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The 2003 severe acute respiratory syndrome coronavirus (SARS-CoV-1) causes more severe disease than SARS-CoV-2, which is responsible for COVID-19. However, our understanding of antibody response to SARS-CoV-1 infection remains incomplete. Herein, we studied the antibody responses in 25 SARS-CoV-1 convalescent patients. Plasma neutralization was higher and lasted longer in SARS-CoV-1 patients than in severe SARS-CoV-2 patients. Among 77 monoclonal antibodies (mAbs) isolated, 60 targeted the receptor-binding domain (RBD) and formed 7 groups (RBD-1 to RBD-7) based on their distinct binding and structural profiles. Notably, RBD-7 antibodies bound to a unique RBD region interfaced with the N-terminal domain of the neighboring protomer (NTD proximal) and were more prevalent in SARS-CoV-1 patients. Broadly neutralizing antibodies for SARS-CoV-1, SARS-CoV-2, and bat and pangolin coronaviruses were also identified. These results provide further insights into the antibody response to SARS-CoV-1 and inform the design of more effective strategies against diverse human and animal coronaviruses.
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COVID-19 , Animales , Humanos , Anticuerpos Antivirales , Formación de Anticuerpos , SARS-CoV-2 , Anticuerpos NeutralizantesRESUMEN
SignificanceSARS-CoV-2 continues to evolve through emerging variants, more frequently observed with higher transmissibility. Despite the wide application of vaccines and antibodies, the selection pressure on the Spike protein may lead to further evolution of variants that include mutations that can evade immune response. To catch up with the virus's evolution, we introduced a deep learning approach to redesign the complementarity-determining regions (CDRs) to target multiple virus variants and obtained an antibody that broadly neutralizes SARS-CoV-2 variants.
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Anticuerpos ampliamente neutralizantes/inmunología , COVID-19/inmunología , SARS-CoV-2/inmunología , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Anticuerpos ampliamente neutralizantes/farmacología , Vacunas contra la COVID-19/inmunología , Regiones Determinantes de Complementariedad , Aprendizaje Profundo , Epítopos/inmunología , Humanos , Inmunoterapia/métodos , Pruebas de Neutralización/métodos , Dominios Proteicos , SARS-CoV-2/patogenicidad , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/inmunologíaRESUMEN
This study employs Reflexive Thematic Analysis to explore youth expressions of suicide on Bilibili, a video platform popular among young audiences. By analyzing comments from three vloggers who died by suicide, the research identified 42 initial codes, leading to 19 themes and seven sub-themes, categorized into three main domains: Perspectives on Suicide, Perspectives on Life, and Perspectives on Death. The "Perspectives on Suicide" domain mainly includes individual assessments, attitudes toward suicide, and attributions of suicide behaviors. "Perspectives on Life" encompasses insights shaped by personal experiences, whereas discussions on death, less frequent, focus on perceptions of death and assumptions about the afterlife. The content reflects a blend of traditional Chinese views and a noticeable shift toward individualism, with the internet playing a significant role in stimulating discussions on suicide and facilitating the expression and exchange of related views. These findings provide critical insights for organizations developing effective suicide prevention strategies.
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Cancer immune escape, metastasis, recurrence, and multidrug resistance are all associated with hypoxia in the tumor microenvironment (TME). We synthesized a CuPPaCC conjugate for reactive oxygen species (ROS)-mediated cancer therapy. CuPPaCC continuously produced cytotoxic ROS and oxygen through a photo-chemocycloreaction, alleviated hypoxia, and inhibited the expression of a hypoxia-inducing factor (HIF-1α). CuPPaCC was synthesized from pyromania phyllophyllic acid a (PPa), cystine (CC), and copper ions, and its structure was characterized by nuclear magnetic resonance (NMR) and mass spectrometry (MS). The ability of CuPPaCC to produce ROS and oxygen after photodynamic therapy (PDT) in vitro and in vivo was investigated. The ability of CuPPaCC to consume glutathione was investigated. CuPPaCC toxicity (light and dark) in CT26 cells was analyzed by MTT and live/dead cell staining. The anticancer effect of CuPPaCC in vivo was investigated in CT26 Balb/c mice. When stimulated by the TME, CuPPaCC released Cu2+ and PPaCC, and the singlet oxygen yield increased from 34 to 56.5%. The dual ROS-generating mechanism via a Fenton-like reaction/photoreaction and dual glutathione depletion via Cu2+/CC multiplied the antitumor efficacy of CuPPaCC. The photo-chemocycloreaction continued to produce oxygen and maintained high ROS levels even after PDT, significantly alleviating hypoxia in the TME and downregulating the expression of HIF-1α. CuPPaCC thus showed excellent antitumor activity in vitro and in vivo. These results showed that the strategy could be effective in improving the antitumor efficacy of CuPPaCC and could be used as a synergistic regimen for cancer therapy.
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Neoplasias , Fotoquimioterapia , Animales , Ratones , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/uso terapéutico , Fármacos Fotosensibilizantes/química , Cobre/química , Cistina/farmacología , Cistina/uso terapéutico , Especies Reactivas de Oxígeno/metabolismo , Línea Celular Tumoral , Fotoquimioterapia/métodos , Neoplasias/tratamiento farmacológico , Oxígeno , Hipoxia/tratamiento farmacológico , Oxígeno Singlete , Glutatión/metabolismo , Microambiente TumoralRESUMEN
The aim of this study is to investigate the effects of Gynostemma pentaphyllum dried with two different methods(air drying and heating) on inflammation in acute lung injury(ALI) mice in vivo and in vitro. Lipopolysaccharide(LPS) was sprayed into the airway of wild type C57BL/6J male mice to establish the model, and the drug was injected into the tail vein 24 h after modeling. Lung function, lung tissue wet/dry weight(W/D) ratio, the total protein concentration, interleukin 6(IL-6), IL-1ß, and tumor necrosis factor-α(TNF-α) in the bronchoalveolar lavage fluid(BALF), and pathological changes of the lung tissue were used to evaluate the effects of different gypenosides on ALI mice. The results showed that total gypenosides(YGGPs) and the gypenosides substituted with one or two glycosyl(GPs_(1-2)) in the air-dried sample improved the lung function, significantly lowered the levels of IL-1ß and TNF-α in BALF, and alleviated the lung inflammation of ALI mice. Moreover, GPs_(1-2) had a more significant effect on inhibiting NO release in RAW264.7 cells. This study showed that different drying methods affected the anti-inflammatory activity of G. pentaphyllum, and the rare saponins in the air-dried sample without heating had better anti-inflammatory activity.
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Gynostemma , Factor de Necrosis Tumoral alfa , Masculino , Ratones , Animales , Factor de Necrosis Tumoral alfa/metabolismo , Ratones Endogámicos C57BL , Pulmón , Antiinflamatorios/farmacología , Antiinflamatorios/metabolismo , Interleucina-6/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Lipopolisacáridos/farmacologíaRESUMEN
Gold nanoclusters (AuNCs) have shown promising applications in biotherapy owing to their ultrasmall size and unique molecular-like properties. In order to better guide the preparations and applications of AuNCs, dihydrolipoic acid-protected AuNCs (DHLA-AuNCs) and glutathione-protected AuNCs (GSH-AuNCs) were selected as models and the interactions between them and calf thymus DNA (ctDNA) were studied in detail. The results showed that there was a small difference in the binding mechanisms and forces between both AuNCs and ctDNA. The quenching mechanisms of both AuNCs to (ctDNA-HO) were completely different. The binding constants indicated that the binding strength between DHLA-AuNCs and ctDNA was greater than those of GSH-AuNCs. The conformation investigations showed that GSH-AuNCs had a greater impact on the conformation of ctDNA, and both AuNCs were more inclined to interact with the A-T base pairs of ctDNA. These results indicate that the surface ligand had a significant effect on the interactions between AuNCs and DNA and might also further affect the applications of AuNCs, and these results could guide the preparations of AuNCs. For DHLA-AuNCs, their good biocompatibility made them a potential candidate for application in imaging, drug treatment, sensing, and so on. The resulting base accumulation of ctDNA and weak interactions made GSH-AuNCs have great potential for application in gene therapy, which was consistent with the current reports on the applications of these two AuNCs. This work has pointed out the directions for the preparations and applications of AuNCs.
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Nanopartículas del Metal , Preparaciones Farmacéuticas , Glutatión , OroRESUMEN
In the era of social media, the influence of food exploration bloggers is increasingly apparent. Sharing their culinary experiences stimulates the audience's interest in visiting and consuming food destinations. This paper seeks to understand how the characteristics of food exploration bloggers on the Douyin platform influence audience perceptions of food and locations and how these perceptions may relate to visiting intentions, using the stimulus-organism-response (SOR) model. A cross-sectional online survey analyzed responses from 437 individuals interested in food exploration videos on Douyin. The results indicate that source credibility is significantly associated with the stimulation of taste desires and the formation of taste awareness. The audience's taste desire and taste awareness are positively linked to the intention to visit. This study contributes to the expansion of the SOR model's application in digital media, underscoring the substantial role of social media in influencing audience consumption intentions. It highlights that as an effective communication tool, social media can significantly impact users' behavioral responses and consumption decisions.
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Bacterial hemoglobins play important roles inside the cell. Phylogenetically, they belong to three different families: the single domain hemoglobin, flavohemoglobin and truncated hemoglobin. Vitreoscilla hemoglobin (VHb) is the first characterized bacterial hemoglobin, and belongs to the single domain hemoglobin family. Heterologous expression of VHb promotes the growth of host cells under microaerobic conditions, and enhances the yield of products during fermentation. Although VHb has been widely applied in the biotechnology field, other bacterial hemoglobins have not demonstrated similar applications. In this study, we identified four bacterial hemoglobins from the microaerobic growing bacterium Sphaerotilus natans, including one flavohemoglobins (FHB) and three truncated hemoglobins (THB1, THB2 and THB3). Absorption spectrum studies validate the existent of the Soret peak and Q-band characteristic to heme and suggest heme groups in FHB and THB1 are hexa- or penta-coordinated, respectively. Our studies demonstrate that FHB and all three truncated hemoglobins have NADH oxidation and radical production activities, which is surprising since truncated hemoglobins do not have a reductase domain that could bind NADH. However, the M. tuberculosis HbN does not show these activities, indicating they are not universal among truncated hemoglobins. Docking studies suggest the nicotinamide ring of NADH may bind to the distal heme pocket of THB1, suggesting the direct electron transfer from NADH to heme might be possible. Our truncated hemoglobins also show peroxidase activities that in THB2 and THB3 could be inhibited by FdR, indicating possible interactions between FdR and truncate hemoglobins. Expression of FHB and THB1 in E. coli could promote cell growth. THB1 also enhances the production of limonene in an engineered E. coli strain, while VHb does not have this effect, which suggests that studies on truncated hemoglobins may lead to the discovery of new and more powerful tools that could have profound impact on biotechnology.
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Escherichia coli , Hemoglobinas Truncadas , Humanos , Hemoglobinas Truncadas/genética , Hemoglobinas Truncadas/metabolismo , Escherichia coli/metabolismo , Limoneno , NAD/metabolismo , Hemoglobinas/genética , Hemoglobinas/metabolismo , Proteínas Bacterianas/metabolismo , Hemo/metabolismoRESUMEN
BACKGROUND: NOP2/Sun domain 2 (NSUN2) is one of the important RNA methyltransferases catalyzing 5-methylcytosine (m5C) formation and participates in many critical bioprocesses. However, the roles and underlying molecular mechanisms of NSUN2-mediated m5C modification in colorectal cancer (CRC) remain unclear. METHODS: To explore the NSUN2 expression in CRC, fresh tissue samples were collected and Nsun2 knockout mouse was constructed. In vitro and in vivo functional assays were conducted to assess the role of NSUN2. RNA array and bisulfite sequencing were used to investigate the potential targets. The mechanisms of NSUN2 function on SKIL were identified by m5C-methylated-RNA immunoprecipitation and RNA stability assays. Additionally, tissue microarray analysis was conducted and patient-derived tumour xenograft mouse (PDX) models were used to define the potential therapeutic targets. RESULTS: NSUN2 was highly expressed in CRC and correlated with poor CRC patient survival. Moreover, silencing NSUN2 suppressed CRC tumourigenesis and progression in Nsun2 knockout mouse models. In vitro and in vivo studies suggested that NSUN2 promoted colorectal cancer cell growth. Mechanistically, SKI-like proto-oncogene (SKIL) is positively regulated by NSUN2, and the NSUN2-SKIL axis is clinically relevant to CRC. NSUN2 induced m5C modification of SKIL and stabilized its mRNA, which was mediated by Y-box binding protein 1 (YBX1). Elevated SKIL levels increased transcriptional coactivator with PDZ-binding motif (TAZ) activation. CONCLUSIONS: Our findings highlight the importance of NSUN2 in the initiation and progression of CRC via m5C-YBX1-dependent stabilization of the SKIL transcript, providing a promising targeted therapeutic strategy for CRC.
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Neoplasias Colorrectales , Metiltransferasas , Animales , Humanos , Ratones , Neoplasias Colorrectales/patología , Péptidos y Proteínas de Señalización Intracelular , Metiltransferasas/genética , Ratones Noqueados , Proteínas Proto-Oncogénicas , ARN , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
Surfactants have been widely used as effective additives to increase the solubility and dissolution rates of amorphous solid dispersions (ASDs). However, they may also generate adverse effects on the physical stability of ASDs. In this study, we systematically investigated the impacts of poloxamer, a frequently used surfactant, on the crystallization of amorphous clotrimazole (CMZ). The added poloxamer significantly decreased the glass transition temperature (Tg) of CMZ and accelerated the growth of Form 1 and Form 2 crystals. It was found that the poloxamer had an accelerating effect on Form 1 and Form 2 but showed a larger accelerating effect on Form 1, which resulted from a combined effect of increased mobility and local phase separation at the crystal-liquid interface. Additionally, the added poloxamer exhibited different effects on nucleation of the CMZ polymorphs, which was more complicated than crystal growth. The nucleation rate of Form 1 was significantly increased by the added poloxamer, and the effect increased with increasing P407 content. However, for Form 2, nucleation was slightly decreased or unchanged. The nucleation of Form 2 may have been influenced by the Form 1 crystallization, and Form 2 converted to Form 1 during nucleation. This study increases our understanding of poloxamer and its impacts on the melt crystallization of drugs.
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Gastric cancer (GC), one of the most common malignant tumors in the world, exhibits a rapid metastasis rate and causes high mortality. Diagnostic markers and potential therapeutic targets for GCs are urgently needed. Here we show that Actin-like protein 6 A (ACTL6A), encoding an SWI/SNF subunit, is highly expressed in GCs. ACTL6A is found to be critical for regulating the glutathione (GSH) metabolism pathway because it upregulates γ-glutamyl-cysteine ligase catalytic subunit (GCLC) expression, thereby reducing reactive oxygen species (ROS) levels and inhibiting ferroptosis, a regulated form of cell death driven by the accumulation of lipid-based ROS. Mechanistic studies show that ACTL6A upregulates GCLC as a cotranscription factor with Nuclear factor (erythroid-derived 2)-like 2 (NRF2) and that the hydrophobic region of ACTL6A plays an important role. Our data highlight the oncogenic role of ACTL6A in GCs and indicate that inhibition of ACTL6A or GCLC could be a potential treatment strategy for GCs.
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Ferroptosis , Neoplasias Gástricas , Humanos , Especies Reactivas de Oxígeno/metabolismo , Neoplasias Gástricas/genética , Ferroptosis/genética , Factores de Transcripción , Glutatión , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Actinas , Proteínas Cromosómicas no Histona/metabolismo , Proteínas de Unión al ADN/metabolismoRESUMEN
Metabolic reprogramming can contribute to colorectal cancer progression and therapy resistance. Identification of key regulators of colorectal cancer metabolism could provide new approaches to improve treatment and reduce recurrence. Here, we demonstrate a critical role for the COP9 signalosome subunit CSN6 in rewiring nucleotide metabolism in colorectal cancer. Transcriptomic analysis of colorectal cancer patient samples revealed a correlation between CSN6 expression and purine and pyrimidine metabolism. A colitis-associated colorectal cancer model established that Csn6 intestinal conditional deletion decreased tumor development and altered nucleotide metabolism. CSN6 knockdown increased the chemosensitivity of colorectal cancer cells in vitro and in vivo, which could be partially reversed with nucleoside supplementation. Isotope metabolite tracing showed that CSN6 loss reduced de novo nucleotide synthesis. Mechanistically, CSN6 upregulated purine and pyrimidine biosynthesis by increasing expression of PHGDH, a key enzyme in the serine synthesis pathway. CSN6 inhibited ß-Trcp-mediated DDX5 polyubiquitination and degradation, which in turn promoted DDX5-mediated PHGDH mRNA stabilization, leading to metabolic reprogramming and colorectal cancer progression. Butyrate treatment decreased CSN6 expression and improved chemotherapy efficacy. These findings unravel the oncogenic role of CSN6 in regulating nucleotide metabolism and chemosensitivity in colorectal cancer. SIGNIFICANCE: CSN6 deficiency inhibits colorectal cancer development and chemoresistance by downregulating PHGDH to block nucleotide biosynthesis, providing potential therapeutic targets to improve colorectal cancer treatment.
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Neoplasias Colorrectales , Resistencia a Antineoplásicos , Humanos , Complejo del Señalosoma COP9/genética , Complejo del Señalosoma COP9/metabolismo , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Pirimidinas , Nucleótidos , ARN Helicasas DEAD-boxRESUMEN
Purpose: To construct humanistic nursing practice guidelines suitable for stroke patients. Design: This study was a development and validation study of guidelines using multiple methods, including literature review, qualitative research, questionnaire survey, thematic discussion, and Delphi expert consultation. Methods: Twenty-five experts from seven provinces and municipalities in China were interviewed over two rounds from December 2020 to February 2021. The first-level index was scored for importance and rationality, while the second-level index was scored for importance and feasibility using a five-point Likert scale. Delphi data was collected via a paper version of the questionnaire. The coefficients of variation and coordination were used to represent the degree of dispersion of expert opinions. Findings: In the two rounds of letter consultation, the questionnaire's recovery and effective rates were both 100%, while the opinion submission rates of the two rounds were 84 and 52%, respectively. Moreover, the expert authority coefficient was 0.91, and the coordination coefficients of expert opinions in the first round were as follows: importance of 0.03 and rationality of 0.07 for the first-level index; importance of 0.09 and feasibility of 0.11 for the secondary index. In round two, the coordination coefficients of expert opinions were as follows: importance of 0.04 and rationality of 0.05 for the first-level indicators; importance of 0.12 and feasibility of 0.10 for the secondary index. The results for the secondary index were P < 0.001 for the two rounds. The humanistic nursing practice guidelines for stroke patients that were ultimately formed included five first-level indicators (physiological care, safety care, emotional care, dignity care, and rehabilitation needs) and 46 s-level indicators. Conclusion: Our results show that the "Practice Guidelines for Humanistic Nursing for Stroke" established by experts adopts Maslow's hierarchy of needs as its structural framework. It meets people's basic needs and can provide a reference for the construction of a humanistic nursing specialty practice for stroke patients. Clinical relevance: Humanistic nursing guidelines for stroke could provide a reference for the construction of humanistic nursing practice in the stroke specialty. Clinical resources: Copeptin and long-term risk of recurrent vascular events after transient ischemic attack and ischemic stroke: population-based study https://pubmed.ncbi.nlm.nih.gov/26451023/. Effectiveness and usage of a decision support system to improve stroke prevention in general practice: a cluster randomized controlled trial https://pubmed.ncbi.nlm.nih.gov/28245247/. Guidelines for adult stroke rehabilitation and recovery: a guideline for healthcare professionals from the American Heart Association/American Stroke Association https://pubmed.ncbi.nlm.nih.gov/27145936/.
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Derivación y Consulta , Accidente Cerebrovascular , Adulto , China , Técnica Delphi , Humanos , Accidente Cerebrovascular/terapia , Encuestas y Cuestionarios , Estados UnidosRESUMEN
BAF53A, an important subunit of the SWI/SNF epigenetic chromatin regulatory complex, has been implicated as the driver of diverse cancers. However, the role of BAF53A in colorectal cancer (CRC) remains poorly understood. Here, we examined the expression of BAF53A in CRC samples and observed that BAF53A was significantly upregulated in CRC tissues compared with paired adjacent normal tissues. In vitro and in vivo studies suggested that ectopic expression of BAF53A promoted colorectal cancer cell proliferation, colony formation, and tumorigenesis, whereas knockdown of BAF53A hindered these cellular functions. DUSP5 (dual-specificity phosphatase 5), an ERK1/2-specific endogenous phosphatase, was expressed at low levels in CRC. We found a negative correlation between BAF53A and DUSP5 expression in a set of CRC samples. Mechanistic studies revealed that P63 was a potential transcription repressor of DUSP5. BAF53A could interact with P63, decreasing the DUSP5 expression level and subsequently promoting ERK1/2 phosphorylation. Thus, our study provides insights into the applicability of the BAF53A-DUSP5-ERK1/2 axis as a potential therapeutic target in CRC.
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Proteínas Cromosómicas no Histona , Neoplasias Colorrectales , Fosfatasas de Especificidad Dual , Humanos , Proliferación Celular , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Fosfatasas de Especificidad Dual/genética , Fosfatasas de Especificidad Dual/metabolismo , Fosforilación , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteínas Cromosómicas no Histona/metabolismoRESUMEN
Chemoresistance limits treatment outcomes in colorectal cancer (CRC) patients. A dimeric metabolite of indole-3-carbinol, 3,3'-diindolylmethane (DIM) is abundant in cruciferous vegetables and has shown anticancer efficacy. The role of DIM in regulating chemosensitivity in CRC remains unknown. In this study, we demonstrated that DIM treatment inhibits the malignant progression of CRC. RNA sequencing indicated that pyrimidine synthesis genes are attenuated by DIM treatment. Stable 13C-labeled glucose tracing revealed that DIM inhibits de novo pyrimidine biosynthesis in CRC. DIM increases 5-FU cytotoxicity in CRC via regulation of the expression of pyrimidine metabolism-related genes. DIM synergizes with 5-FU to enhance its inhibitory effects on CRC both in vivo and in vitro. Our results suggest that DIM improves the therapeutic outcomes of FU-based chemotherapy in CRCs by inhibiting pyrimidine metabolism, identifying a new strategy for clinical therapy.
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As SARS-CoV-2 Omicron and other variants of concern (VOCs) continue spreading worldwide, development of antibodies and vaccines to confer broad and protective activity is a global priority. Here, we report on the identification of a special group of nanobodies from immunized alpaca with potency against diverse VOCs including Omicron subvariants BA.1, BA.2 and BA.4/5, SARS-CoV-1, and major sarbecoviruses. Crystal structure analysis of one representative nanobody, 3-2A2-4, discovers a highly conserved epitope located between the cryptic and the outer face of the receptor binding domain (RBD), distinctive from the receptor ACE2 binding site. Cryo-EM and biochemical evaluation reveal that 3-2A2-4 interferes structural alteration of RBD required for ACE2 binding. Passive delivery of 3-2A2-4 protects K18-hACE2 mice from infection of authentic SARS-CoV-2 Delta and Omicron. Identification of these unique nanobodies will inform the development of next generation antibody therapies and design of pan-sarbecovirus vaccines.
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COVID-19 , Camélidos del Nuevo Mundo , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo , Anticuerpos de Dominio Único , Animales , Ratones , SARS-CoV-2 , Enzima Convertidora de Angiotensina 2 , COVID-19/prevención & control , Anticuerpos Neutralizantes , Glicoproteína de la Espiga del Coronavirus , Anticuerpos AntiviralesRESUMEN
This study was to evaluate the antifatigue effect of T. heterochaetus and explore the underlying mechanism of action. T. heterochaetus extract was treated to mice for 28 days. On the 28th day, after weight loaded swimming test. The levels of antioxidant enzymes and levels of pro- and anti-inflammatory cytokines in the liver and muscles of exercised mice were evaluated. mRNA and protein expression levels of Nrf2, SOD, HO-1, and Keap-1 were evaluated using RT-PCR and western blot analysis. The low (2.70 mg/0.5 ml/20 g) and medium (5.41 mg/0.5 ml/20 g) dose enhanced the activities of antioxidant enzymes like SOD, CAT and GPx in the liver and skeletal muscle thereby enhancing the antifatigue effect. The low and medium doses showed good anti-inflammatory effects by evaluating the levels of pro and anti-inflammatory cytokines such as TNF-α, IL-1ß, IL-6, and IL-10 both in the liver and skeletal muscle. Furthermore, RT-PCR and western blot analysis showed increased expression of HO-1, SOD, Nrf2, and decreased expression of Keap-1 gene and proteins in liver and skeletal muscle of T. heterochaetus treated group mice. The current results indicate that T. heterochaetus exert the antifatigue effect through attenuating oxidative stress injury and inflammatory responses through the Nrf2/ARE-mediated signaling pathway.
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Antioxidantes/metabolismo , Fatiga Muscular/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Poliquetos/química , Transducción de Señal/efectos de los fármacos , Extractos de Tejidos/farmacología , Animales , Animales no Consanguíneos , Western Blotting , Relación Dosis-Respuesta a Droga , Hígado/efectos de los fármacos , Ratones , Músculo Esquelético/efectos de los fármacos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , NataciónRESUMEN
BACKGROUND: Colorectal cancer (CRC) is one of the most common cancers in China. However, detailed clinical characteristics and survival information are limited. This study aimed to investigate the potential epidemiological and clinical risk factors affecting the survival of CRC patients in southern China. METHODS: Patients with primary CRC between 1994 and 2019 at the First and the Sixth Affiliated Hospitals of Sun Yat-sen University (Guangzhou, China) were included. Clinical characteristics and survival outcomes were collected from medical records. The Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS), and Cox's proportional-hazards regression model was used to estimate hazard ratios and 95% confidence intervals. RESULTS: Of all 13,328 patients, 60.1% were men; the mean age was 61.3 years; 53.5% had colon cancer. Among all patients, 1,864 (14.0%) were diagnosed with stage IV disease. The 3- and 5-year OS rates were 79.90% and 71.50%, respectively, whereas the 3- and 5-year PFS rates were 70.30% and 63.90%, respectively. The median OS and PFS times were 189 and 149 months, respectively. Among 13,328 patients, 428 (14.0%) patients with poor/undifferentiated cancer suffered recurrence. In patients with stage III and stage IV diseases, the median PFS times of the patients who received chemotherapy were significantly longer than those in patients who had not received chemotherapy (stage III: 147 vs 62 months, P < 0.001; stage IV: 14 vs 9.5 months, P < 0.001). CONCLUSIONS: This retrospective cohort study illustrates the current status of the clinical characteristics of patients with CRC in southern China. Sex, age, family history, location of cancer occurrence, differentiation status, T status, N status, M status, clinical stage, operation, and surgical margin are independent factors associated with the OS of CRC patients.
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Radiation proctopathy (RP) is characterized by inflammation of colorectal tissue and is a common complication of radiation therapy for pelvic malignancies with high incidence but lacking effective treatment. Here, we found that platelet-derived growth factor C (PDGF-C) and fibrosis markers were up-regulated in tissue samples from patients with RP and in rectal tissues after irradiation in a mouse model of RP. Genetic deletion of Pdgf-c in mice ameliorated RP-induced injuries. Genome-wide gene expression profiling and in vitro assays revealed that the promotive effect of PDGF-C in RP development was mediated by activation of PDGF receptors (PDGFRs) and C-X-C motif chemokine receptor 4, a proinflammatory chemokine regulated by transcription factor ETS variant transcription factor 1. Treatment with crenolanib, a selective inhibitor of PDGFRs, prevented or reduced RP in mice after irradiation. These results reveal that inhibition of PDGF-C signaling may have therapeutic value for the treatment of RP.