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Introduction: Since their identification in 1974, circoviruses have caused clinicopathological diseases in various animal species, including humans. However, their origin, transmission, and genetic evolution remain poorly understood. Methods: In this study, the genome sequences of circovirus were obtained from GenBank, and the Bayesian stochastic search variable selection algorithm was employed to analyzed the evolution and origin of circovirus. Results: Here, the evolutionary origin, mode of transmission, and genetic recombination of the circovirus were determined based on the available circovirus genome sequences. The origin of circoviruses can be traced back to fish circovirus, which might derive from fish genome, and human contributes to transmission of fish circovirus to other species. Furthermore, mosquitos, ticks, bats, and/or rodents might play a role as intermediate hosts in circovirus intra- and inter-species transmission. Two major lineages (A and B) of circoviruses are identified, and frequent recombination events accelerate their variation and spread. The time to the most recent common ancestor of circoviruses can be traced back to around A.D. 600 and has been evolving at a rate of 10-4 substitutions site-1 year-1 for a long time. Discussion: These comprehensive findings shed light on the evolutionary origin, population dynamics, transmission model, and genetic recombination of the circovirus providing valuable insights for the development of prevention and control strategies against circovirus infections.
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Infecciones por Circoviridae , Circovirus , Evolución Molecular , Filogenia , Recombinación Genética , Animales , Humanos , Circovirus/genética , Infecciones por Circoviridae/transmisión , Infecciones por Circoviridae/virología , Infecciones por Circoviridae/veterinaria , Genoma Viral , Teorema de BayesRESUMEN
Background: The incidence and mortality of gynaecological cancers can significantly impact women's quality of life and increase the health care burden for organisations globally. The objective of this study was to evaluate global inequalities in the incidence and mortality of gynaecological cancers in 2022, based on The Global Cancer Observatory (GLOBOCAN) 2022 estimates. The future burden of gynaecological cancers (GCs) in 2050 was also projected. Methods: Data regarding to the total cases and deaths related to gynaecological cancer, as well as cases and deaths pertaining to different subtypes of GCs, gathered from the GLOBOCAN database for the year 2022. Predictions for the number of cases and deaths in the year 2050 were derived from global demographic projections, categorised by world region and Human Development Index (HDI). Results: In 2022, there were 1 473 427 new cases of GCs and 680 372 deaths. The incidence of gynecological cancer reached 30.3 per 100 000, and the mortality rate hit 13.2 per 100 000. The age-standardised incidence of GCs in Eastern Africa is higher than 50 per 100 000, whereas the age-standardised incidence in Northern Africa is 17.1 per 100 000. The highest mortality rates were found in East Africa (ASMR (age-standardised mortality rates) of 35.3 per 100 000) and the lowest in Australia and New Zealand (ASMR of 8.1 per 100 000). These are related to the endemic areas of HIV and HPV. Very High HDI countries had the highest incidence of GCs, with ASIR (age-standardised incidence rates) of 34.8 per 100 000, and low HDI countries had the second highest incidence rate, with an ASIR of 33.0 per 100 000. Eswatini had the highest incidence and mortality (105.4 per 100 000; 71.1 per 100 000) and Yemen the lowest (5.8 per 100 000; 4.4 per 100 000). If the current trends in morbidity and mortality are maintained, number of new cases and deaths from female reproductive tract tumours is projected to increase over the next two decades. Conclusions: In 2022, gynaecological cancers accounted for 1 473 427 new cases and 680 372 deaths globally, with significant regional disparities in incidence and mortality rates. The highest rates were observed in Eastern Africa and countries with very high and low HDI, with Eswatini recording the most severe statistics. If current trends continue, the number of new cases and deaths from gynaecological cancers is expected to rise over the next two decades, highlighting the urgent need for effective interventions.
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Neoplasias de los Genitales Femeninos , Salud Global , Humanos , Femenino , Neoplasias de los Genitales Femeninos/epidemiología , Neoplasias de los Genitales Femeninos/mortalidad , Salud Global/estadística & datos numéricos , Incidencia , Predicción , Carga Global de Enfermedades/tendencias , Costo de EnfermedadRESUMEN
BACKGROUND: Selecting intervention strategies for renal artery aneurysms (RAAs) is challenging especially for those located at the vessel bifurcation. The relationship between the aneurysm and renal branches could not always be accurately viewed from traditional computed tomography angiography (CTA) images. CASE PRESENTATION: This study proposed a new method to investigate the anatomy and affected vessel branches of RAAs using automated software. Two patients with RAAs located at the renal artery bifurcation underwent Cone beam CTA (CBCTA) analysis. We sequentially coupled the "two-click AVA" function of Vessel IQ Xpress (GE Healthcare) with the "vascular tree extraction" function from FlightPlan for Embolization (GE Healthcare) to evaluate the relationship among the main renal artery, vessel branches, and aneurysms. The results showed that one patient had 1 out of 3 branches affected by the aneurysm, whereas the other's branches were all affected. Endovascular repair and open surgery were performed respectively based on the image analysis. Both patients recovered well at follow-up examination. CONCLUSIONS: Based on CBCTA analysis, the combination use of the "two-click AVA" function of VesselIQ Xpress and FlightPlan for Embolization software could assist in aneurysm assessment and intervention choices for RAAs.
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Brevibacillus laterosporus S62-9 has been shown to improve broiler growth performance and immunity. In the present study, we aimed to evaluate the effects of B. laterosporus S62-9 on the immunity and lipid metabolism of broilers by means of transcriptomic analysis. A total of 160 1-day-old broilers were randomly allocated to a S62-9 group, the diet of which was supplemented with 106 CFU/g B. laterosporus S62-9 daily, and a control group, which was not. After 42 d of feeding, the broilers in the S62-9 group had higher body mass (7.2%) and feed conversion ratio (5.19%) than the control group. Supplementation with B. laterosporus S62-9 resulted in lower serum total cholesterol and low-density lipoprotein-cholesterol concentrations and higher high-density lipoprotein-cholesterol concentrations. An analysis of the fatty acid composition of the broiler's thigh muscles revealed that the proportions of the unsaturated fatty acids myristoleic acid (C14:1) and arachidonic acid (C20:1) were higher for birds in the S62-9 group. Transcriptomic analysis also showed an upregulation of immunity-related genes in the S62-9 group. Gene Ontology functional enrichment analysis showed that the mitogen-activated protein kinase pathway was enriched in the liver, the defense response was enriched in the duodenum, and immunoglobulin-related entries were enriched in the jejunum of the S62-9 group. Furthermore, the expression of key genes involved in unsaturated fatty acid synthesis (SCD, encoding stearoyl-CoA desaturase) and fatty acid metabolism (HACD2, encoding 3-hydroxyacyl-CoA dehydratase 2) was upregulated in the liver, and the expression of genes associated with fat biosynthesis and accumulation, such as PLIN1, encoding perilipin 1, and FABP4, encoding fatty acid binding protein 4, was upregulated in the ileum of the birds in the S62-9 group. In summary, supplementation with B. laterosporus S62-9 could improve immune defense and the fatty acid metabolism of broiler chickens, thereby enhancing their disease resistance and promoting growth and development.
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BRCA1, a breast cancer susceptibility gene, has emerged as a central mediator that brings together multiple signaling complexes in response to DNA damage. The A, B, and C complexes of BRCA1, which are formed based on their phosphorylation-dependent interactions with the BRCA1-C-terminal domains, contribute to the roles of BRCA1 in DNA repair and cell cycle checkpoint control. However, their functions in DNA damage response remain to be fully appreciated. Specifically, there has been no systematic investigation of the roles of BRCA1-A, -B, and -C complexes in the regulation of BRCA1 localization and functions, in part because of cellular lethality associated with loss of CtIP protein, which is an essential component in BRCA1-C complex. To systematically investigate the functions of these complexes in DNA damage response, we depleted a key component in each of these complexes. We used the degradation tag system to inducibly deplete endogenous CtIP and obtained a series of RAP80/FANCJ/CtIP single-, double-, and triple-knockout cells. We showed that loss of BRCA1-B/FANCJ and BRCA1-C/CtIP, but not BRCA1-A/RAP80, resulted in reduced cell proliferation and increased sensitivity to DNA damage. BRCA1-C/CtIP and BRCA1-A/RAP80 were involved in BRCA1 recruitment to sites of DNA damage. However, BRCA1-A/RAP80 was not essential for damage-induced BRCA1 localization. Instead, RAP80/H2AX and CtIP have redundant roles in BRCA1 recruitment. Altogether, our systematic analysis uncovers functional differences between BRCA1-A, -B, and -C complexes and provides new insights into the roles of these BRCA1-associated protein complexes in DNA damage response and DNA repair.
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Proteína BRCA1 , Daño del ADN , Reparación del ADN , Humanos , Proteína BRCA1/metabolismo , Proteína BRCA1/genética , Chaperonas de Histonas/metabolismo , Chaperonas de Histonas/genética , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Proteínas Portadoras/metabolismo , Proteínas Portadoras/genética , Proteínas del Grupo de Complementación de la Anemia de Fanconi/metabolismo , Proteínas del Grupo de Complementación de la Anemia de Fanconi/genética , Línea Celular TumoralRESUMEN
Research on plant and animal peptides has garnered significant attention, but there is a lack of studies on the functional properties of Tenebrio molitor peptides, particularly in relation to their potential mitigating effect on radiation damage and the underlying mechanisms. This study aims to explore the protective effects of Tenebrio molitor peptides against radiation-induced damage. Mice were divided into five groups: normal, radiation model, and low-, medium-, and high-dose Tenebrio molitor peptide (TMP) groups (0.15 g per kg BW, 0.30 g per kg BW, and 0.60 g per kg BW). Various parameters such as blood cell counts, bone marrow DNA content, immune organ indices, serum levels of D-lactic acid, diamine oxidase (DAO), endotoxin (LPS), and inflammatory factors were assessed at 3 and 15 days post gamma irradiation. Additionally, the intestinal tissue morphology was examined through H&E staining, RT-qPCR experiments were conducted to analyze the expression of inflammatory factors in the intestine, and immunohistochemistry was utilized to evaluate the expression of tight junction proteins ZO-1 and Occludin in the intestine. The findings revealed that high-dose TMP significantly enhanced the hematopoietic system function in mice post radiation exposure, leading to increased spleen index, thymus index, blood cell counts, and bone marrow DNA production (p < 0.05). Moreover, TMP improved the intestinal barrier integrity and reduced the intestinal permeability. Mechanistic insights suggested that these peptides may safeguard intestinal barrier function by downregulating the gene expression of inflammatory factors TNF-α, IL-1ß, and IL-6, while upregulating the expression of tight junction proteins ZO-1 and Occludin (p < 0.05). Overall, supplementation with TMP mitigates radiation-induced intestinal damage by enhancing the hematopoietic system and the intestinal barrier, offering valuable insights for further investigations into the mechanisms underlying the protective effects of these peptides against ionizing radiation.
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Mucosa Intestinal , Péptidos , Tenebrio , Animales , Ratones , Péptidos/farmacología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efectos de la radiación , Mucosa Intestinal/efectos de los fármacos , Masculino , Sistema Hematopoyético/efectos de los fármacos , Sistema Hematopoyético/efectos de la radiación , Protectores contra Radiación/farmacología , Proteína de la Zonula Occludens-1/metabolismo , Proteína de la Zonula Occludens-1/genética , Rayos gamma/efectos adversos , Ocludina/metabolismo , Ocludina/genética , Intestinos/efectos de los fármacos , Intestinos/efectos de la radiaciónRESUMEN
OBJECTIVES: Interleukin 33 (IL-33) is a crucial inflammatory factor that functions as an alarm signal in endometriosis (EMs). Epithelial-mesenchymal transition (EMT), a process related to inflammatory signals, intracellular reactive oxygen species (ROS) production, and lipid peroxidation, have been proposed as potential mechanisms that contribute to the development and progression of EMs. IL-33 is highly upregulated in the ectopic milieu. Moreover, ectopic endometrial cells constitutively express interleukin-33 receptor ST2 (IL-33R). However, the role of IL-33/ST2 in the EMT of EMs remains largely unknown. In this study, we aimed to mechanistically determine the role of IL-33/ST2 in EMs-associated fibrosis. MATERIALS AND METHODS: We established a non-lethal oxidative stress model to explore the conditions that trigger IL-33 induction. We performed α-smooth muscle actin (α-SMA) protein detection, cell counting kit-8 (CCK-8) assays, and scratch assays to analyze the impact of IL-33 on primary endometrial stromal cells (ESCs) proliferation and invasion. Clinical samples from patients with or without EMs were subjected to immunohistochemical (IHC) and and immunofluorescence(IF) staining to assess the clinical relevance of IL-33 receptor ST2 and EMT-related proteins. Furthermore, we used the ectopic human endometrial epithelial cell line 12Z and normal human epithelial cell line EEC to evaluate the effects of IL-33 on Wnt/ß-catenin signaling. The effect of IL-33 on EMT-associated fibrosis was validated in vivo by intraperitoneal injections of IL-33 and antiST2. RESULTS: We observed that ectopic milieu, characterized by ROS, TGF-ß1, and high level of estrogen, triggers the secretion of IL-33 from ectopic ESCs. Ectopic endometrial lesions exhibited higher level of fibrotic characteristics and ST2 expression than that in the normal endometrium. Exogenous recombinant human (rhIL-33) enhanced ESC migration and survival. Similarly, 12Z cells displayed a higher degree of EMT characteristics with elevated expression of CCN4 and Fra-1, downstream target genes of the WNT/ß-catenin pathway, than that observed in EECs. Conversely, blocking IL-33 with neutralizing antibodies, knocking down ST2 or ß-catenin with siRNA, and ß-catenin dephosphorylation abolished its effects on EMT promotion. In vivo validation demonstrated that IL-33 significantly promotes EMs-related fibrosis through the activation of Wnt/ß-catenin signaling. CONCLUSION: Our data strongly support the vital role of the IL-33/ST2 pathway in EMs-associated fibrosis and emphasize the importance of the EMT in the pathophysiology of fibrosis. Targeting the IL-33/ST2/Wnt/ß-catenin axis may hold promise as a feasible therapeutic approach for controlling fibrosis in EMs.
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Endometriosis , Transición Epitelial-Mesenquimal , Proteína 1 Similar al Receptor de Interleucina-1 , Interleucina-33 , beta Catenina , Femenino , Endometriosis/metabolismo , Endometriosis/patología , Endometriosis/genética , Interleucina-33/metabolismo , Interleucina-33/genética , Transición Epitelial-Mesenquimal/genética , Humanos , Proteína 1 Similar al Receptor de Interleucina-1/metabolismo , Proteína 1 Similar al Receptor de Interleucina-1/genética , beta Catenina/metabolismo , Animales , Fosforilación , Ratones , Endometrio/patología , Endometrio/metabolismo , Adulto , Proliferación Celular , Movimiento Celular , Transducción de SeñalRESUMEN
Antiphospholipid syndrome is a rare autoimmune disease characterized by persistent antiphospholipid antibodies. Immunoglobulin G plays a vital role in disease progression, with its structure and function affected by glycosylation. We aimed to investigate the changes in the serum immunoglobulin G glycosylation pattern in antiphospholipid syndrome patients. We applied lectin microarray on samples from 178 antiphospholipid syndrome patients, 135 disease controls (including Takayasu arteritis, rheumatoid arthritis and cardiovascular disease) and 100 healthy controls. Lectin blots were performed for validation of significant differences. Here, we show an increased immunoglobulin G-binding level of soybean agglutinin (p = 0.047, preferring N-acetylgalactosamine) in antiphospholipid syndrome patients compared with healthy and disease controls. Additionally, the immunoglobulin G from antiphospholipid syndrome patients diagnosed with pregnancy events had lower levels of fucosylation (p = 0.001, recognized by Lotus tetragonolobus) and sialylation (p = 0.030, recognized by Sambucus nigra I) than those with simple thrombotic events. These results suggest the unique serum immunoglobulin G glycosylation profile of antiphospholipid syndrome patients, which may inform future studies to design biomarkers for more accurate diagnosis of antiphospholipid syndrome and even for the prediction of clinical symptoms in patients.
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Síndrome Antifosfolípido , Inmunoglobulina G , Humanos , Síndrome Antifosfolípido/inmunología , Síndrome Antifosfolípido/sangre , Síndrome Antifosfolípido/diagnóstico , Glicosilación , Femenino , Masculino , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Adulto , Persona de Mediana Edad , Embarazo , Lectinas/sangre , Lectinas/metabolismo , Lectinas/inmunología , Biomarcadores/sangre , Análisis por Matrices de Proteínas/métodos , Anticuerpos Antifosfolípidos/sangre , Anticuerpos Antifosfolípidos/inmunología , Lectinas de Plantas/metabolismo , Lectinas de Plantas/inmunología , Anciano , GlicoproteínasRESUMEN
Poly(ADP-ribose)ylation or PARylation by PAR polymerase 1 (PARP1) and dePARylation by poly(ADP-ribose) glycohydrolase (PARG) are equally important for the dynamic regulation of DNA damage response. PARG, the most active dePARylation enzyme, is recruited to sites of DNA damage via pADPr-dependent and PCNA-dependent mechanisms. Targeting dePARylation is considered an alternative strategy to overcome PARP inhibitor resistance. However, precisely how dePARylation functions in normal unperturbed cells remains elusive. To address this challenge, we conducted multiple CRISPR screens and revealed that dePARylation of S phase pADPr by PARG is essential for cell viability. Loss of dePARylation activity initially induced S-phase-specific pADPr signaling, which resulted from unligated Okazaki fragments and eventually led to uncontrolled pADPr accumulation and PARP1/2-dependent cytotoxicity. Moreover, we demonstrated that proteins involved in Okazaki fragment ligation and/or base excision repair regulate pADPr signaling and cell death induced by PARG inhibition. In addition, we determined that PARG expression is critical for cellular sensitivity to PARG inhibition. Additionally, we revealed that PARG is essential for cell survival by suppressing pADPr. Collectively, our data not only identify an essential role for PARG in normal proliferating cells but also provide a potential biomarker for the further development of PARG inhibitors in cancer therapy.
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Antineoplásicos , Poli Adenosina Difosfato Ribosa , Supervivencia Celular , Fase S , Poli Adenosina Difosfato Ribosa/metabolismo , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Antineoplásicos/farmacologíaRESUMEN
Rumexpatientia L. ×Rumextianshanicus A. Los (RRL), known as "protein grass" in China, was recognized as a new food ingredient in 2021. However, the cultivation and product development of RRL are still at an early stage, and no peptide research has been reported. In this study, two novel antioxidant peptides, LKPPF and LPFRP, were purified and identified from RRL and applied to H2O2-induced HepG2 cells to investigate their antioxidant properties. It was shown that 121 peptides were identified by ultrafiltration, gel filtration chromatography, and LC-MS/MS, while computer simulation and molecular docking indicated that LKPPF and LPFRP may have strong antioxidant properties. Both peptides were not cytotoxic to HepG2 cells at low concentrations and promoted cell growth, which effectively reduced the production of intracellular ROS and MDA, and increased cell viability and the enzymatic activities of SOD, GSH-Px, and CAT. Therefore, LKPPF and LPFRP, two peptides, possess strong antioxidant activity, which provides a theoretical basis for their potential as food additives or functional food supplements, but still need to be further investigated through animal models as well as cellular pathways.
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Radiation therapy (RT) is one of the most commonly used anticancer therapies. However, the landscape of cellular response to irradiation, especially to a single high-dose irradiation, remains largely unknown. In this study, we performed a whole-genome CRISPR loss-of-function screen and revealed temporal inherent and acquired responses to RT. Specifically, we found that loss of the IL1R1 pathway led to cellular resistance to RT. This is in part because of the involvement of radiation-induced IL1R1-dependent transcriptional regulation, which relies on the NF-κB pathway. Moreover, the mitochondrial anti-apoptotic pathway, particularly the BCL2L1 gene, is crucially important for cell survival after radiation. BCL2L1 inhibition combined with RT dramatically impeded tumor growth in several breast cancer cell lines and syngeneic models. Taken together, our results suggest that the combination of an apoptosis inhibitor such as a BCL2L1 inhibitor with RT may represent a promising anticancer strategy for solid cancers including breast cancer.
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Neoplasias de la Mama , Mutaciones Letales Sintéticas , Proteína bcl-X , Femenino , Humanos , Proteína bcl-X/genética , Proteína bcl-X/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/radioterapia , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas/genética , FN-kappa B/genética , FN-kappa B/metabolismo , Mutaciones Letales Sintéticas/genéticaRESUMEN
PURPOSE: Renal artery aneurysm (RAA) is a rare disease. This study proposed and evaluated a new classification for RAA to assist in surgical decision-making. MATERIALS AND METHODS: Single-center data of 105 patients with RAAs from the vascular department of vascular surgery were collected retrospectively. A new classification scheme was proposed. Type I aneurysms arise from the main trunk, accessory branch, or first-order branches away from any bifurcation. Type II aneurysms arise from the first bifurcation with narrow necks (defined as dome-to-neck ratio >2) or from intralobular branches. Type III aneurysms with a wide neck arise from the first bifurcation and affect 2 or more branches that cannot be sacrificed without significant infarction of the kidney. RESULTS: There was 50 (47.62%) type I, 33 (31.43%) type II, and 22 (20.95%) type III aneurysms. The classification assigned endovascular repair as first-line treatment (for type I or II), while open techniques were conducted if anatomically suitable (for type III). A kappa level of 0.752 was achieved by the classification compared with a level of 0.579 from the classic Rundback classification. Technical primary success was achieved in 100% and 96.05%, and symptoms were completely resolved in 100% and 84.85%, while hypertension was relieved in 84.21% and 72.92% of patients receiving open surgery or endovascular repair, respectively. No significant difference was observed for perioperative or long-term complications among the 3 classification types. CONCLUSION: The new classification proved to be a convenient and effective method for facilitating choice of intervention for RAAs. CLINICAL IMPACT: This study proposed and evaluated a new classification scheme for renal artery aneurysms, which proved to be a convenient and effective method for facilitating surgical decision-making. Coil embolization was the first-line treatment if suitable, while aneurysm resection and reconstruction with vein graft were conducted for some complex lesions. The safety and efficacy of both open and endovascular methods were validated.
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Avian metapneumovirus subgroup C (aMPV/C) causes respiratory diseases and egg dropping in chickens and turkeys, resulting in severe economic losses to the poultry industry worldwide. Integrin ß1 (ITGB1), a transmembrane cell adhesion molecule, is present in various cells and mediates numerous viral infections. Herein, we demonstrate that ITGB1 is essential for aMPV/C infection in cultured DF-1 cells, as evidenced by the inhibition of viral binding by EDTA blockade, Arg-Ser-Asp (RSD) peptide, monoclonal antibody against ITGB1, and ITGB1 short interfering (si) RNA knockdown in cultured DF-1 cells. Simulation of the binding process between the aMPV/C fusion (F) protein and avian-derived ITGB1 using molecular dynamics showed that ITGB1 may be a host factor benefiting aMPV/C attachment or internalization. The transient expression of avian ITGB1-rendered porcine and feline non-permissive cells (DQ cells and CRFK cells, respectively) is susceptible to aMPV/C infection. Kinetic replication of aMPV/C in siRNA-knockdown cells revealed that ITGB1 plays an important role in aMPV/C infection at the early stage (attachment and internalization). aMPV/C was also able to efficiently infect human non-small cell lung cancer (A549) cells. This may be a consequence of the similar structures of both metapneumovirus F protein-specific motifs (RSD for aMPV/C and RGD for human metapneumovirus) recognized by ITGB1. Overexpression of avian-derived ITGB1 and human-derived ITGB1 in A549 cells enhanced aMPV/C infectivity. Taken together, this study demonstrated that ITGB1 acts as an essential receptor for aMPV/C attachment and internalization into host cells, facilitating aMPV/C infection.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Metapneumovirus , Humanos , Animales , Gatos , Porcinos , Metapneumovirus/genética , Integrina beta1/genética , Pollos , Anticuerpos AntiviralesRESUMEN
Chronic risk factors for pseudoaneurysm (PSA) or penetrating aortic ulcer (PAU) have not been fully clarified. This study aims to evaluate the association of aortic calcification with PSA or PAU of different etiologies. Totally 77 pseudoaneurysms, 80 PAU, and 160 healthy controls (HCs) were retrospectively included, of which 30 were infected, 34 were immunological, and 93 were atherosclerotic etiologies. The aortic calcification status, position of aortic tears/ulcers, and risk factors for disease or acute aortic syndrome (AAS) were identified. Atherosclerotic patients aged more than 65 and infective patients aged more than 60 had significantly higher calcification scores. The immunological group had a lower level of calcification in the infrarenal aorta. For patients of infective or atherosclerotic etiology, 60% (18/30) and 60.22% (56/93) of the tears/ulcers occurred at the aortic parts with the highest level of calcification. Patients with longitudinal calcification exceeding 1/3 of the aortic arch had an increased risk of acquiring diseases (OR = 13.231). The presence of longitudinal calcification of the descending aorta or cross-sectional calcification of the infrarenal aorta increased the risks of acquiring diseases (OR = 8.484 and 8.804). After adjusting for age, longitudinal calcification of the descending aorta exceeding 1/3 length was found to be associated with AAS (OR = 4.662). Tears/ulcers of pseudoaneurysm and PAU were both generally found at the part of the aorta with most calcification. Distinct aorta calcification characteristics were observed for lesions of different etiologies. Longitudinal thoracic and cross-sectional infrarenal abdominal aortic calcification increased the risk of acquiring diseases, and descending aortic calcification was associated with symptomatic patients.
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Aneurisma Falso , Enfermedades de la Aorta , Aterosclerosis , Úlcera Aterosclerótica Penetrante , Humanos , Aneurisma Falso/etiología , Enfermedades de la Aorta/complicaciones , Enfermedades de la Aorta/diagnóstico por imagen , Úlcera/patología , Estudios Retrospectivos , Estudios Transversales , Aorta Torácica/patología , Aterosclerosis/patología , Aorta Abdominal/diagnóstico por imagen , Aorta Abdominal/patologíaRESUMEN
OBJECTIVE: This study investigates the positivity and relevance of non-criteria aPLs with clinical phenotypes in patients highly suspected of or diagnosed with APS. METHODS: Outpatient cases were included from a prospectively maintained database, and patients were grouped into APS (n = 168), seronegative APS (SNAPS, n = 9), those meeting the diagnostic criteria for clinical events without laboratory results (only-event, n = 15), those that had aPL positivity without clinical manifestations (asymptomatic APA, n = 39), and healthy controls (n = 88). Criteria aPL results and APS-related clinical features were extracted. Sixteen non-criteria aPLs were tested and analysed. RESULTS: LA, aCL and anti-ß2 glycoprotein-I were positive in 84.5%, 61.3% and 74.4% of APS patients, and 61.5%, 59.0% and 74.4% of asymptomatic APA patients, respectively. In patients negative for criteria serological tests, 23 out of 24 were positive for at least one non-criteria aPL. Triple-positive patients also had significantly higher tests of some aPLs in comparison with other groups. Stroke was associated with anti-phosphatidyl-inositol (aPI) IgG and anti-phosphatidyl-glycerol (aPG) IgG. Late embryonic loss correlated with aPI IgM, and premature birth/eclampsia was associated with aPI IgG and aPG IgG. There were also positive associations between heart valve lesions and anti-phosphatidylserine-prothrombin (aPS/PT) IgM, APS nephropathy and anti-phosphatidyl-choline IgG or aPS/PT IgG, and livedo reticularis and anti-phosphatidyl-ethanolamine IgM. CONCLUSION: The prevalence of non-criteria aPLs differed from diagnostic biomarkers in patients diagnosed with or suspected of APS. Detection of aPLs provided additive value in the evaluation of APS-related clinical manifestations.
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Anticuerpos Antifosfolípidos , Síndrome Antifosfolípido , Femenino , Embarazo , Humanos , Síndrome Antifosfolípido/complicaciones , Relevancia Clínica , Protrombina , Inmunoglobulina G , Inmunoglobulina MRESUMEN
Poly(ADP-ribose)ylation or PARylation by PAR polymerase 1 (PARP1) and dePARylation by poly(ADP-ribose) glycohydrolase (PARG) are equally important for the dynamic regulation of DNA damage response. PARG, the most active dePARylation enzyme, is recruited to sites of DNA damage via pADPr-dependent and PCNA-dependent mechanisms. Targeting dePARylation is considered an alternative strategy to overcome PARP inhibitor resistance. However, precisely how dePARylation functions in normal unperturbed cells remains elusive. To address this challenge, we conducted multiple CRISPR screens and revealed that dePARylation of S phase pADPr by PARG is essential for cell viability. Loss of dePARylation activity initially induced S phase-specific pADPr signaling, which resulted from unligated Okazaki fragments and eventually led to uncontrolled pADPr accumulation and PARP1/2-dependent cytotoxicity. Moreover, we demonstrated that proteins involved in Okazaki fragment ligation and/or base excision repair regulate pADPr signaling and cell death induced by PARG inhibition. In addition, we determined that PARG expression is critical for cellular sensitivity to PARG inhibition. Additionally, we revealed that PARG is essential for cell survival by suppressing pADPr. Collectively, our data not only identify an essential role for PARG in normal proliferating cells but also provide a potential biomarker for the further development of PARG inhibitors in cancer therapy.
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Gemcitabinebased chemotherapy has been widely adopted as the standard and preferred chemotherapy regimen for treating advanced pancreatic cancer. However, the contribution of multidrug resistance protein 5 (MRP5) to gemcitabine resistance and pancreatic cancer progression remains controversial. In the present study, the effect of silencing MRP5 on gemcitabine resistance and cell proliferation and migration of human pancreatic cancer MIA Paca2 and PANC1 cells was investigated by using shorthairpin RNA delivered by lentiviral vector transduction. The knockdown of MRP5 was confirmed on both mRNA and protein levels using qPCR and surface staining assays, respectively. MRP5regulated gemcitabine sensitivity was assessed by MTT, PrestoBlue and apoptosis assays. The effect of MRP5 on pancreatic cancer cell proliferation and migration was determined using colonyformation, woundhealing and Transwell migration assays. The interaction of gemcitabine and cyclic guanosine monophosphate (cGMP) with MRP5 protein was explored using molecular docking. The results indicated that the MRP5 mRNA and protein levels were significantly reduced in all the MIA Paca2 and PANC1 clones. MRP5 affected gemcitabine cytotoxicity and the rate of gemcitabineinduced apoptosis. Silencing MRP5 decreased cell proliferation and migration in both MIA Paca2 and PANC1 cells. Docking studies showed high binding affinity of cGMP towards MRP5, indicating the potential of MRP5mediated cGMP accumulation in the microenvironment. In conclusion, MRP5 has an important role in cancer proliferation and migration in addition to its drug efflux functions in two widely available pancreatic tumour cell lines (MIA Paca2 and PANC1).
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Gemcitabina , Neoplasias Pancreáticas , Humanos , Desoxicitidina , Simulación del Acoplamiento Molecular , Resistencia a Antineoplásicos/genética , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Proliferación Celular , Línea Celular Tumoral , Resistencia a Múltiples Medicamentos/genética , ARN Mensajero , Microambiente Tumoral , Neoplasias PancreáticasRESUMEN
Type II topoisomerases (TOP2) form transient TOP2 cleavage complexes (TOP2ccs) during their catalytic cycle to relieve topological stress. TOP2ccs are covalently linked TOP2-DNA intermediates that are reversible but can be trapped by TOP2 poisons. Trapped TOP2ccs block transactions on DNA and generate genotoxic stress, which are the mechanisms of action of TOP2 poisons. How cells avoid TOP2cc accumulation remains largely unknown. In this study, we uncovered RAD54 like 2 (RAD54L2) as a key factor that mediates a TOP2-specific DNA damage avoidance pathway. RAD54L2 deficiency conferred unique sensitivity to treatment with TOP2 poisons. RAD54L2 interacted with TOP2A/TOP2B and ZATT/ZNF451 and promoted the turnover of TOP2 from DNA with or without TOP2 poisons. Additionally, inhibition of proteasome activity enhanced the chromatin binding of RAD54L2, which in turn led to the removal of TOP2 from chromatin. In conclusion, we propose that RAD54L2-mediated TOP2 turnover is critically important for the avoidance of potential TOP2-linked DNA damage under physiological conditions and in response to TOP2 poisons.
Asunto(s)
Venenos , ADN-Topoisomerasas de Tipo II/genética , Daño del ADN , Reparación del ADN , ADN/química , Cromatina/genéticaRESUMEN
A novel gene (BbFFase9), with an ORF of 1557 bp that encodes ß-d-fructofuranosidase from Bifidobacteriaceae bacterium, was cloned and expressed in Escherichia coli. The recombinant protein (BbFFase9) was successfully purified and showed a single band with a molecular mass of 66.2 kDa. This was confirmed as a ß-d-fructofuranosidase and exhibited a high specific activity of 209.2 U/mg. Although BbFFase9 was a soluble protein, it exhibited excellent tolerance to proteases such as pepsin, trypsin, acidic protease, neutral protease and Flavourzyme®, indicating its potential applicability in different fields. BbFFase9 exhibited typical invertase activity, and highly catalyzed the hydrolysis of the α1â2ß glycosidic linkage in molecules containing fructosyl moieties but with no detectable fructosyltransferase activity. It was optimally active at pH 6.5 and 50 °C and stable between pH 6.0 and 9.0 at a temperature of up to 45 °C for 30 min BbFFase9 could also effectively hydrolyze galacto-oligosaccharides, which are a flatulence factor in soybean meal, thus releasing new types of product such as melibiose and mannotriose, or degrading them into invert sugars, the sweeter fructose and glucose. This study is the first to report the application of this type of ß-d-fructofuranosidase.
RESUMEN
Walnuts are one of the world's most important nut species and are popular for their high nutritional value, but the processing of walnuts produces numerous by-products. Among them, Diaphragma Juglandis Fructus has attracted the attention of researchers due to its complex chemical composition and diverse bioactivities. However, comprehensive reviews of extract activity and mechanistic studies, chemical composition functionality, and product types are scarce. Therefore, the aim of this review is to analyze the extracts, chemical composition, and product development of Diaphragma Juglandis Fructus. Conclusions: For extracts, the biological activities of aqueous and ethanol extracts have been studied more extensively than those of methanol extracts, but almost all of the studies have been based on crude extracts, with fewer explorations of their mechanisms. For chemical composition, the bioactivities of polyphenols and polysaccharides were more intensively studied, while other chemical constituents were at the stage of content determination. For product development, walnuts are mainly used in food and medicine, but the product range is limited. In the future, research on the bioactivity and related mechanisms of Diaphragma Juglandis Fructus can be further expanded to improve its value as a potential natural plant resource applied in multiple industries.