl-37775619

ABSTRACT

PURPOSE: Intermittent hypoxia (IH) is a hallmark of obstructive sleep apnea (OSA), which is related to tumorigenesis and progression. Although micro-ribonucleic acid-210-3p (miR-210-3p) is correlated with hypoxia-induced tumor development, its role in the relationship between IH and tumor function remains poorly understood. The present work focused on elucidating the molecular mechanism through which miR-210-3p drives tumor progression under IH. METHODS: MiR-210-3p levels were quantified within tumor samples from patients with lung adenocarcinoma who had or did not have OSA. Correlations between miR-210-3p and polysomnographic variables were analyzed. For in vitro experiments, miR-210-3p was inhibited or overexpressed via transfection under IH conditions. Cell viability, growth, invasion and migration assays were carried out. For in vivo modeling of IH using mouse xenografts, a miR-210-3p antagomir was intratumorally injected, tumor biological behaviors were evaluated, and reverse transcription-quantitative polymerase chain reaction (RT-qPCR), immunohistochemistry and western blot were carried out for detecting miR-210-3p and E2F transcription factor 3 (E2F3) expression. RESULTS: For patients with lung adenocarcinoma and OSA, high miR-210-3p levels showed positive relation to polysomnographic variables, such as oxygen desaturation index, apnea-hypopnea index, and proportion of total sleep time with oxygen saturation in arterial blood < 90%. IH enhanced tumor viability, proliferation, migration, and invasion, downregulated E2F3 expression, and increased miR-210-3-p levels. miR-210-3p overexpression induced similar changes. These changes were reversed by miR-210-3p inhibition in vitro or miR-210-3p antagomir through intratumoral injection in vivo. CONCLUSIONS: IH-induced tumor development is driven through miR-210-3p by E2F3 suppression. MiR-210-3p represents a potential therapeutic target among patients with concomitant cancer and OSA.

19.
Front Endocrinol (Lausanne) ; 14: 1193992, 2023.
Article in English | MEDLINE | ID: mdl-37745699

ABSTRACT

Background: Polycystic ovary syndrome (PCOS), a common endocrine and reproductive disorder, lacks precise diagnostic strategies. Necroptosis was found to be crucial in reproductive and endocrine disorders, but its function in PCOS remains unclear. We aimed to identify differentially diagnostic genes for necroptosis (NDDGs), construct a diagnostic model to assess the progression of PCOS and explore the potential therapeutic drugs. Methods: Gene expression datasets were combined with weighted gene co-expression network analysis (WGCNA) and necroptosis gene sets to screen the differentially expressed genes for PCOS. Least absolute shrinkage and selection operator (LASSO) regression analysis was used to construct a necroptosis-related gene signatures. Independent risk analyses were performed using nomograms. Pathway enrichment of NDDGs was conducted with the GeneMANIA database and gene set enrichment analysis (GSEA). Immune microenvironment analysis was estimated based on ssGSEA algorithm analysis. The Comparative Toxicogenomics Database (CTD) was used to explore potential therapeutic drugs for NDDGs. The expression of NDDGs was validated in GSE84958, mouse model and clinical samples. Results: Four necroptosis-related signature genes, IL33, TNFSF10, BCL2 and PYGM, were identified to define necroptosis for PCOS. The areas under curve (AUC) of receiver operating characteristic curve (ROC) for training set and validation in diagnostic risk model were 0.940 and 0.788, respectively. Enrichment analysis showed that NDDGs were enriched in immune-related signaling pathways such as B cells, T cells, and natural killer cells. Immune microenvironment analysis revealed that NDDGs were significantly correlated with 13 markedly different immune cells. A nomogram was constructed based on features that would benefit patients clinically. Several compounds, such as resveratrol, tretinoin, quercetin, curcumin, etc., were mined as therapeutic drugs for PCOS. The expression of the NDDGs in the validated set, animal model and clinical samples was consistent with the results of the training sets. Conclusion: In this study, 4 NDDGs were identified to be highly effective in assessing the progression and prognosis of PCOS and exploring potential targets for PCOS treatment.


Subject(s)
Polycystic Ovary Syndrome , Animals , Mice , Female , Humans , Polycystic Ovary Syndrome/drug therapy , Polycystic Ovary Syndrome/genetics , Necroptosis/genetics , Algorithms , Area Under Curve , B-Lymphocytes , Tumor Microenvironment
20.
Int J Biol Macromol ; 253(Pt 3): 126944, 2023 Dec 31.
Article in English | MEDLINE | ID: mdl-37722646

ABSTRACT

Exopolysaccharide (EPS), as a secondary metabolite of microorganisms, has been commonly used in the dairy industry to replace the traditional stabilizers. However, the EPS production by microorganism is generally low, which limits its application. A litchi polysaccharide (Lzp2-2) with the promoting effect on EPS production by Weissella confusa was purified. The SEM and FT-IR analysis indicated that Lzp2-2 displayed a compact netlike structure and typical bands of carbohydrates. The structure of Lzp2-2 was further elucidated, which was comprised of a major backbone structure [→3)-ß-D-Galp-(1→6)-ß-D-Galp-(1 â†’ 6)-ß-D-Galp-(1 â†’ 3)-ß-D-Glcp-(1 â†’ 6)-α-D-Glcp-(1 â†’ 3)-α-D-Glcp-(1→] linked with two side chains [α-L-Araf-(1 â†’ 5)-α-L-Araf-(1→, and ß-D-Glcp-(1 â†’ or α-L-Araf-(1→] at the O-3 and O-6) of ß-D-Galp-(1→, respectively. Finally, Lzp2-2 was applied as an additive to the medium of yoghurt fermented by W. confusa. The results indicated Lzp2-2 not only promoted the EPS production to improve the viscosity, texture and mouthfeel of yoghurt, but also facilitated the generation of other secondary metabolites (volatile organic compounds), thus elevating the flavor of yoghurt.


Subject(s)
Litchi , Weissella , Spectroscopy, Fourier Transform Infrared , Polysaccharides/chemistry , Weissella/chemistry
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