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1.
Artículo en Inglés | MEDLINE | ID: mdl-38558156

RESUMEN

Metastasis is a major contributor to treatment failure and death in urological cancers, representing an important biomedical challenge at present. Metastases form as a result of cancer cells leaving the primary site, entering the vasculature and lymphatic vessels, and colonizing clones elsewhere in the body. However, the specific regulatory mechanisms of action underlying the metastatic process of urological cancers remain incompletely elucidated. With the deepening of research, circular RNAs (circRNAs) have been found to not only play a significant role in tumor progression and prognosis but also show aberrant expression in various tumor metastases, consequently impacting tumor metastasis through multiple pathways. Therefore, circRNAs are emerging as potential tumor markers and treatment targets. This review summarizes the research progress on elucidating how circRNAs regulate the urological cancer invasion-metastasis cascade response and related processes, as well as their role in immune microenvironment remodeling and circRNA vaccines. This body of work highlights circRNA regulation as an emerging therapeutic target for urological cancers, which should motivate further specific research in this regard.

2.
Nature ; 570(7760): 252-256, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-31142835

RESUMEN

Characterizing the genome of mature virions is pivotal to understanding the highly dynamic processes of virus assembly and infection. Owing to the different cellular fates of DNA and RNA, the life cycles of double-stranded (ds)DNA and dsRNA viruses are dissimilar. In terms of nucleic acid packing, dsDNA viruses, which lack genome segmentation and intra-capsid transcriptional machinery, predominantly display single-spooled genome organizations1-8. Because the release of dsRNA into the cytoplasm triggers host defence mechanisms9, dsRNA viruses retain their genomes within a core particle that contains the enzymes required for RNA replication and transcription10-12. The genomes of dsRNA viruses vary greatly in the degree of segmentation. In members of the Reoviridae family, genomes consist of 10-12 segments and exhibit a non-spooled arrangement mediated by RNA-dependent RNA polymerases11-14. However, whether this arrangement is a general feature of dsRNA viruses remains unknown. Here, using cryo-electron microscopy to resolve the dsRNA genome structure of the tri-segmented bacteriophage ɸ6 of the Cystoviridae family, we show that dsRNA viruses can adopt a dsDNA-like single-spooled genome organization. We find that in this group of viruses, RNA-dependent RNA polymerases do not direct genome ordering, and the dsRNA can adopt multiple conformations. We build a model that encompasses 90% of the genome, and use this to quantify variation in the packing density and to characterize the different liquid crystalline geometries that are exhibited by the tightly compacted nucleic acid. Our results demonstrate that the canonical model for the packing of dsDNA can be extended to dsRNA viruses.


Asunto(s)
Bacteriófago phi 6/química , Bacteriófago phi 6/ultraestructura , Microscopía por Crioelectrón , Empaquetamiento del ADN , Cristales Líquidos , Conformación de Ácido Nucleico , ARN Bicatenario/ultraestructura , ARN Viral/ultraestructura , Bacteriófago phi 6/genética , Genoma Viral , Modelos Moleculares , ARN Bicatenario/química , ARN Viral/química , ARN Polimerasa Dependiente del ARN/metabolismo
3.
Nano Lett ; 2024 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-38619219

RESUMEN

Current density imaging is helpful for discovering interesting electronic phenomena and understanding carrier dynamics, and by combining pressure distributions, several pressure-induced novel physics may be comprehended. In this work, noninvasive, high-resolution two-dimensional images of the current density and pressure gradient for graphene ribbon and hBN-graphene-hBN devices are explored using nitrogen-vacancy (NV) centers in diamond under high pressure. The two-dimensional vector current density is reconstructed by the vector magnetic field mapped by the near-surface NV center layer in the diamond. The current density images accurately and clearly reproduce the complicated structure and current flow of graphene under high pressure. Additionally, the spatial distribution of the pressure is simultaneously mapped, rationalizing the nonuniformity of the current density under high pressure. The current method opens a significant new avenue to investigate electronic transport and conductance variations in two-dimensional materials and electrical devices under high pressure as well as for nondestructive evaluation of semiconductor circuits.

4.
Am J Physiol Cell Physiol ; 326(2): C400-C413, 2024 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-38105755

RESUMEN

Kidney fibrosis is a prominent pathological feature of hypertensive kidney diseases (HKD). Recent studies have highlighted the role of ubiquitinating/deubiquitinating protein modification in kidney pathophysiology. Ovarian tumor domain-containing protein 6 A (OTUD6A) is a deubiquitinating enzyme involved in tumor progression. However, its role in kidney pathophysiology remains elusive. We aimed to investigate the role and underlying mechanism of OTUD6A during kidney fibrosis in HKD. The results revealed higher OTUD6A expression in kidney tissues of nephropathy patients and mice with chronic angiotensin II (Ang II) administration than that from the control ones. OTUD6A was mainly located in tubular epithelial cells. Moreover, OTUD6A deficiency significantly protected mice against Ang II-induced kidney dysfunction and fibrosis. Also, knocking OTUD6A down suppressed Ang II-induced fibrosis in cultured tubular epithelial cells, whereas overexpression of OTUD6A enhanced fibrogenic responses. Mechanistically, OTUD6A bounded to signal transducer and activator of transcription 3 (STAT3) and removed K63-linked-ubiquitin chains to promote STAT3 phosphorylation at tyrosine 705 position and nuclear translocation, which then induced profibrotic gene transcription in epithelial cells. These studies identified STAT3 as a direct substrate of OTUD6A and highlighted the pivotal role of OTUD6A in Ang II-induced kidney injury, indicating OTUD6A as a potential therapeutic target for HKD.NEW & NOTEWORTHY Ovarian tumor domain-containing protein 6 A (OTUD6A) knockout mice are protected against angiotensin II-induced kidney dysfunction and fibrosis. OTUD6A promotes pathological kidney remodeling and dysfunction by deubiquitinating signal transducer and activator of transcription 3 (STAT3). OTUD6A binds to and removes K63-linked-ubiquitin chains of STAT3 to promote its phosphorylation and activation, and subsequently enhances kidney fibrosis.


Asunto(s)
Hipertensión Renal , Nefritis , Neoplasias Ováricas , Humanos , Ratones , Animales , Femenino , Angiotensina II/farmacología , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Riñón/metabolismo , Hipertensión Renal/metabolismo , Hipertensión Renal/patología , Células Epiteliales/metabolismo , Fibrosis , Neoplasias Ováricas/metabolismo , Ubiquitinas/metabolismo , Ratones Endogámicos C57BL
5.
J Proteome Res ; 23(1): 25-39, 2024 01 05.
Artículo en Inglés | MEDLINE | ID: mdl-38088868

RESUMEN

Periodontitis is a prevalent oral inflammatory disease that can result in tooth loss and is closely linked to type 2 diabetes (T2D). In this study, we analyzed the salivary proteome and intact N-glycopeptides (IGPs) of individuals with mild-moderate, severe, aggressive periodontitis, and periodontitis with T2D, including those treated with antidiabetic drugs, to identify specific signatures associated with the disease. Our results revealed that salivary proteins and glycoproteins were altered in all periodontitis groups (PRIDE ID: 1-20230612-72345), with fucose- and sialic acid-containing N-glycans showing the greatest increase. Additionally, differentially expressed proteins were classified into 9 clusters, including those that were increased in all periodontitis groups and those that were only altered in certain types of periodontitis. Interestingly, treatment with antidiabetic drugs reversed many of the changes observed in the salivary proteome and IGPs in T2D-related periodontitis, suggesting a potential therapeutic approach for managing periodontitis in patients with T2D. Consistent with MS/MS results, the expression of salivary IGHA2 and Fucα1-3/6GlcNAc (AAL) was significantly increased in MP. These findings provide new insights into the pathogenesis of periodontitis and highlight the potential of salivary biomarkers for diagnosis, prognosis, and monitoring of disease progression and treatment response.


Asunto(s)
Diabetes Mellitus Tipo 2 , Periodontitis , Humanos , Proteoma/genética , Proteoma/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Glicopéptidos/metabolismo , Espectrometría de Masas en Tándem , Biomarcadores/metabolismo , Hipoglucemiantes , Saliva/metabolismo
6.
Mol Biol Evol ; 40(6)2023 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-37341536

RESUMEN

Three prevalent SARS-CoV-2 variants of concern (VOCs) emerged and caused epidemic waves. It is essential to uncover advantageous mutations that cause the high transmissibility of VOCs. However, viral mutations are tightly linked, so traditional population genetic methods, including machine learning-based methods, cannot reliably detect mutations conferring a fitness advantage. In this study, we developed an approach based on the sequential occurrence order of mutations and the accelerated furcation rate in the pandemic-scale phylogenomic tree. We analyzed 3,777,753 high-quality SARS-CoV-2 genomic sequences and the epidemiology metadata using the Coronavirus GenBrowser. We found that two noncoding mutations at the same position (g.a28271-/u) may be crucial to the high transmissibility of Alpha, Delta, and Omicron VOCs although the noncoding mutations alone cannot increase viral transmissibility. Both mutations cause an A-to-U change at the core position -3 of the Kozak sequence of the N gene and significantly reduce the protein expression ratio of ORF9b to N. Using a convergent evolutionary analysis, we found that g.a28271-/u, S:p.P681H/R, and N:p.R203K/M occur independently on three VOC lineages, suggesting that coordinated changes of S, N, and ORF9b proteins are crucial to high viral transmissibility. Our results provide new insights into high viral transmissibility co-modulated by advantageous noncoding and nonsynonymous changes.


Asunto(s)
COVID-19 , COVID-19/genética , SARS-CoV-2/genética , Evolución Biológica , Mutación , Pandemias
7.
Small ; : e2400867, 2024 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-38770993

RESUMEN

Photodynamic therapy (PDT) is receiving extensive attention as an antimicrobial strategy that does not cause drug resistance by reactive oxygen species (ROS). Herein, hierarchical Ag-ZnIn2S4 (Ag-ZIS) core-shell nanowires are synthesized by in situ Metal-Organic Framework derived method for efficient PDT of Candida albicans (C. albicans). The core-shell structure enables spatial synergy strategy to regulate the charge transfer pathway under visible light excitation, in which the Ag nanowires are like the highway for the photogenerated electrons. The enhanced charge carrier separation efficiency greatly increased the chances for the generation of ROS. As expected, the optimized Ag-ZIS nanowires exhibit excellent performance for inactivation of C. albicans under visible light irradiation (λ ≥ 420 nm, 15 min), and the effective sterilization concentration is as high as 107CFU mL-1. Moreover, in vivo infection experiments suggested that the PDT effect of Ag-ZIS nanowires on the mouse wound healing is better than that of the clinical Ketoconazole drug. The PDT antifungal mechanism of Ag-ZIS nanowires is also investigated, and superoxide anion is found to be the predominant active species to causes C. albicans damage. This work provides a new perspective for designing novel interface structures to regulate charge transfer to achieve efficient PDT antifungal therapy.

8.
Mol Carcinog ; 63(6): 1117-1132, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38421204

RESUMEN

Breast cancer stem cells (BCSCs) are key players in carcinogenesis and development. Small nucleolar RNAs (snoRNAs) seem to have a crucial influence on regulating stem cell-like properties in various cancers, but the underlying mechanism in breast cancer has not been determined. In this study, we first found that the expression of SNORA51 might be strongly and positively related to BCSCs-like properties. SNORA51 expression was assessed in breast cancer tissues (n = 158 patients) by in situ hybridization. Colony formation, cell counting kit-8, and sphere formation assays were used to detect cell proliferation and self-renewal, respectively. Wound healing and transwell assays were used to detect cell migration. Coimmunoprecipitation and molecular docking were used to determine the underlying mechanism through which SNORA51 regulates BCSCs-like properties. High SNORA51 expression was associated with a worse prognosis, overall survival, and disease-free survival, in 158 breast cancer patients and was also closely related to lymph node status, ER status, the Ki-67 index, histological grade, and TNM stage. Further analysis proved that SNORA51 could enhance and maintain stem cell-like properties, including cell proliferation, self-renewal, and migration, in breast cancer. Moreover, high SNORA51 expression could reduce nucleolar RPL3 expression, induce changes in the expression of NPM1 in the nucleolus and nucleoplasm, and ultimately increase c-MYC expression. Taken together, our findings demonstrated that SNORA51 could enhance BCSCs-like properties via the RPL3/NPM1/c-MYC pathway both in vitro and in vivo. Therefore, SNORA51 might be a significant biomarker and potential therapeutic target and might even provide a new viewpoint on the regulatory mechanism of snoRNAs in breast cancer or other malignant tumors.


Asunto(s)
Neoplasias de la Mama , Proliferación Celular , Células Madre Neoplásicas , Nucleofosmina , Proteínas Proto-Oncogénicas c-myc , ARN Nucleolar Pequeño , Proteínas Ribosómicas , Humanos , Femenino , Neoplasias de la Mama/patología , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , ARN Nucleolar Pequeño/genética , ARN Nucleolar Pequeño/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Persona de Mediana Edad , Proteínas Ribosómicas/genética , Proteínas Ribosómicas/metabolismo , Pronóstico , Regulación Neoplásica de la Expresión Génica , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Movimiento Celular , Transducción de Señal , Animales , Línea Celular Tumoral , Ratones
9.
Arch Biochem Biophys ; 751: 109823, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-37984760

RESUMEN

This study is mainly based on T helper type 17 (Th17) cells analysis of the mechanism of prostaglandin E2 (PGE2) promoting the progression of dry eye (DE). Scopolamine and dry environment were used to induce mice DE model. Celecoxib was used to inhibit PGE2. Corneal epithelial cells and CD4+ T cells were used to construct a co-culture system. The osmotic pressure was increased by adding NaCl to simulate DE in vitro. AH6809 and E7046 were used to pre-culture to inhibit EP2/4 in T cells to verify the effect of exogenous PGE2 on Th17 cell differentiation and corneal epithelial cell apoptosis. The function of Th17 cells was analyzed by detecting RORγt and interleukin-17 (IL-17). PGE2 was instilled on the ocular surface to induce DE symptoms of mice. AH6809 and E7046 were used to inhibit EP2/4. The corneal epithelial cell apoptosis was observed by TUNEL. The proportion of Th17 cells in corneal tissue and draining lymph nodes (DLNs) was detected by flow cytometry. In DE mice, the concentration of PGE2 and IL-17 increased in tears, and the proportion of Th17 increased, while inhibition of PGE2 alleviated the symptoms of DE and inhibited Th17 differentiation. Hypertonic environment induces corneal epithelial cells to secrete PGE2. PGE2 promoted the expression of EP2/4 and the differentiation of Th17 cells in vitro. The hypertonic environment promoted PGE2 level and the apoptosis of corneal epithelial cells in the co-culture system. PGE2 alone did not cause corneal epithelial cell apoptosis, while PGE2 promoted apoptosis by promoting Th17. Blocking EP2/4 reduced the induction of Th17 differentiation by PGE2 and the promoted corneal epithelial cell apoptosis. Animal experiments showed that exogenous PGE2 induced DE symptoms. Blocking EP2/4 not only inhibited the proportion of Th17, but also alleviated the apoptosis of corneal epithelial cells caused by PGE2. PGE2 induces aggravation of inflammation by promoting the level of Th17 in the ocular surface, and causes corneal epithelial cell apoptosis, thereby participating in the progression of DE.


Asunto(s)
Dinoprostona , Síndromes de Ojo Seco , Ratones , Animales , Dinoprostona/metabolismo , Interleucina-17/farmacología , Diferenciación Celular , Células Epiteliales/metabolismo , Síndromes de Ojo Seco/metabolismo , Apoptosis
10.
Langmuir ; 40(11): 5992-6003, 2024 Mar 19.
Artículo en Inglés | MEDLINE | ID: mdl-38445586

RESUMEN

When the electric field strength (E) surpasses a certain threshold, secondary droplets are generated during the coalescence between water droplets in oil and the oil-water interface (so-called the droplet-interface partial coalescence phenomenon), resulting in a lower efficiency of droplet electrocoalescence. This study employs molecular dynamics (MD) simulations to investigate the droplet-interface partial coalescence phenomenon under direct current (DC) electric fields. The results demonstrate that intermolecular interactions, particularly the formation of hydrogen bonds, play a crucial role in dipole-dipole coalescence. Droplet-interface partial coalescence is categorized into five regimes based on droplet morphology. During the contact and fusion of the droplet with the water layer, the dipole moment of the droplet exhibits alternating increases and decreases along the electric field direction. Electric field forces acting on sodium ions and the internal interactions within droplets promote the process of droplet-interface partial coalescence. High field strengths cause significant elongation of the droplet, leading to its fragmentation into multiple segments. The migration of hydrated ions has a dual impact on the droplet-interface partial coalescence, with both facilitative and suppressive effects. The time required for droplet-interface partial coalescence initially decreases and subsequently increases as the field strength increases, depending on the competitive relationship between the extent of droplet stretching and the electric field force. This work provides molecular insights into the droplet-interface coalescence mechanisms in water-in-oil emulsions under DC electric fields.

11.
J Periodontal Res ; 2024 Mar 29.
Artículo en Inglés | MEDLINE | ID: mdl-38551200

RESUMEN

Periodontitis, the second most common oral disease, is primarily initiated by inflammatory responses and osteoclast differentiation, in which the MAPK signaling pathway and mitochondrial function play important roles. 3-methyl-1H-indol-1-yl dimethylcarbamodithioate (3o), a hybrid of indole and dithiocarbamate, was first synthesized by our group. It has shown anti-inflammatory activity against lipopolysaccharide-induced acute lung injury. However, it is not known if 3o can exert effects in periodontitis. In vitro study: LPS-induced macrophage inflammation initiation and a receptor activator of nuclear factor κB ligand-stimulated osteoclast differentiation model were established. Cell viability, inflammatory cytokines, osteoclast differentiation, the MAPK signaling pathway, and mitochondrial function before and after treatment with 3o were investigated. In vivo study: Alveolar bone resorption, inflammatory cytokine expression, osteoclast differentiation, and the underlying mechanisms were assessed in mice with periodontitis. Inflammatory cytokine expression and osteoclast differentiation appeared downregulated after 3o treatment. 3o inhibited the MAPK signaling pathway and restored mitochondrial function, including mitochondrial reactive oxygen species, mitochondrial membrane potential, and ATP production. Meanwhile, 3o reduced inflammation activation and bone resorption in mice with periodontitis, reflected by the decreased expression of inflammatory cytokines and osteoclasts, implying that 3o inhibited the MAPK signaling pathway and the mitochondrial oxidative DNA damage marker 8-OHdG. These results highlight the protective role of 3o in periodontitis in mice and reveal an important strategy for preventing periodontitis.

12.
Mol Breed ; 44(5): 34, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38725797

RESUMEN

Members of the permease gene family are responsible for important biological functions in the growth and development of rice. Here, we show that OsAAP8 is a constitutive expression gene, and its translated protein is localized on the cell membrane. Mutation of the OsAAP8 can promote the expression of genes related to protein and amylopectin synthesis, and also promote the enlargement of protein bodies in its endosperm, leading to an increase in the protein, amylopectin, and total amino acid content of grains in OsAAP8 mutants. Seeds produced by the OsAAP8 mutant were larger, and the chalkiness traits of the OsAAP8 mutants were significantly reduced, thereby improving the nutritional quality and appearance of rice grains. The OsAAP8 protein is involved in the transport of various amino acids; OsAAP8 mutation significantly enhanced the root absorption of a range of amino acids and might affect the distribution of various amino acids. Therefore, OsAAP8 is an important quality trait gene with multiple biological functions, which provides important clues for the molecular design of breeding strategies for developing new high-quality varieties of rice. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-024-01473-w.

13.
BMC Med Imaging ; 24(1): 160, 2024 Jun 26.
Artículo en Inglés | MEDLINE | ID: mdl-38926814

RESUMEN

PURPOSE: This study aimed to investigate the feasibility of using computed tomography (CT) attenuation values to differentiate hypodense brain lesions, specifically acute ischemic stroke (AIS) from asymmetric leukoaraiosis (LA) and old cerebral infarction (OCI). MATERIALS AND METHODS: This retrospective study included patients with indeterminate hypodense lesions identified via brain CT scans conducted between June 2019 and June 2021. All lesions were confirmed through head MRI/diffusion-weighted imaging within 48 h after CT. CT attenuation values of hypodense lesions and symmetrical control regions were measured. Additionally, CT attenuation value difference (ΔHU) and ratio (RatioHU) were calculated. One-way analysis of variance (ANOVA) was used to compare age and CT parameters (CT attenuation values, ΔHU and RatioHU) across the groups. Finally, receiver operating characteristic (ROC) analysis was performed to determine the cutoff values for distinguishing hypodense lesions. RESULTS: A total of 167 lesions from 146 patients were examined. The CT attenuation values for AIS(n = 39), LA(n = 53), and OCI(n = 75) were 18.90 ± 6.40 HU, 17.53 ± 4.67 HU, and 11.90 ± 5.92 HU, respectively. The time interval between symptom onset and CT scans for AIS group was 32.21 ± 26.85 h. ANOVA revealed significant differences among the CT parameters of the hypodense lesion groups (all P < 0.001). The AUC of CT values, ΔHU, and RatioHU for distinguishing AIS from OCI were 0.802, 0.896 and 0.878, respectively (all P < 0.001). Meanwhile, the AUC for distinguishing OCI from LA was 0.789, 0.883, and 0.857, respectively (all P < 0.001). Nevertheless, none of the parameters could distinguish AIS from LA. CONCLUSION: CT attenuation parameters can be utilized to differentiate between AIS and OCI or OCI and LA in indeterminate hypodense lesions on CT images. However, distinguishing AIS from LA remains challenging.


Asunto(s)
Infarto Cerebral , Estudios de Factibilidad , Accidente Cerebrovascular Isquémico , Leucoaraiosis , Tomografía Computarizada por Rayos X , Humanos , Leucoaraiosis/diagnóstico por imagen , Masculino , Femenino , Anciano , Estudios Retrospectivos , Accidente Cerebrovascular Isquémico/diagnóstico por imagen , Tomografía Computarizada por Rayos X/métodos , Persona de Mediana Edad , Diagnóstico Diferencial , Infarto Cerebral/diagnóstico por imagen , Curva ROC , Anciano de 80 o más Años
14.
Proc Natl Acad Sci U S A ; 118(22)2021 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-34031242

RESUMEN

Contact guidance is a powerful topographical cue that induces persistent directional cell migration. Healthy tissue stroma is characterized by a meshwork of wavy extracellular matrix (ECM) fiber bundles, whereas metastasis-prone stroma exhibit less wavy, more linear fibers. The latter topography correlates with poor prognosis, whereas more wavy bundles correlate with benign tumors. We designed nanotopographic ECM-coated substrates that mimic collagen fibril waveforms seen in tumors and healthy tissues to determine how these nanotopographies may regulate cancer cell polarization and migration machineries. Cell polarization and directional migration were inhibited by fibril-like wave substrates above a threshold amplitude. Although polarity signals and actin nucleation factors were required for polarization and migration on low-amplitude wave substrates, they did not localize to cell leading edges. Instead, these factors localized to wave peaks, creating multiple "cryptic leading edges" within cells. On high-amplitude wave substrates, retrograde flow from large cryptic leading edges depolarized stress fibers and focal adhesions and inhibited cell migration. On low-amplitude wave substrates, actomyosin contractility overrode the small cryptic leading edges and drove stress fiber and focal adhesion orientation along the wave axis to mediate directional migration. Cancer cells of different intrinsic contractility depolarized at different wave amplitudes, and cell polarization response to wavy substrates could be tuned by manipulating contractility. We propose that ECM fibril waveforms with sufficiently high amplitude around tumors may serve as "cell polarization barriers," decreasing directional migration of tumor cells, which could be overcome by up-regulation of tumor cell contractility.


Asunto(s)
Polaridad Celular , Matriz Extracelular/patología , Adhesiones Focales , Metástasis de la Neoplasia , Neoplasias/patología , Fibras de Estrés/patología , Humanos
15.
Stroke ; 54(7): 1920-1929, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-37021568

RESUMEN

Ischemic stroke profoundly influences the peripheral immune system, which responds quickly to brain ischemia and participates in the evolution of poststroke neuroinflammation, while a period of systemic immunosuppression ensues. Poststroke immunosuppression brings harmful consequences, including increased infection rates and escalated death. As the most abundant cell population in the fast-responding innate immune system, myeloid cells including neutrophils and monocytes play an indispensable role in systemic immunosuppression after stroke. The change in myeloid response after stroke can be regulated by circulating DAMPs (damage-associated molecular patterns) and neuromodulatory mechanisms, which contain sympathetic nervous system, hypothalamic-pituitary-adrenal, and parasympathetic nervous system. In this review, we summarize the emerging roles and newly identified mechanisms underlying myeloid cell response in poststroke immunosuppression. Deeper understanding of the above points may pave the way for future development of novel therapeutic strategies to treat poststroke immunosuppression.


Asunto(s)
Isquemia Encefálica , Accidente Cerebrovascular , Humanos , Terapia de Inmunosupresión , Células Mieloides , Sistema Inmunológico
16.
Biochem Biophys Res Commun ; 644: 15-24, 2023 02 12.
Artículo en Inglés | MEDLINE | ID: mdl-36621148

RESUMEN

Titanium (Ti) ion can stimulate osteoblast apoptosis and therefore have a high potential to play a negative role in the aseptic loosening of implants. Mitochondrial abnormalities are closely related to osteoblast dysfunction. However, the mitochondrial molecular mechanism of Ti ion induced osteoblastic cell apoptosis is still unclear. This study investigated in vitro mitochondrial oxidative stress (mtROS) mediated mitochondrial dysfunction involved in Ti ion-induced apoptosis of murine MC3T3-E1 osteoblastic cells. In addition to reducing mitochondrial membrane potential (MMP) and decreasing adenosine triglyceride production, exposure to Ti ions increased mitochondrial oxidative stress. Moreover, mitochondrial abnormalities significantly contributed to Ti ion induction of osteoblastic cellular apoptosis. A mitochondria-specific antioxidant, mitoquinone (MitoQ), alleviated Ti ion-induced mitochondrial dysfunction and apoptosis in osteoblastic cells, indicating that Ti ion mainly induces mitochondrial oxidative stress to produce a cytotoxic effect on osteoblasts. Here we show that the primary regulator of mitochondrial permeability transition pore (mPTP), cyclophilin D (CypD), is involved in mitochondrial dysfunction and osteoblast cell apoptosis induced by Ti ion. Overexpression of CypD exacerbates osteoblast apoptosis and impairs osteogenic function. Moreover, detrimental effects of CypD were rescued by cyclosporin A (CsA), an inhibitor of CypD, which shows its protective effect on mitochondrial and osteogenic osteoblast functions. Based on new insights into the mitochondrial mechanisms underlying Ti ion-induced apoptosis of osteoblastic cells, the findings of this study lay the foundation for the clinical use of CypD inhibitors to prevent or treat implant failure.


Asunto(s)
Estrés Oxidativo , Titanio , Ratones , Animales , Peptidil-Prolil Isomerasa F/metabolismo , Titanio/farmacología , Ciclofilinas/metabolismo , Ciclosporina/farmacología , Mitocondrias/metabolismo , Proteínas de Transporte de Membrana Mitocondrial/metabolismo
17.
Proc Biol Sci ; 290(2002): 20231175, 2023 07 12.
Artículo en Inglés | MEDLINE | ID: mdl-37434523

RESUMEN

Humans and other animals value information that reduces uncertainty or leads to pleasurable anticipation, even if it cannot be used to gain tangible rewards or change outcomes. In exchange, they are willing to incur significant costs, sacrifice rewards or invest effort. We investigated whether human participants were also willing to endure pain-a highly salient and aversive cost-to obtain such information. Forty participants performed a computer-based task. On each trial, they observed a coin flip, with each side associated with different monetary rewards of varying magnitude. Participants could choose to endure a painful stimulus (low, moderate or high pain) to learn the outcome of the coin flip immediately. Importantly, regardless of their choice, winnings were always earned, rendering this information non-instrumental. Results showed that agents were willing to endure pain in exchange for information, with a lower likelihood of doing so as pain levels increased. Both higher average rewards and a larger variance between the two possible rewards independently increased the willingness to accept pain. Our results show that the intrinsic value of escaping uncertainty through non-instrumental information is sufficient to offset pain experiences, suggesting a shared mechanism through which these can be directly compared.


Asunto(s)
Afecto , Renta , Animales , Humanos , Aprendizaje , Dolor , Probabilidad
18.
J Transl Med ; 21(1): 328, 2023 05 18.
Artículo en Inglés | MEDLINE | ID: mdl-37198593

RESUMEN

BACKGROUND: Oral squamous cell carcinoma (OSCC) is one of the most prevalent and fatal oral cancers. Mitochondria-targeting therapies represent promising strategies against various cancers, but their applications in treating OSCC are limited. Alantolactone (ALT) possesses anticancer properties and also regulates mitochondrial events. In this study, we explored the effects of ALT on OSCC and the related mechanisms. METHODS: The OSCC cells were treated with varying concentrations and duration of ALT and N-Acetyl-L-cysteine (NAC). The cell viability and colony formation were assessed. The apoptotic rate was evaluated by flow cytometry with Annexin V-FITC/PI double staining. We used DCFH-DA and flow cytometry to detect reactive oxygen species (ROS) production and DAF-FM DA to investigate reactive nitrogen species (RNS) level. Mitochondrial function was reflected by mitochondrial reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and ATP levels. KEGG enrichment analyses determined the mitochondrial-related hub genes involved in OSCC progression. Dynamin-related protein 1 (Drp1) overexpression plasmids were further transfected into the cells to analyze the role of Drp1 in OSCC progression. Immunohistochemistry staining and western blot verified the expression of the protein. RESULTS: ALT exerted anti-proliferative and pro-apoptosis effects on OSCC cells. Mechanistically, ALT elicited cell injury by promoting ROS production, mitochondrial membrane depolarization, and ATP depletion, which were reversed by NAC. Bioinformatics analysis showed that Drp1 played a crucial role in OSCC progression. OSCC patients with low Drp1 expression had a higher survival rate. The OSCC cancer tissues presented higher phosphorylated-Drp1 and Drp1 levels than the normal tissues. The results further showed that ALT suppressed Drp1 phosphorylation in OSCC cells. Moreover, Drp1 overexpression abolished the reduced Drp1 phosphorylation by ALT and promoted the cell viability of ALT-treated cells. Drp1 overexpression also reversed the mitochondrial dysfunction induced by ALT, with decreased ROS production, and increased mitochondrial membrane potential and ATP level. CONCLUSIONS: ALT inhibited proliferation and promoted apoptosis of oral squamous cell carcinoma cells via impairment of mitochondrial homeostasis and regulation of Drp1. The results provide a solid basis for ALT as a therapeutic candidate for treating OSCC, with Drp1 being a novel therapeutic target in treating OSCC.


Asunto(s)
Dinaminas , Neoplasias de la Boca , Carcinoma de Células Escamosas de Cabeza y Cuello , Humanos , Adenosina Trifosfato/metabolismo , Apoptosis , Línea Celular Tumoral , Regulación hacia Abajo , Dinaminas/metabolismo , Dinaminas/farmacología , Dinaminas/uso terapéutico , Mitocondrias/metabolismo , Neoplasias de la Boca/tratamiento farmacológico , Neoplasias de la Boca/patología , Fosforilación , Especies Reactivas de Oxígeno/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello/patología
19.
Cytokine ; 161: 156052, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36375397

RESUMEN

BACKGROUND: IL-38, a recently discovered cytokine of IL-1 family, exerts immunoregulatory activities in multi-type inflammatory diseases. However, its expression level and underlying clinical importance for IL-38 in respiratory bacterial infections remain unknown. METHODS: Thirty-five patients with bacterial pneumonia and twenty age- and gender- matched healthy individuals were enrolled in the study to determine serum IL-38 concentrations by ELISA. Then, the correlation between serum IL-38 levels and clinical features were analyzed and ROC curve was used to evaluate the potential diagnostic value for bacterial infections. In vitro, LPS-stimulated human respiratory epithelial cell model was employed to explore immunomodulatory mechanism of IL-38 in pulmonary infections. RESULTS: Elevated serum levels of IL-38 were determined in patients with bacterial pneumonia when compared with healthy controls. In addition, serum IL-38 levels were negatively correlated with clinical inflammation parameters, including WBC count, CRP, PCT and proinflammatory IL-6 and IL-8. In vitro, we demonstrated that recombinant IL-38 was able to remarkably inhibit expression of proinflammatory IL-6, IL-8, IL-1ß and TNF-α as well as adhesion molecule ICAM-1, which were partially mediated by attenuated activation of STAT3 and NF-κB signal cascades in BEAS-2B cells. Furthermore, we identified the diagnostic efficiency of IL-38 in discriminating patients with bacterial pneumonia from healthy individuals. CONCLUSIONS: Our study indicates higher serum IL-38 levels in patients with bacterial pneumonia are involved in anti-inflammatory activities in respiratory infections revealing a critical role of IL-38 in attenuating excessive pulmonary inflammation against exogenous pathogens. More importantly, IL-38 exhibited a potential novel biomarker for bacterial pneumonia. Thus, our data may provide useful insights for both clinical and basic research for bacterial pneumonia diagnosis.


Asunto(s)
Neumonía Bacteriana , Neumonía , Humanos , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Citocinas , Factor de Necrosis Tumoral alfa , Interleucinas
20.
BMC Cancer ; 23(1): 528, 2023 Jun 09.
Artículo en Inglés | MEDLINE | ID: mdl-37296415

RESUMEN

BACKGROUND: New immunotherapeutic strategies based on predictors are urgently needed. Toll-like receptor adaptor interacting with SLC15A4 on the lysosome (TASL) was recently confirmed to fulfill an important role in the innate immune response. However, whether TASL is involved in tumor development and immunotherapy response prediction has not been reported. METHODS: TCGA and GTEx were used to yield transcriptional, genetic, and epigenetic levels of TASL in 33 cancer types. CIBERSORT was used to explore the correlation between TASL expression and multiple immune-related signatures and tumor-infiltrating immune cell content in different cancer types. The ability of TASL to predict tumor immunotherapy response was analyzed in seven datasets. Finally, we tested TASL expression in human glioma cell lines and tissue samples and analyzed its correlation with clinicopathological parameters. RESULTS: TASL is widely heterogeneous at the transcriptional, genetic, and epigenetic levels. High TASL expression is an independent poor prognostic factor for immune "cold" tumor Low-Grade Glioma (LGG) but an opposite factor for "hot" tumors Lung Adenocarcinoma (LUAD) and Skin Cutaneous Melanoma (SKCM). TASL may affect tumor immune infiltration by mediating tumor-infiltrating lymphocytes and tumor-associated macrophages. It may differentially affect the prognosis of the three cancers by regulating the immunosuppressive microenvironment in LGG and the immunostimulatory microenvironment in LUAD and SKCM. High TASL expression is a potential biomarker for the positive response to immunotherapy in cancers such as SKCM and was also experimentally confirmed to be positively associated with adverse clinicopathological features of gliomas. CONCLUSION: TASL expression is an independent prognostic factor for LGG, LUAD, and SKCM. High TASL expression is a potential biomarker for the positive response to immunotherapy in certain cancer types such as SKCM. Further basic studies focusing on TASL expression and tumor immunotherapy are urgently needed.


Asunto(s)
Adenocarcinoma del Pulmón , Glioma , Neoplasias Pulmonares , Melanoma , Neoplasias Cutáneas , Humanos , Pronóstico , Biomarcadores , Inmunoterapia , Microambiente Tumoral , Melanoma Cutáneo Maligno
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