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Neonicotinoid insecticides, which target insect nicotinic acetylcholine receptors (nAChRs), have been widely and intensively used to control the whitefly, Bemisia tabaci, a highly damaging, globally distributed, crop pest. This has inevitably led to the emergence of populations with resistance to neonicotinoids. However, to date, there have been no reports of target-site resistance involving mutation of B. tabaci nAChR genes. Here we characterize the nAChR subunit gene family of B. tabaci and identify dual mutations (A58T&R79E) in one of these genes (BTß1) that confer resistance to multiple neonicotinoids. Transgenic D. melanogaster, where the native nAChR Dß1 was replaced with BTß1A58T&R79E, were significantly more resistant to neonicotinoids than flies where Dß1 were replaced with the wildtype BTß1 sequence, demonstrating the causal role of the mutations in resistance. The two mutations identified in this study replace two amino acids that are highly conserved in >200 insect species. Three-dimensional modelling suggests a molecular mechanism for this resistance, whereby A58T forms a hydrogen bond with the R79E side chain, which positions its negatively-charged carboxylate group to electrostatically repulse a neonicotinoid at the orthosteric site. Together these findings describe the first case of target-site resistance to neonicotinoids in B. tabaci and provide insight into the molecular determinants of neonicotinoid binding and selectivity.
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Hemípteros , Insecticidas , Receptores Nicotínicos , Animales , Receptores Nicotínicos/genética , Insecticidas/farmacología , Hemípteros/genética , Drosophila melanogaster , Neonicotinoides/farmacología , MutaciónRESUMEN
BACKGROUND & AIMS: Natural killer (NK) cell-based anti-hepatocellular carcinoma (HCC) therapy is an increasingly attractive approach that warrants further study. Siglec-9 interacts with its ligand (Siglec-9L) and restrains NK cell functions, suggesting it is a potential therapeutic target. However, in situ Siglec-9/Siglec-9L interactions in HCC have not been reported, and a relevant interventional strategy is lacking. Herein, we aim to illustrate Siglec-9/Siglec-9L-mediated cell sociology and identify small-molecule inhibitors targeting Siglec-9 that could improve the efficacy of NK cell-based immunotherapy for HCC. METHODS: Multiplexed immunofluorescence staining was performed to analyze the expression pattern of Siglec-7, -9 and their ligands in HCC tissues. Then we conducted docking-based virtual screening combined with bio-layer interferometry assays to identify a potent small-molecule Siglec-9 inhibitor. The therapeutic potential was further evaluated in vitro and in hepatoma-bearing NCG mice. RESULTS: Siglec-9 expression, rather than Siglec-7, was markedly upregulated on tumor-infiltrating NK cells, which correlated significantly with reduced survival of patients with HCC. Moreover, the number of Siglec-9L+ cells neighboring Siglec-9+ NK cells was increased in HCC tissues and was also associated with tumor recurrence and reduced survival, further suggesting that Siglec-9/Siglec-9L interactions are a potential therapeutic target in HCC. In addition, we identified a small-molecule Siglec-9 inhibitor MTX-3937 which inhibited phosphorylation of Siglec-9 and downstream SHP1 and SHP2. Accordingly, MTX-3937 led to considerable improvement in NK cell function. Notably, MTX-3937 enhanced cytotoxicity of both human peripheral and tumor-infiltrating NK cells. Furthermore, transfer of MTX-3937-treated NK92 cells greatly suppressed the growth of hepatoma xenografts in NCG mice. CONCLUSIONS: Our study provides the rationale for HCC treatment by targeting Siglec-9 on NK cells and identifies a promising small-molecule inhibitor against Siglec-9 that enhances NK cell-mediated HCC surveillance. IMPACT AND IMPLICATIONS: Herein, we found that Siglec-9 expression is markedly upregulated on tumor-infiltrating natural killer (TINK) cells and correlates with reduced survival in patients with hepatocellular carcinoma (HCC). Moreover, the number of Siglec-9L+ cells neighboring Siglec-9+ NK cells was increased in HCC tissues and was also associated with tumor recurrence and reduced survival. More importantly, we identified a small-molecule inhibitor targeting Siglec-9 that augments NK cell functions, revealing a novel immunotherapy strategy for liver cancer that warrants further clinical investigation.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Animales , Ratones , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Recurrencia Local de Neoplasia/metabolismo , Células Asesinas Naturales/patología , Inmunoterapia , Lectinas Similares a la Inmunoglobulina de Unión a Ácido Siálico/metabolismo , Ligandos , PronósticoRESUMEN
While the evidence for the implication of opioid receptors (OPr) in ageing is growing, there is, to our knowledge, no study focusing directly on changes in vivo cutaneous OPr expression with increasing age. We thus investigated OPr expression in 30 healthy female Asian volunteers in Southern China whose ages range from the early 20s to the early 60s. Excisional biopsies were taken from the sun-exposed extensor area of the lower arm and the photo-protected area of the upper inner arm. The thickness of the epidermal layers, melanin content, as well as expression of mu-opioid receptors (MOPr) and delta-opioid receptors (DOPr) were compared between different age ranges and photo-exposure status. Significant increased epidermal hypertrophy on the extensor surface was observed. There was significant reduction of DOPr in the epidermis with increasing age, independent of photo-ageing. The increase of melanin was significantly correlated with epidermal DOPr expression, not with MOPr expression. DOPr expression could thus serve as a marker for real biological ageing unaffected by chronic photo-exposure. Additionally, DOPr expression was inversely correlated with the deposition of melanin. Based on these results, we hypothesise that regulation of DOPr expression could be used to improve aged skin, including hyperpigmentation.
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Pueblo Asiatico , Melaninas , Receptores Opioides delta , Envejecimiento de la Piel , Humanos , Femenino , Melaninas/metabolismo , Melaninas/biosíntesis , Adulto , Receptores Opioides delta/metabolismo , Persona de Mediana Edad , Adulto Joven , Epidermis/metabolismo , Receptores Opioides mu/metabolismo , ChinaRESUMEN
The 4th Davos Declaration was developed during the Global Allergy Forum in Davos which aimed to elevate the care of patients with atopic dermatitis (AD) by uniting experts and stakeholders. The forum addressed the high prevalence of AD, with a strategic focus on advancing research, treatment, and management to meet the evolving challenges in the field. This multidisciplinary forum brought together top leaders from research, clinical practice, policy, and patient advocacy to discuss the critical aspects of AD, including neuroimmunology, environmental factors, comorbidities, and breakthroughs in prevention, diagnosis, and treatment. The discussions were geared towards fostering a collaborative approach to integrate these advancements into practical, patient-centric care. The forum underlined the mounting burden of AD, attributing it to significant environmental and lifestyle changes. It acknowledged the progress in understanding AD and in developing targeted therapies but recognized a gap in translating these innovations into clinical practice. Emphasis was placed on the need for enhanced awareness, education, and stakeholder engagement to address this gap effectively and to consider environmental and lifestyle factors in a comprehensive disease management strategy. The 4th Davos Declaration marks a significant milestone in the journey to improve care for people with AD. By promoting a holistic approach that combines research, education, and clinical application, the Forum sets a roadmap for stakeholders to collaborate to improve patient outcomes in AD, reflecting a commitment to adapt and respond to the dynamic challenges of AD in a changing world.
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Phosphatase and tensin homolog (PTEN) loss tightly correlates with prostate cancer (PCa) progression and metastasis. Inactivation of PTEN leads to abnormal activation of PI3K/AKT pathway. However, results from clinical trials with AKT inhibitors in PCa have been largely disappointing. Identification of novel regulators of PTEN in PTEN-dysfunctional PCa is urgently needed. Here we demonstrated that the expression level of PTEN is inversely correlated with the signature score of unfolded protein response (UPR) in PCa. Importantly, PTEN suppresses the activity of ATF6α, via interacting to de-phosphorylate ATF6α and consequently inhibiting its nuclear translocation. Conversely, ATF6α promotes the ubiquitination and degradation of PTEN by inducing CHIP expression. Thus, ATF6α and PTEN forms a negative feedback loop during PCa progression. Combination of ATF6α inhibitor with AKT inhibitor suppresses tumor cell proliferation and xenograft growth. Importantly, this study highlighted ATF6α as a therapeutic vulnerability in PTEN dysfunctional PCa.
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Fosfatidilinositol 3-Quinasas , Neoplasias de la Próstata , Masculino , Humanos , Retroalimentación , Proteínas Proto-Oncogénicas c-akt , Neoplasias de la Próstata/genética , Próstata , Inhibidores de la Angiogénesis , Inhibidores de Proteínas Quinasas , Fosfohidrolasa PTEN/genéticaRESUMEN
The study investigated the protective effect and mechanism of 2-phenylethyl-beta-glucopyranoside(Phe) from Huaizhong No.1 Rehmannia glutinosa on hypoxic pulmonary hypertension(PH), aiming to provide a theoretical basis for clinical treatment of PAH. Male C57BL/6N mice were randomly divided into normal group, model group, positive drug(bosentan, 100 mg·kg~(-1)) group, and low-and high-dose Phe groups(20 and 40 mg·kg~(-1)). Except for the normal group, all other groups were continuously subjected to model induction in a 10% hypoxic environment for 5 weeks, with oral administration for 14 days starting from the 3rd week. The cardiopulmonary function, right ventricular pressure, cough and asthma index, lung injury, cell apoptosis, oxidative stress-related indicators, immune cells, and phosphatidylinositol 3-kinase(PI3K)/protein kinase B(Akt)/mammalian target of rapamycin(mTOR)/hypoxic inducible factor 1α(HIF-1α) pathway-related proteins or mRNA levels were examined. Furthermore, hypoxia-induced pulmonary arterial smooth muscle cell(PASMC) were used to further explore the mechanism of Phe intervention in PH combined with PI3K ago-nist(740Y-P). The results showed that Phe significantly improved the cardiopulmonary function of mice with PH, decreased right ventricular pressure, cough and asthma index, and lung injury, reduced cell apoptosis, oxidative stress-related indicators, and nuclear levels of phosphorylated Akt(p-Akt) and phosphorylated mTOR(p-mTOR), inhibited the expression levels of HIF-1α and PI3K mRNA and proteins, and maintained the immune cell homeostasis in mice. Further mechanistic studies revealed that Phe significantly reduced the viability and migration ability of hypoxia-induced PASMC, decreased the expression of HIF-1α and PI3K proteins and nuc-lear levels of p-Akt and p-mTOR, and this effect was blocked by 740Y-P. Therefore, it is inferred that Phe may exert anti-PH effects by alleviating the imbalance of oxidative stress and apoptosis in lung tissues and regulating immune levels, and its mechanism may be related to the regulation of the PI3K/Akt/mTOR/HIF-1α pathway. This study is expected to provide drug references and research ideas for the treatment of PH.
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Glucósidos , Hipertensión Pulmonar , Subunidad alfa del Factor 1 Inducible por Hipoxia , Hipoxia , Ratones Endogámicos C57BL , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Rehmannia , Serina-Treonina Quinasas TOR , Animales , Masculino , Serina-Treonina Quinasas TOR/metabolismo , Serina-Treonina Quinasas TOR/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Ratones , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/fisiopatología , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Rehmannia/química , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Glucósidos/farmacología , Hipoxia/tratamiento farmacológico , Hipoxia/fisiopatología , Hipoxia/metabolismo , Transducción de Señal/efectos de los fármacos , Humanos , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/administración & dosificación , Medicamentos Herbarios Chinos/química , Apoptosis/efectos de los fármacosRESUMEN
BACKGROUND: Immune checkpoint inhibitors (ICIs) have improved survival outcomes and resulted in long-term responses in primary liver cancer in some patients. Nevertheless, not all patients with PLC could benefit from immunotherapy. Therefore, it is necessary to identify patients suitable for such therapy. METHODS: 215 patients with primary liver cancer with immunotherapy from Nanfang Hospital were screened between August 2018 and October 2020 as a training set and our validation set included 71 patients of hepatocellular carcinoma from Jiangxi Cancer Hospital from May 2019 to July 2021. The primary endpoint was the disease control rate (DCR), and the secondary endpoints were overall survival (OS) and progression-free survival. RESULTS: In the training set, neutrophil-lymphocyte ratio (NLR) ≥3 and alpha-fetoprotein (AFP) level ≥20 ng/mL were independently associated with non-DCR in the training set after adjusting for distant metastasis at baseline and targeted therapy combination. Furthermore, a hepatic immune predictive index (HIPI) based on NLR and AFP level was developed and patients with poor HIPI associated with worse clinical outcomes. In validation set, high HIPI was associated with poor OS. CONCLUSION: HIPI, based on NLR and AFP level, is an effective indicator in ICI-treated patients with primary liver cancer. Our findings may help guide the selection and on-treatment strategies for immunotherapies for primary liver cancer patients.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , alfa-Fetoproteínas , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Linfocitos , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , PronósticoRESUMEN
BACKGROUND: There is limited data on the mechanisms of aspirin desensitization in patients with nonsteroidal anti-inflammatory drug (NSAID)-induced urticaria/angioedema (NIUA). OBJECTIVES: We sought to characterize the transcriptomic and metabolomic profiles of patients with NIUA undergoing aspirin desensitization. METHODS: PBMCs and plasma were separated from the blood of patients with NIUA undergoing aspirin desensitization for coronary artery disease and NSAID-tolerant controls. RNA was isolated from PBMCs and subjected to messenger RNA (mRNA)- and long noncoding RNA (lncRNA)-sequencing. Plasma samples were analyzed using LC-MS/MS for metabolite shifts using a semitargeted metabolomics panel. RESULTS: Eleven patients with NIUA and 10 healthy controls were recruited. The mRNA gene profiles of predesensitization versus postdesensitization and healthy control versus postdesensitization did not differ significantly. However, we identified 739 mRNAs and 888 lncRNAs as differentially expressed from preaspirin desensitization patients and controls. A 12-mRNA gene signature was trained using a machine learning algorithm to distinguish between controls, postdose, and predose samples. Ingenuity Pathway Analysis identified 5 canonical pathways that were significantly enriched in preaspirin desensitization samples. IL-22 was the most upregulated pathway. To investigate the potential regulatory roles of the differentially expressed lncRNA on the mRNAs, 9 lncRNAs and 12 mRNAs showed significantly correlated expression patterns in the IL-22 pathway. To validate the transcriptomics data, IL-22 was measured in the plasma samples of the subjects using ELISA. IL-22 was significantly higher in preaspirin desensitization patients compared with controls. In parallel, metabolomic analysis revealed stark differences in plasma profiles of preaspirin desensitization patients and healthy controls. In particular, 2-hydroxybenzoic acid (salicylic acid) was significantly lower in preaspirin desensitization patients compared with healthy controls. CONCLUSIONS: This is the first study to combine both transcriptomic and metabolomic approaches in patients with NIUA, which contributes to a deeper understanding about the pathogenesis of NIUA and may potentially pave the way toward a molecular diagnosis of NSAID hypersensitivity.
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Angioedema , Antiinflamatorios no Esteroideos , Aspirina , Urticaria , Humanos , Aspirina/efectos adversos , Cromatografía Liquida , ARN Largo no Codificante , ARN Mensajero , Espectrometría de Masas en Tándem , Antiinflamatorios no Esteroideos/efectos adversos , Urticaria/inducido químicamente , Angioedema/inducido químicamente , Desensibilización InmunológicaRESUMEN
BACKGROUND: Immune checkpoint inhibitors (ICIs) have been used to successfully treat primary liver cancer (PLC); however, identifying modifiable patient factors associated with therapeutic benefits is challenging. Obesity is known to be associated with increased survival after ICI treatment; however, the relationship between body composition (muscle, fat) and outcomes is unclear. This study aimed to evaluate the association between sarcopenia and CT-derived fat content and the prognosis of ICIs for the treatment of PLC. METHODS: In this retrospective cohort study of 172 patients with PLC, we measured the skeletal muscle index (SMI), skeletal muscle density, visceral adipose tissue index, subcutaneous adipose tissue index, total adipose tissue index (TATI), and visceral-to-subcutaneous adipose tissue area ratio using CT. In addition, we analyzed the impact of body composition on the prognosis of the patients. Multivariate Cox regression analysis was used to screen for influencing factors. RESULTS: Among the seven body composition components, low SMI (sarcopenia) and low TATI were significantly associated with poor clinical outcomes. Multivariate analysis revealed that sarcopenia (hazard ratio [HR], 5.39; 95% confidence interval [CI], 1.74-16.74; p = 0.004) was a significant predictor of overall survival (OS). Kaplan-Meier curves showed that sarcopenia and TATI were significant predictors of OS. Body mass index was not associated with survival outcomes. CONCLUSIONS: Sarcopenia and fat tissue content appear to be independently associated with reduced survival rates in patients with PLC treated with ICIs.
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Neoplasias Hepáticas , Sarcopenia , Composición Corporal/fisiología , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/tratamiento farmacológico , Pronóstico , Estudios Retrospectivos , Sarcopenia/diagnóstico por imagen , Tomografía Computarizada por Rayos XRESUMEN
To investigate the oxidative stress and adaptive compensation of kidneys in rats in high-altitude hypoxia environments, 20 Wistar rats (3 months) were randomly and equally grouped. The rats in the test group were fed in a low-pressure oxygen chamber, and those in the control group (controls) were fed in a normal environment. On the 5th, 10th, 20th, and 30th day, the excretion of uric acid in rats was detected by a biochemical analyzer, the level of desmin protein in rat podocytes was detected by immunohistochemistry, and the activity of Na+-K+- ATPase in rat proximal tubular epithelial cells was measured by liquid scintillation method. The results showed that with the increased time, the level of uric acid in the blood of rats in the test group increased dramatically (P<0.05). On the 30th day, the blood uric acid content of the test group was 52.33µmol/L, and that of the control group was 38.43µmol/L. The blood uric acid content in the test group was dramatically increased relative to the control group. Immunohistochemistry showed that the desmin protein in podocytes of the test group (0.14) was considerably higher than that in the control group (P<0.05). The Na+-K+- ATPase activity of proximal renal tubular epithelial cells in the test group was 611.2 pmol pi/mg protein/h, which was considerably lower than the versus control group (P<0.05). In summary, in high altitude hypoxia environment, uric acid accumulated in the body, and renal filtration and excretion ability was limited.
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Mal de Altura , Podocitos , Mal de Altura/metabolismo , Animales , Desmina/metabolismo , Desmina/farmacología , Hipoxia , Túbulos Renales Proximales/metabolismo , Oxígeno/metabolismo , Podocitos/metabolismo , Ratas , Ratas Wistar , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Ácido Úrico/metabolismo , Ácido Úrico/farmacologíaRESUMEN
BACKGROUND: Dyslipidemia is a significant contributor to cardiovascular and cerebrovascular diseases. Research on the relationship between breakfast consumption frequency and dyslipidemia in the working population is lacking. Therefore, we aimed to investigate this relationship based on a retrospective cohort study of a large working population in China. METHODS: This retrospective cohort study used data from the physical examinations and questionnaire survey of working participants at Nanfang Hospital from January 20, 2015 to October 16, 2020. Univariate and multivariate analyses were conducted to explore the relationship between breakfast consumption frequency and dyslipidemia in this working population (n = 7644). RESULTS: The prevalence of dyslipidemia among the participants was 26.4%. The univariate logistic regression test showed that the breakfast consumption frequency was inversely correlated with dyslipidemia. After adjusting for multiple factors, such as sex, age, body mass index, hypertension, hyperuricaemia, diabetes, smoking status, alcohol consumption, education level, marital status, long-term exposure to kitchen oil fumes, attending business dinners, and sleep time, it was found that breakfast consumption remained inversely associated with dyslipidaemia. The odds ratio for daily breakfast consumption was 0.466 (95% confidence interval 0.283-0.770, P = 0.003). After adjusting for confounding factors, we found that the higher the frequency of breakfast consumption, the lower the odds ratios for hypertriglyceridaemia. CONCLUSIONS: This study demonstrated that breakfast consumption frequency was inversely correlated with dyslipidemia. The higher the frequency of breakfast, the lower the risk of hypertriglyceridaemia. This study provides a basis on which dietary suggestions for the working population and lifestyle guidance for patients with a clinical need to prevent dyslipidemia can be made.
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Desayuno , Dislipidemias , Índice de Masa Corporal , Dislipidemias/epidemiología , Conducta Alimentaria , Humanos , Estudios RetrospectivosRESUMEN
Melampsora larici-populina (Mlp), M. medusae (Mmed), M. magnusiana (Mmag), and M. pruinosae (Mpr) are epidemic rust fungi in China. The first two are macrocyclic rust fungi distributed in temperate humid environments. The latter two are hemicyclic rusts, mainly distributed in arid and semi-arid areas. Ontogenetic variation that comes with this arid-resistance is of great interest-and may help us predict the influence of a warmer, drier, climate on fungal phylogeny. To compare the differences in the life history and ontogeny between the two types of rust, we cloned mating type genes, STE3.4 and STE3.3 using RACE-smart technology. Protein structures, functions, and mutant loci were compared across each species. We also used microscopy to compare visible cytological differences at each life stage for the fungal species, looking for variation in structure and developmental timing. Quantitative PCR technology was used to check the expression of nuclear fusion and division genes downstream of STE3.3 and STE3.4. Encoding amino acids of STE3.3 and STE3.4 in hemicyclic rusts are shorter than these in the macrocyclic rusts. Both STE3.3 and STE3.4 interact with a protein kinase superfamily member EGG12818 and an E3 ubiquitin protein ligase EGG09709 directly, and activating G-beta conformational changes. The mutation at site 74th amino acid in the conserved transmembrane domain of STE3.3 ascribes to a positive selection, in which alanine (Ala) is changed to phenylalanine (Phe) in hemicyclic rusts, and a mutation with Tyr lost at site 387th in STE3.4, where it is the binding site for ß-D-Glucan. These mutants are speculated corresponding to the insensitivity of hemicyclic rust pheromone receptors to interact with MFa pheromones, and lead to Mnd1 unexpressed in teliospora, and they result in the diploid nuclei division failure and the sexual stage missing in the life cycle. A Phylogenic tree based on STE3.4 gene suggests these two rust types diverged about 14.36 million years ago. Although these rusts share a similar uredia and telia stage, they show markedly different wintering strategies. Hemicyclic rusts overwinter in the poplar buds endophytically, their urediniospores developing thicker cell walls. They form haustoria with a collar-like extrahaustorial membrane neck and induce host thickened callose cell walls, all ontogenetic adaptations to arid environments.
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Basidiomycota , Populus , Basidiomycota/genética , Populus/genética , Populus/microbiología , Filogenia , Feromonas , China , Enfermedades de las Plantas/genética , Enfermedades de las Plantas/microbiologíaRESUMEN
Triple-negative breast cancer (TNBC) is a major challenge in clinical practice due to its aggressiveness and lack of targeted treatment. Cancer stem-like traits contribute to tumorigenesis and immune privilege of TNBC. However, the relationship of stemness and immunosurveillance remains unclear. Here, we demonstrate that BTF3 expression is related with stem-like properties in TNBC cells. BTF3 modulates stemness, migration and proliferation of TNBC in vitro. Bioinformatics analysis revealed that interferon signaling pathways and IRF7, both of which participate in the immune escape of TNBC, are closely related to BTF3 in TNBC cells. Knockdown of BTF3 activates IRF7 expression through increased degradation of BMI1, a protein that can represses IRF7 transcription by directly binding to its promotor region. BTF3 links stem-like traits and the interferon signaling pathway, revealing the potential connection of stemness and immunomodulation in TNBC. Clinically, we suggest that BTF3 is predictive of poor prognosis in patients with TNBC. Together, our findings highlight an important role of BTF3 in regulating the progression of TNBC cells.
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Interferón Tipo I/metabolismo , Proteínas Nucleares/metabolismo , Transducción de Señal , Factores de Transcripción/metabolismo , Neoplasias de la Mama Triple Negativas/metabolismo , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Factor 7 Regulador del Interferón/genética , Factor 7 Regulador del Interferón/metabolismo , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Fenotipo , Complejo Represivo Polycomb 1/metabolismo , Biosíntesis de Proteínas , ARN Mensajero/genética , ARN Mensajero/metabolismo , Resultado del Tratamiento , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/patologíaRESUMEN
Traditionally, it is theorized that skin sensation is initiated when cutaneous sensory afferents and Merkel cells receive sensory stimuli, while epidermal keratinocytes were deemed to have no role. However, mounting evidence has shown that keratinocytes can initiate skin sensation by receiving sensory stimuli and transmitting sensory information to sensory afferents. Knowledge regarding the mechanisms by which keratinocytes receive exogenous stimuli is limited, with TRP channels and olfactory receptors having been proposed to serve as receptors for exogenous stimuli in keratinocytes. Recently, expression analyses have demonstrated the expression of multiple TAS2R genes in human skin. TAS2Rs are chemosensory GPCRs employed by taste cells to detect bitter-tasting substances. However, only subtypes TAS2R1 and TAS2R38 have been characterized in epidermal keratinocytes. We present evidence suggesting that subtype TAS2R14 is functionally expressed in epidermal keratinocytes. TAS2R14 transcripts and protein were detected in primary and N/TERT-1 keratinocytes. Additionally, keratinocytes responded to α-thujone, a TAS2R14 ligand, with an increase in intracellular free Ca2+ concentration. The tastant-evoked Ca2+ signals were found to be mediated by wild-type TAS2R14 and heterotrimeric G proteins. We conclude that TAS2R14 serves as a chemosensory receptor in epidermal keratinocytes and hypothesize that it enables the cells to recognize potentially harmful chemical substances.
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Queratinocitos/metabolismo , ARN/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Monoterpenos Bicíclicos/farmacología , Calcio/metabolismo , Línea Celular , Epidermis/metabolismo , Expresión Génica , Técnicas de Inactivación de Genes , Humanos , Ligandos , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genéticaRESUMEN
Pinus bungeana is one of indigenous trees in China and widely distributed in poor and arid regions for vegetation and industrial woody use. However, since a high-incidence disease threatens the growth of mature P. bungeana tree in the garden and in the plantation every year, the overwintering shoots were infected and died in the next spring with a ratio over 70%, but the cause was beyond understood. A total of 120 fungal isolates were separated from symptomatic twigs by histological isolation methods, including Pestalotiopsis spp., Fusarium spp., Trichothecium spp., Penicillium and some unknown fungal species. Pestalotiopsis spp. was dominant, accounting for 85%. Morphological observation under microcopy showed all Pestalotiopsis species are identical, and six isolations among them were randomly selected for pathogenicity tests. Fulfilling Koch's postulates showed that all six isolates of Pestalotiopsis spp. were pathogens of twig blight, causing the same symptoms as observed in the field, while other non-Pestalotiopsis isolates were avirulent to P. bungeana twigs. Multi-gene (ITS, tub2 and TEF1) analysis and morphological observation revealed that all the six Pestalotiopsis isolates belonged to P. trachicarpicola. To our knowledge, this is the first study reporting P. trachicarpicola as the pathogens responsible for P. bungeana twig blight in China.
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Pinaceae , Pinus , China , Pestalotiopsis , Filogenia , Enfermedades de las PlantasRESUMEN
Phytohormones are a class of small organic molecules that are widely used in higher plants and microalgae as chemical messengers. Phytohormones play a regulatory role in the physiological metabolism of cells, including promoting cell division, increasing stress tolerance, and improving photosynthetic efficiency, and thereby increasing biomass, oil, chlorophyll, and protein content. However, traditional abiotic stress methods for inducing the accumulation of energy storage substances in microalgae, such as high light intensity, high salinity, and heavy metals, will affect the growth of microalgae and will ultimately limit the efficient accumulation of energy storage substances. Therefore, the addition of phytohormones not only helps to reduce production costs but also improves the efficiency of biofuel utilization. However, accurate and sensitive phytohormones determination and analytical methods are the basis for plant hormone research. In this study, the characteristics of phytohormones in microalgae and research progress for regulating the accumulation of energy storage substances in microalgae by exogenous phytohormones, combined with abiotic stress conditions at home and abroad, are summarized. The possible metabolic mechanism of phytohormones in microalgae is discussed, and possible future research directions are put forward, which provide a theoretical basis for the application of phytohormones in microalgae.
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Microalgas/metabolismo , Reguladores del Crecimiento de las Plantas/metabolismo , Biomarcadores , Biomasa , Vías Biosintéticas , Cromatografía de Gases , Cromatografía Líquida de Alta Presión , Técnicas Electroquímicas , Microalgas/química , Estrés Oxidativo , Fotosíntesis , Reguladores del Crecimiento de las Plantas/química , Especies Reactivas de Oxígeno/metabolismo , Estrés FisiológicoRESUMEN
BACKGROUND: Castrate-resistant prostate cancer (CRPC) is an aggressive and lethal disease. The pathogenesis of CRPC is not fully understood and novel therapeutic targets need to be identified to improve the patients' prognosis. MicroRNA-30a (miR-30a) has been demonstrated to be a tumor suppressor in many types of solid malignancies. However, its role in androgen-independent (AI) growth of prostate cancer (PCa) received limited attention as yet. METHODS: The clinical association of miR-30a and its potential targets with AI growth was characterized by bioinformatics analyses. Regulation of cell proliferation and colony formation rates by miR-30a were tested using PCa cell models. Xenograft models were used to measure the regulation of prostate tumor growth by miR-30a. The real-time quantitative polymerase chain reaction was used to validate whether miR-30a and its targets regulate cell cycle control genes and androgen receptor (AR)-dependent transcription. Bioinformatics tools, Western blot, and luciferase reporter assays were utilized to identify miR-30a targets. RESULTS: Bioinformatic analysis showed that low expression of miR-30a is associated with castration resistance of PCa patients and poor outcomes. Transfection of miR-30a mimics inhibited the AI growth of PCa cells in vitro and in vivo. Upregulation of miR-30a in 22RV1 cells altered the expression of cell cycle control genes and AR-mediated transcription, while downregulation of miR-30a in LNCaP cells had the opposite effects to AR-mediated transcription. MYBL2, FOXD1, and SOX4 were identified as miR-30a targets. Downregulation of MYBL2, FOXD1, and SOX4 affected the expression of cell cycle control genes and AR-mediated transcription and suppressed the AI growth of 22RV1 cells. CONCLUSIONS: Our results suggest that miR-30a inhibits AI growth of PCa by targeting MYBL2, FOXD1, and SOX4. They provide novel insights into developing new treatment strategies for CRPC.
Asunto(s)
Proteínas de Ciclo Celular/metabolismo , Factores de Transcripción Forkhead/metabolismo , MicroARNs/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/patología , Factores de Transcripción SOXC/metabolismo , Transactivadores/metabolismo , Antagonistas de Andrógenos/metabolismo , Andrógenos/metabolismo , Animales , Proteínas de Ciclo Celular/genética , Procesos de Crecimiento Celular/fisiología , Línea Celular Tumoral , Regulación hacia Abajo , Factores de Transcripción Forkhead/genética , Células HEK293 , Xenoinjertos , Humanos , Masculino , Ratones , Ratones Desnudos , MicroARNs/genética , Pronóstico , Neoplasias de la Próstata Resistentes a la Castración/genética , Receptores Androgénicos/metabolismo , Factores de Transcripción SOXC/genética , Transactivadores/genética , Regulación hacia ArribaRESUMEN
A vortex is a common ratchet phenomenon in active systems. The spatial symmetry is usually broken by introducing asymmetric shapes or spontaneously by collective motion in the presence of hydrodynamic interactions or other alignment effects. Unexpectedly, we observe, by simulations, the formation of a vortex in the simplest model of a circular obstacle immersed in a bath of spherical self-propelled particles. No symmetry-breaking factors mentioned above are included in this model. The vortex forms only when the particle activity is high, i.e. large persistence. The obstacle size is also a key factor and the vortex only forms in a limited range of obstacle sizes. The sustainment of the vortex originates from the bias of the rotating particle cluster around the obstacle in accepting the incoming particles based on their propelling directions. Our results provide new understanding of and insights into the spontaneous symmetry-breaking and ratchet phenomena in active matter.
RESUMEN
BACKGROUND: Cullin 4B (CUL4B), a scaffold protein that assembles CRL4B ubiquitin ligase complexes, is overexpressed in many types of solid tumors and contributes to epigenetic silencing of tumor suppressors. However, its clinical significance and underlying molecular mechanisms in prostate cancer (PCa) remain unknown. METHODS: The clinical significance of CUL4B in PCa was characterized by in silico method. RT-qPCR and Western blot were used to study the transcript and protein expression levels of CUL4B and C-MYC. Bioinformatics tools, chromatin immunoprecipitation (ChIP) and luciferase reporter assay were utilized to identify and characterize the microRNAs (miRNAs) regulated by CUL4B. The biological function of CUL4B and miR-33b-5p was evaluated by MTS, transwell, and wound healing assays, accordingly. RESULTS: CUL4B is significantly overexpressed in PCa tissues compared with benign prostatic tissues and its overexpression is correlated with poor prognosis. CUL4B promotes proliferation and aggressiveness of PCa cells in vitro. Mechanistically, we demonstrate that CUL4B upregulates the expression of C-MYC at post-transcriptional level through epigenetic silencing of miR-33b-5p. Importantly, CUL4B-induced oncogenic activity in PCa by targeting C-MYC is repressed by miR-33b-5p. CONCLUSIONS: Our results suggested a novel CUL4B/miR-33b/C-MYC axis implicated in PCa cell growth and progression. This might provide novel insight into how CUL4B contributed to PCa aggressiveness and progression.
Asunto(s)
Proteínas Cullin/genética , MicroARNs/genética , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Proteínas Proto-Oncogénicas c-myc/genética , Línea Celular Tumoral , Proliferación Celular/fisiología , Proteínas Cullin/biosíntesis , Progresión de la Enfermedad , Epigénesis Genética , Células HEK293 , Humanos , Masculino , MicroARNs/biosíntesis , Células PC-3 , Pronóstico , Neoplasias de la Próstata/metabolismo , Proteínas Proto-Oncogénicas c-myc/biosíntesis , Transducción de Señal , Transcripción GenéticaRESUMEN
OBJECTIVES: The predictive value of the histological parameters and molecular markers for neoadjuvant hormonal therapy (NHT) in prostate cancer (PCa) has not been well established. The aim of this study is to determine pathological variables that can predict differences in response to NHT in PCa. METHODS: A total of 85 locally high risk PCa patients with matched preoperative needle biopsies and radical prostatectomy (RP) specimens were included. All patients were treated with NHT for at least 3 months. We quantified the response to NHT using a new proposed pathological grading system. The system classified tumors into five groups (grades 0-4) according to the severity of histological response. We then categorized the PCa patients into drug-sensitive (DS) group (Grades 2-4) and drug-resistant (DR) group (Grades 0-1). Two pathologists assessed each pretreated tumors for presence or absence of nine morphological features. The expression of androgen receptor (AR), ERG, and PTEN were evaluated by immunohistochemistry (IHC) as well. Statistical analysis was performed to identify significant associations between differentially histological response to NHT and morphological features as well as molecular aberrations. We evaluated different prediction models using receiver operating characteristic (ROC) curves and area under the ROC curve (AUC) analysis. RESULTS: 73% (n = 62/85) of tumors in our cohort belonged to DS group, whereas 27% (n = 23/85) of tumors were DR. Univariate logistic analysis suggested four pathological variables, cribriform growth pattern, macronucleoli, ductal adenocarcinoma differentiation, and PTEN loss in needle biopsies were significantly associated with DR effect, all with P-value < 0.05. Multivariate logistic regression analysis revealed that the three parameters as significant predictive factors for predicting DR effect. These were macronucleoli (RR = 4.008, P = 0.002), ductal adenocarcinoma differentiation (RR = 11.659, P = 0.009) and PTEN loss expression (RR = 7.275, P = 0.015). The AUC of three integrated indicators model was 0.781. CONCLUSIONS: Our study suggested that the presence of tumor cribriform growth pattern, macronucleoli, ductal adenocarcinoma differentiation, and PTEN loss in needle biopsies are of value in predicting tumor response to NHT regimen. Multivariate logistic regression analysis revealed the performance of combined pathological indicators in predicting DR response was better than that of model based on individual factor alone.