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Farmed mammals may act as hosts for zoonotic viruses that can cause disease outbreaks in humans. This SnapShot shows which farmed mammals, and to what extent, are of particular risk of harboring and spreading viruses from viral families that are commonly associated with zoonotic disease. It also discusses genome surveillance methods and biosafety measures. To view this SnapShot, open or download the PDF.
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Viruses , Zoonoses , Animals , Humans , Mammals , Disease Outbreaks , Risk AssessmentABSTRACT
USP25 encodes ubiquitin-specific proteases 25, a key member of deubiquitinating enzyme family and is involved in neural fate determination. Although abnormal expression in Down's syndrome was reported previously, the specific role of USP25 in human diseases has not been defined. In this study, we performed trio-based whole exome sequencing in a cohort of 319 cases (families) with generalized epilepsy of unknown etiology. Five heterozygous USP25 variants including two de novo and three co-segregated variants were determined in eight individuals affected by generalized seizures and/or febrile seizures from five unrelated families. The frequency of USP25 variants showed a significantly high aggregation in this cohort compared to the East Asian population and all populations in the gnomAD database. The mean onset ages of febrile and afebrile seizures were 10 months (infancy) and 11.8 years (juvenile), respectively. The patients achieved seizure freedom except one had occasional nocturnal seizures at the last follow-up. Two patients exhibited intellectual disability. Usp25 was ubiquitously expressed in mouse brain with two peaks on embryonic days (E14âE16) and postnatal day 21, respectively. Similarly, USP25 expressed in fetus/early childhood stage with a second peak at approximately 12â20 years old in human brain, consistent with the seizure onset age at infancy and juvenile in the patients. To investigate the functional impact of USP25 deficiency in vivo, we established Usp25 knock-out mice, which showed increased seizure susceptibility compared to wild-type mice in pentylenetetrazol-induced seizure test. To explore the impact of USP25 variants, we employed multiple functional detections. In HEK293T cells, the severe phenotype associated variant (p.Gln889Ter) led to a significant reduction of mRNA and protein expressions but formed a stable truncated dimers with increment of deubiquitinating enzyme activities and abnormal cellular aggregations, indicating a gain-of-function effect. The p.Gln889Ter and p.Leu1045del increased neuronal excitability in mice brain, with a higher firing ability in p.Gln889Ter. These functional impairments align with the severity of the observed phenotypes, suggesting a genotype-phenotype correlation. Hence, a moderate association between USP25 and epilepsy was noted, indicating USP25 is potentially a predisposing gene for epilepsy. Our results from Usp25 null mice and the patient-derived variants indicated that USP25 would play epileptogenic role via loss-of-function or gain-of-function effects. The truncated variant p.Gln889Ter would have profoundly different effect on epilepsy. Together, our results underscore the significance of USP25 heterozygous variants in epilepsy, thereby highlighting the critical role of USP25 in the brain.
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BACKGROUND: IFIH1 variants have been reported to be associated with immune-related disorders with/without seizures. It is unknown whether IFIH1 variants are associated with common epilepsy without acquired causes and the mechanism underlying phenotypic variation remains elusive. METHODS: Trio-based whole-exome sequencing was performed on patients with febrile seizures or epilepsy with antecedent febrile seizures. Previously reported variants were systematically reviewed to investigate genotype-phenotype associations. RESULTS: Two de novo heterozygous and three biallelic missense variants were identified in five patients with generalised epilepsy with antecedent febrile seizures. The variants were predicted to be damaging by in silico tools and were associated with hydrogen bonding changes to neighbouring amino acids or decreased protein stability. Patients exhibited an early onset age and became seizure-free with favourable outcome. Further analysis revealed that de novo missense variants located in the Hel region resulted in seizures with multiple neurological abnormalities, while those in the pincer domain or C-terminal domain led to seizures with normal neurodevelopment, suggesting a sub-molecular effect. Biallelic missense variants, which were inherited from unaffected parents and presented low allele frequencies in general populations, were associated with seizures without neurological abnormalities. Truncation variants were related to refractory epilepsy and severe developmental delay, suggesting a genotype-phenotype correlation. IFIH1 is predominantly expressed in the neonatal stage and decreases dramatically in the adulthood, which is consistent with the early onset age and favourable outcome of the patients. CONCLUSIONS: IFIH1 variants are potentially associated with generalised epilepsy with antecedent febrile seizures. The sub-molecular implication and genotype-phenotype association help explain phenotype variations of IFIH1 variants.
Subject(s)
Epilepsy, Generalized , Exome Sequencing , Genetic Association Studies , Interferon-Induced Helicase, IFIH1 , Mutation, Missense , Seizures, Febrile , Humans , Seizures, Febrile/genetics , Epilepsy, Generalized/genetics , Male , Female , Interferon-Induced Helicase, IFIH1/genetics , Mutation, Missense/genetics , Child, Preschool , Infant , Child , Genetic Predisposition to Disease , Adult , PhenotypeABSTRACT
BACKGROUND: The ZFHX3 gene plays vital roles in embryonic development, cell proliferation, neuronal differentiation and neuronal death. This study aims to explore the relationship between ZFHX3 variants and epilepsy. METHODS: Whole-exome sequencing was performed in a cohort of 378 patients with partial (focal) epilepsy. A Drosophila Zfh2 knockdown model was used to validate the association between ZFHX3 and epilepsy. RESULTS: Compound heterozygous ZFHX3 variants were identified in eight unrelated cases. The burden of ZFHX3 variants was significantly higher in the case cohort, shown by multiple/specific statistical analyses. In Zfh2 knockdown flies, the incidence and duration of seizure-like behaviour were significantly greater than those in the controls. The Zfh2 knockdown flies exhibited more firing in excitatory neurons. All patients presented partial seizures. The five patients with variants in the C-terminus/N-terminus presented mild partial epilepsy. The other three patients included one who experienced frequent non-convulsive status epilepticus and two who had early spasms. These three patients had also neurodevelopmental abnormalities and were diagnosed as developmental epileptic encephalopathy (DEE), but achieved seizure-free after antiepileptic-drug treatment without adrenocorticotropic-hormone/steroids. The analyses of temporal expression (genetic dependent stages) indicated that ZFHX3 orthologous were highly expressed in the embryonic stage and decreased dramatically after birth. CONCLUSION: ZFHX3 is a novel causative gene of childhood partial epilepsy and DEE. The patients of infantile spasms achieved seizure-free after treatment without adrenocorticotropic-hormone/steroids implies a significance of genetic diagnosis in precise treatment. The genetic dependent stage provided an insight into the underlying mechanism of the evolutional course of illness.
Subject(s)
Epilepsies, Partial , Homeodomain Proteins , Spasms, Infantile , Animals , Child , Child, Preschool , Female , Humans , Infant , Male , Epilepsies, Partial/genetics , Epilepsies, Partial/drug therapy , Exome Sequencing , Genetic Predisposition to Disease , Homeodomain Proteins/genetics , Mutation , Spasms, Infantile/genetics , DrosophilaABSTRACT
We aimed to examine the l differences in the assessment of neurocognitive impairment (NCI) using cognitive screening tools between PLWH and HIV-negative individuals and further compare the neurocognitive profiles between the two groups. This was baseline evaluation of Pudong HIV Aging Cohort, including 465 people living with HIV (PLWH) and 465 HIV-negative individuals aged over 50 years matched by age (± 3 years), sex and education. NCI was assessed using the Chinese version of Mini-mental State Examination (MMSE), the International HIV Dementia Scale (IHDS) and Beijing version of Montreal Cognitive Assessment (MoCA). In total, 258 (55.5%), 91 (19.6%), 273 (58.7%) of PLWH were classified as having NCI by the IHDS, MMSE and MoCA, compared to 90 (19.4%), 25 (5.4%), 135 (29.0%) of HIV-negative individuals, respectively (p < 0.05); such associations remained significant in multivariable analysis. PLWH showed a larger overlap of NCI detected by IHDS, MMSE, and MoCA. IHDS and MoCA detected almost all of the NCI detected by MMSE. IHDS-motor and psychomotor speeds and MoCA-executive function showed the greatest disparities between two groups. In multivariable analysis, older age and more depressive symptoms were positively associated with NCI regardless of the screening tools or HIV serostatus. PLWH over 50 years old display a higher prevalence of NCI and distinct neurocognitive profiles compared to HIV-negative individuals, despite viral suppression. Given the more considerable overlap in NCI classification in PLWH, it is advisable to choose one screening tool such as IHDS or MoCA to identify those potentially having NCI and then refer to more comprehensive neuropsychological assessment.
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INTRODUCTION: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease caused by the SFTS virus (SFTSV), which has a wide geographic distribution. The primary clinical manifestations of SFTS are fever and thrombocytopenia, with multiorgan failure being the leading cause of death. While most patients recover with treatment, little is known about the potential long-term metabolic effects of SFTSV infection. OBJECTIVES: This study aimed to shed light on dysregulated metabolic pathways and cytokine responses following SFTSV infection, which pose significant risks to the short-term and long-term health of affected individuals. METHODS: Fourteen laboratory-confirmed clinical SFTS cases and thirty-eight healthy controls including 18 SFTSV IgG-positive and 20 IgG-negative individuals were recruited from Taizhou city of Zhejiang province, Eastern China. Inclusion criteria of healthy controls included residing in the study area for at least one year, absence of fever or other symptoms in the past two weeks, and no history of SFTS diagnosis. Ultrahigh-performance liquid chromatography-mass spectrometry (UHPLC-MS) was used to obtain the relative abundance of plasma metabolites. Short-term metabolites refer to transient alterations present only during SFTSV infection, while long-term metabolites persistently deviate from normal levels even after recovery from SFTSV infection. Additionally, the concentrations of 12 cytokines were quantified through fluorescence intensity measurements. Differential metabolites were screened using orthogonal projections to latent structures discriminant analysis (OPLS-DA) and the Wilcoxon rank test. Metabolic pathway analysis was performed using MetaboAnalyst. Between-group differences of metabolites and cytokines were examined using the Wilcoxon rank test. Correlation matrices between identified metabolites and cytokines were analyzed using Spearman's method. RESULTS AND CONCLUSIONS: We screened 122 long-term metabolites and 108 short-term metabolites by analytical comparisons and analyzed their correlations with 12 cytokines. Glycerophospholipid metabolism (GPL) was identified as a significant short-term metabolic pathway suggesting that the activation of GPL might be linked to the self-replication of SFTSV, whereas pentose phosphate pathway and alanine, aspartate, and glutamate metabolism were indicated as significant long-term metabolic pathways playing a role in combating long-standing oxidative stress in the patients. Furthermore, our study suggests a new perspective that α-ketoglutarate could serve as a dietary supplement to protect recovering SFTS patients.
Subject(s)
Cytokines , Phlebovirus , Severe Fever with Thrombocytopenia Syndrome , Humans , Severe Fever with Thrombocytopenia Syndrome/metabolism , Severe Fever with Thrombocytopenia Syndrome/virology , Cytokines/metabolism , Cytokines/blood , Middle Aged , Male , Female , Phlebovirus/metabolism , Aged , Adult , Chromatography, High Pressure Liquid , Metabolomics/methods , Case-Control Studies , Metabolic Networks and Pathways , Mass Spectrometry/methods , ChinaABSTRACT
Claudin18.2 is a tight junction protein, highly selective, generally expressed only in normal gastric mucosal epithelial cells, which can effectively maintain the polarity of epithelial and endothelial cells, thus effectively regulating the permeability and conductance of the paracellular pathway. Abnormal expression of Claudin18.2 can occur in various primary malignant tumors, especially gastrointestinal tumors, and even in metastatic foci. It regulates its expression by activating the aPKC/MAPK/AP-1 pathway, and therefore, the Claudin18.2 protein is a pan-cancer target expressed in primary and metastatic lesions in human cancer types. Zolbetuximab (IMAB362), an antibody specific for Claudin18.2, has been successfully tested in a phase III clinical trial, and the results of the study showed that combining Zolbetuximab with chemotherapy notably extends patients' survival and is expected to be a potential first-line treatment for patients with Claudin18.2(+)/HER-2(-) gastric cancer. Here, we systematically describe the biological properties and oncogenic effects of Claudin18.2, centering on its clinical-pathological aspects and the progress of drug studies in gastric cancer, which can help to further explore its clinical value.
Subject(s)
Claudins , Stomach Neoplasms , Humans , Stomach Neoplasms/drug therapy , Stomach Neoplasms/pathology , Stomach Neoplasms/metabolism , Claudins/metabolism , Claudins/geneticsABSTRACT
OBJECTIVE: To compare the impact of telerehabilitation versus conventional rehabilitation on the recovery outcomes of patients with chronic respiratory disease (CRD). METHODS: The Cochrane Library, MEDLINE, Web of Science and Embase were searched to collect randomized controlled trials (RCTs) on telerehabilitation for the rehabilitation of patients with chronic respiratory system diseases since the establishment of the database to November 14, 2023. Two researchers independently screened the literature and extracted valid data according to the inclusion criteria. The quality assessment of included studies was conducted individually by using the RoB 2(Risk of Bias 2) tool, followed by meta-analysis using RevMan5.3 software. RESULTS: Based on inclusion and exclusion criteria, 21 RCTs were included, comprising 3030 participants, with 1509 in the telerehabilitation group and 1521 in the conventional rehabilitation group. Meta-analysis results indicated that compared to conventional rehabilitation, video conference-based telerehabilitation demonstrated significant improvements in short-term (≤ 6 months) outcomes, including 6-min walk distance (6MWD) (MD = 7.52, 95% CI: 2.09, 12.94), modified Medical Research Council Dyspnea Scale (mMRC) (MD = -0.29, 95% CI: -0.41, -0.18), COPD assessment test (CAT) (MD = -1.77, 95% CI: -3.52, -0.02), HADS (MD = -0.44, 95% CI: -0.86, -0.03), and St. George's Respiratory Questionnaire (SGRQ's) activity, impact, and symptom scores. In the long term (> 6 months), although improvements persisted in 6WMD [MD = 12.89, 95% CI (-0.37, 26.14)], mMRC [MD = -0.38, 95% CI (-0.56, -0.21)], CAT [MD = -1.39, 95% CI (-3.83, 1.05)], Hospital anxiety and depression scale (HADS) [MD = -0.34, 95% CI (-0.66, -0.03)], and SGRQ's Activity, Impact, and Symptom scores between intervention and control groups, statistically significant differences were observed only for mMRC and HADS. Without considering time factors, the intervention group exhibited some improvement in FEV1% predicted and the forced expiratory volume in the first one second (FEV1)/ forced vital capacity (FVC) (%) without statistical significance compared to the control group. CONCLUSION: Telerehabilitation therapy demonstrates short-term benefits in enhancing patients' daily activity capacity, improving respiratory function, and enhancing mental health status, thereby improving patients' quality of life. However, further high-quality, large-sample RCTs are required to ascertain its long-term effectiveness conclusively. TRIAL REGISTRATION: This study protocol was approved and registered in PROSPERO: CRD 42024509154.
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Telerehabilitation , Humans , Chronic Disease , Quality of Life , Randomized Controlled Trials as Topic , Walk Test , Respiratory Tract Diseases/physiopathology , Respiratory Tract Diseases/rehabilitationABSTRACT
OBJECTIVE: The objective of this study was to elucidate the molecular mechanisms underlying the potential contribution of commonly utilized plasticizers, including Diethyl phthalate (DEP), Dimethyl phthalate (DMP), and Dioctyl phthalate (DOP), to the pathogenesis of breast cancer. This study aimed to highlight the complex interactions between these environmental chemicals and key molecular pathways implicated in tumorigenesis. METHODS: We employed network toxicology and molecular docking techniques to analyze the interactions between plasticizers and key proteins implicated in breast cancer. Utilizing databases such as the TCGA, we performed an expression analysis of selected key genes in breast cancer tissue compared to normal controls. Enrichment analysis was conducted to identify the biological pathways associated with these genes. RESULTS: Enrichment analysis highlighted the association of these plasticizer-targeted genes with pathways integral to adenocarcinoma development, suggesting a broad impact of plasticizers on hormone-dependent and other forms of cancers. Subsequent expression analysis using data from the TCGA breast cancer database indicated significant upregulation or downregulation of these genes in breast cancer tissues compared to normal controls, confirming their pivotal roles in tumor biology. Furthermore, the molecular docking analysis revealed that plasticizers, including DEP, DMP, and DOP, exhibit specific binding interactions with key proteins such as MAPK1, AKT1, SRC, ESR1, and ALB, which are crucial in the regulation of breast cancer pathogenesis. CONCLUSION: The study provides evidence that exposure to plasticizers may influence breast cancer pathogenesis through interactions with critical proteins and signaling pathways. By employing network pharmacology, protein interactions, and molecular docking, our findings highlight the potential risks posed by plasticizers. These results underscore the need for further epidemiological and clinical research to fully understand the implications of plasticizer exposure on breast cancer risk, thus informing future preventive and therapeutic strategies.
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Diffuse large B cell lymphoma (DLBCL) is a common and aggressive form of B cell lymphoma. Approximately 40% of DLBCL patients are incurable despite modern therapeutic approaches. To explore the molecular mechanisms driving the growth and progression of DLBCL, we analyzed genes with differential expression in DLBCL using the Gene Expression Profiling Interactive Analysis database. Enkurin domain-containing protein 1 (ENKD1), a centrosomal protein-encoding gene, was found to be highly expressed in DLBCL samples compared with normal samples. The phylogenetic analysis revealed that ENKD1 is evolutionarily conserved. Depletion of ENKD1 in cultured DLBCL cells induced apoptosis, suppressed cell proliferation, and blocked cell cycle progression in the G2/M phase. Moreover, ENKD1 expression positively correlates with the expression levels of a number of cellular homeostatic regulators, including Sperm-associated antigen 5, a gene encoding an important mitotic regulator. These findings thus demonstrate a critical function for ENKD1 in regulating the cellular homeostasis and suggest a potential value of targeting ENKD1 for the treatment of DLBCL.
Subject(s)
Lymphoma, Large B-Cell, Diffuse , Microtubule Proteins , Humans , Apoptosis/genetics , Cell Line, Tumor , Cell Proliferation , Gene Expression Regulation, Neoplastic/genetics , Lymphoma, Large B-Cell, Diffuse/genetics , Lymphoma, Large B-Cell, Diffuse/metabolism , Lymphoma, Large B-Cell, Diffuse/pathology , Microtubule Proteins/metabolism , Phylogeny , Up-Regulation/geneticsABSTRACT
OBJECTIVE: We aimed to examine whether HIV infection was independently associated with frailty status and its individual components. METHODS: This cross-sectional investigation included people living with HIV (PLWH) and HIV-negative individuals from the baseline survey of the Comparative HIV and Aging Research in Taizhou (CHART) cohort, China. Frailty phenotype was based on five components: weight loss, low physical activity, exhaustion, weak grip strength and slow gait speed. Frailty was defined as the presence of at least three components, and prefrailty was defined as one or two components. Logistic regression models were used to analyse the factors associated with frailty and its components. RESULTS: In all, 2475 people living with HIV (age 45.5 ± 14.9 years; 76.2% male) and 4948 HIV-negative individuals (age 45.5 ± 14.8 years; 76.3% male) were included. Among PLWH, median CD4 count was 395 cells/µL and 78% were currently on antiretroviral therapy (ART). Frailty and prefrailty were significantly more prevalent in PLWH (3.2% vs 1.9% and 32.9% vs 27.9%) overall and at ages 18-39 (1.4% vs 0.2% and 22.7% vs 19.0%), 40-59 (2.5% vs 0.9% and 30.9% vs 27.9%) and 60-90 years (8.4% vs 7.4% and 57.1% vs 45.8%). HIV infection was associated with frailty and prefrailty [adjusted odds ratio (aOR) = 1.48, 95% confidence interval (CI): 1.06-2.08; and aOR = 1.18, 95% CI: 1.05-1.33, respectively] after adjusting for confounding variables, but were strengthened with further adjustment for multimorbidity (aOR = 1.62, 95% CI: 1.14-2.28; and aOR = 1.22, 95% CI: 1.09-1.37), and were no longer significant with further adjustment for depressive symptoms and sleep disorders (aOR = 1.02, 95% CI: 0.71-1.46; and aOR = 1.06, 95% CI: 0.94-1.20). Among individual components, HIV infection was positively associated with weak grip strength and slow gait speed, but negatively associated with low physical activity and exhaustion in all the adjusted models described. CONCLUSIONS: Frailty and prefrailty occur more often and earlier in PLWH. However, grip strength and gait speed are affected to a greater extent, highlighting their potential as screening and intervention targets to prevent or slow frailty among PLWH.
Subject(s)
Frailty , HIV Infections , Male , Humans , Female , HIV Infections/complications , HIV Infections/drug therapy , HIV Infections/epidemiology , Frailty/epidemiology , Frailty/diagnosis , Cross-Sectional Studies , China/epidemiology , CD4 Lymphocyte CountABSTRACT
With the recent endorsement of PrEP by the Chinese government, research is urgently needed to better understand factors impacting PrEP uptake among gay, bisexual, and other men who have sex with men (GBMSM) in China. This study examined willingness to use PrEP for HIV prevention among GBMSM in China through structural equation modeling. We examined the relationship among PrEP-related attitudes, subjective norms, PrEP-related knowledge and beliefs about medicines and willingness to use PrEP. The analysis showed a good fit between the data and both the measurement model (RMSEA = 0.060) and structural model (RMSEA = 0.054). Knowledge, attitudes, and subjective norms were significantly related to intention to use PrEP, whereas the effect of general beliefs about medicines was insignificant. These effect mechanisms point to the importance of designing interventions to support PrEP uptake that target knowledge, enhance positive attitudes about PrEP within social networks, and build positive social norms around PrEP among sexually active GBMSM.
Subject(s)
HIV Infections , Pre-Exposure Prophylaxis , Sexual and Gender Minorities , Male , Humans , Homosexuality, Male , Latent Class Analysis , HIV Infections/prevention & control , ChinaABSTRACT
Intimate partner violence (IPV) is associated with adverse mental and physical outcomes among men who have sex with men (MSM) living with HIV. Few studies focus on psychological IPV, such as verbal threats. This study examined the associations between different forms of IPV and depression and CD4+ cell count, with depression as a mediator for the association between IPV and CD4+ cell count. Data for these analyses were derived from a larger cross-sectional study on HIV-HCV co-infection among MSM in Shanghai, China (N = 1623). We estimated the average causal mediation effects (ACME) and average direct effects (ADE) through three steps. About 16% of participants experienced IPV, with forced sex (7%), verbal threats (5%), and thrown objects (4%) being most common. Verbal threats showed the strongest link with depression and low CD4+ cell count. Depression fully mediated the relationship between verbal abuse and low CD4+ cell count, suggesting it as a potential pathway between psychological IPV and poorer HIV-related health outcomes. More research on psychological IPV is warranted to examine its health impacts. Mental health could be a potential focus of intervention to enhance HIV-related health outcomes among MSM with IPV experience.
Subject(s)
HIV Infections , Hepatitis C , Intimate Partner Violence , Sexual and Gender Minorities , Male , Humans , Homosexuality, Male/psychology , Cross-Sectional Studies , Depression/epidemiology , China/epidemiology , Intimate Partner Violence/psychology , CD4 Lymphocyte Count , Prevalence , Risk FactorsABSTRACT
BACKGROUND: Few studies have analyzed the clinical characteristics and adverse factors affecting prognosis in older patients with tuberculous meningitis (TBM). This study aimed to compare the clinical characteristics of TBM in older patients with those in younger and middle-aged patients. METHODS: This single-center retrospective study extracted data on the clinical features, cerebrospinal fluid changes, laboratory results, imaging features, and outcomes of patients with TBM from patient medical records and compared the findings in older patients (aged 60 years and older) with those of younger and middle-aged patients (aged 18-59 years). RESULTS: The study included 197 patients with TBM, comprising 21 older patients aged 60-76 years at onset, and 176 younger and middle-aged patients aged 18-59 years at onset. Fever was common in both older (81%) and younger and middle-aged patients (79%). Compared with younger and middle-aged patients, older patients were more likely to have changes in awareness levels (67% vs. 40%), peripheral nerve dysfunction (57% vs. 29%), changes in cognitive function (48% vs. 20%), and focal seizures (33% vs. 6%), and less likely to have headache (71% vs. 93%), neck stiffness on meningeal stimulation (38% vs. 62%), and vomiting (47% vs. 68%). The Medical Research Council staging on admission of older patients was stage II (52%) and stage III (38%), whereas most younger and middle-aged patients had stage I (33%) and stage II (55%) disease. Neurological function evaluated on the 28th day of hospitalization was more likely to show poor prognosis in older patients than in younger and middle-aged patients (76% vs. 25%). Older patients had significantly higher red blood cell counts and blood glucose levels, and significantly lower serum albumin and sodium levels than those in younger and middle-aged patients. The cerebrospinal fluid protein levels, nucleated cell counts, glucose levels, and chloride levels did not differ significantly by age. CONCLUSION: In patients with TBM, older patients have more severe clinical manifestations, a higher incidence of hydrocephalus and cerebral infarction, and longer hospital stays than younger and middle-aged patients. Older patients thus require special clinical attention.
Subject(s)
Hydrocephalus , Tuberculosis, Meningeal , Middle Aged , Humans , Aged , Tuberculosis, Meningeal/diagnosis , Tuberculosis, Meningeal/epidemiology , Tuberculosis, Meningeal/cerebrospinal fluid , Retrospective Studies , Prognosis , Cerebral Infarction , Hydrocephalus/etiologyABSTRACT
Fangwen Jiuwei Decoction is a traditional Chinese medicine preparation for the treatment of pneumonia developed by Shenzhen Bao'an Chinese Medicine Hospital, which shows remarkable clinical responses. Qualitative and quantitative analyses of the main active compounds are crucial for the quality control of traditional Chinese medicine prescription in clinical application. In this study, we identified nine active compounds essential for the pharmacological effects of Fangwen Jiuwei Decoction based on the analysis of the Network Pharmacology and relevant literature. Moreover, these compounds can interact with several crucial drug targets in pneumonia based on molecular docking. We applied high-performance liquid chromatography-tandem mass spectrometry method was established these nine active ingredients' qualitative and quantitative detections. The possible cleavage pathways of nine active components were determined based on secondary ions mass spectrometry. The results of high-performance liquid chromatography-tandem mass spectrometry were further validated, which show a satisfactory correlation coefficient (r > 0.99), recovery rate (≥93.31%), repeatability rate (≤5.62%), stability (≤7.95%), intra-day precision (≤6.68%), and inter-day precision (≤9.78%). The limit of detection was as low as 0.01 ng/ml. In this study, we established a high-performance liquid chromatography-tandem mass spectrometry method to qualitatively and quantitatively analyze the chemical components in the Fangwen Jiuwei Decoction extract.
Subject(s)
Drugs, Chinese Herbal , Drugs, Chinese Herbal/analysis , Tandem Mass Spectrometry/methods , Molecular Docking Simulation , Medicine, Chinese Traditional , Chromatography, High Pressure Liquid/methodsABSTRACT
AIM: Hematopoietic stem cells are the origin of all hematopoietic cells. They have the self-renewal ability and can differentiate into various blood cells. In physiological state, most of the hematopoietic stem cells are dormant, and only a few cells proliferate to maintain hematopoietic homeostasis. METHODS: This precise steady-state maintenance is regulated by complex mechanisms. Bone marrow adipocytes make up half of all cells in the bone marrow cavity, a feature that has attracted the attention of researchers from multiple fields. The adipocyte density within marrow increases during aging and obesity. RESULTS: Recent studies have shown that bone marrow adipocytes play important roles in regulating hematopoiesis, but the effects of bone marrow adipocytes on hematopoiesis are often conflicting. Bone marrow adipocytes, participating in the formation of bone marrow hematopoietic microenvironment, influence hematopoiesis positively or negatively. In addition, other adipose tissue, especially white adipose tissue, also regulates hematopoiesis. CONCLUSION: In this review, we describe the role of adipose tissue in hematological malignancies, which may be useful for understanding hematopoiesis and the pathogenesis of related diseases.
Subject(s)
Adipose Tissue , Bone Marrow Cells , Humans , Bone Marrow Cells/physiology , Bone Marrow , Hematopoiesis/physiology , Hematopoietic Stem Cells/physiologyABSTRACT
OBJECTIVES: To assess the diagnostic performance of the modified LR-M method of CEUS LI-RADS version 2017 with nodules of different sizes. METHODS: This retrospective study included consecutive patients with high risk for HCC who underwent CEUS between 2019 and 2021, demonstrating an LR-M observed using CEUS LI-RADS version 2017. Four modified LR-M methods were used to evaluate nodules of different sizes. The diagnostic performances of the four modified LR-M methods were assessed in LR-M nodules of different sizes by the area under the receiver operating characteristic curve (AUC). RESULTS: The 261 patients with LR-M observations included 166 HCCs and 95 non-HCCs. A total of 133 nodules were <30 mm and defined as group A, 78 nodules were 30-50 mm in size and defined as group B, and 50 nodules were >50 mm and defined as group C. The AUCs between criterion I, II, III, and IV were not significantly different in all LR-M nodules. The AUCs of the ROC curves between criterion I, II, III, and IV were not significantly different in group A. However, the AUC of criterion IV was significantly higher than that of criterion I and III in group B, and the AUCs of criterion I and criterion III were both not significant in group B; the AUC of criterion IV was not significant in group C. CONCLUSIONS: The modified LR-M method could moderate the detection effectiveness in differentiating HCC from other lesions. According to tumor size, the selection of appropriate modified LR-M diagnostic criteria could effectively improve the diagnostic performance of LR-M.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Humans , Carcinoma, Hepatocellular/diagnostic imaging , Liver Neoplasms/diagnostic imaging , Liver Neoplasms/pathology , Retrospective Studies , Contrast Media , Magnetic Resonance Imaging/methods , Sensitivity and SpecificityABSTRACT
The JAK/STAT3 signaling pathway is aberrantly hyperactivated in many cancers, promoting cell proliferation, survival, invasiveness, and metastasis. Thus, inhibitors targeting JAK/STAT3 have enormous potential for cancer treatment. Herein, we modified aldisine derivatives by introducing the isothiouronium group, which can improve the antitumor activity of the compounds. We performed a high-throughput screen of 3157 compounds and identified compounds 11a, 11b, and 11c, which contain a pyrrole [2,3-c] azepine structure linked to an isothiouronium group through different lengths of carbon alkyl chains and significantly inhibited JAK/STAT3 activities. Further results showed that compound 11c exhibited the optimal antiproliferative activity and was a pan-JAKs inhibitor capable of inhibiting constitutive and IL-6-induced STAT3 activation. In addition, compound 11c influenced STAT3 downstream gene expression (Bcl-xl, C-Myc, and Cyclin D1) and induced the apoptosis of A549 and DU145 cells in a dose-dependent manner. The antitumor effects of 11c were further demonstrated in an in vivo subcutaneous tumor xenograft experiment with DU145 cells. Taken together, we designed and synthesized a novel small molecule JAKs inhibitor targeting the JAK/STAT3 signaling pathway, which has predicted therapeutic potential for JAK/STAT3 overactivated cancer treatment.
Subject(s)
Isothiuronium , Signal Transduction , Humans , Isothiuronium/pharmacology , Cell Line, Tumor , Cell Proliferation , Apoptosis , Azepines/pharmacology , Pyrroles/pharmacology , STAT3 Transcription Factor/metabolismABSTRACT
Four new magnolol derivatives were synthesized and evaluated for their in vitro anti-cancer properties. Among these, compound 3 showed the most potent cytotoxic activity against the SMMC-7721, SUN-449, and HepG2 human hepatocellular carcinoma cell lines, with IC50 values of 3.39, 4.11, and 6.88 µM, respectively. Compound 3 also induced apoptosis of SMMC-7721 cells by down-regulating Bcl-2 and Akt protein levels, up-regulating of Bax protein level, and cleaving caspase-9 and -3. In addition, transwell assays showed that compound 3 significantly suppressed the migration and invasion of SMMC-7721 cells, which was confirmed based on the down-regulation of hypoxia inducible factor-1α (HIF-1α), matrix metalloproteinase-2 and -9 (MMP-2, and MMP-9) protein levels.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Humans , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , Liver Neoplasms/drug therapy , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Matrix Metalloproteinase 2/metabolism , Cell Line, Tumor , Cell Movement , Neoplasm Invasiveness , Apoptosis , Cell ProliferationABSTRACT
The Janus kinase/signal transducer and activator of the transcription 3 (JAK/STAT3) signaling pathway controls multiple biological processes, including cell survival, proliferation, and differentiation. Abnormally activated STAT3 signaling promotes tumor cell growth, proliferation, and survival, as well as tumor invasion, angiogenesis, and immunosuppression. Hence, JAK/STAT3 signaling has been considered a promising target for antitumor therapy. In this study, a number of ageladine A derivative compounds were synthesized. The most effective of these was found to be compound 25. Our results indicated that compound 25 had the greatest inhibitory effect on the STAT3 luciferase gene reporter. Molecular docking results showed that compound 25 could dock into the STAT3 SH2 structural domain. Western blot assays demonstrated that compound 25 selectively inhibited the phosphorylation of STAT3 on the Tyr705 residue, thereby reducing STAT3 downstream gene expression without affecting the expression of the upstream proteins, p-STAT1 and p-STAT5. Compound 25 also suppressed the proliferation and migration of A549 and DU145 cells. Finally, in vivo research revealed that 10 mg/kg of compound 25 effectively inhibited the growth of A549 xenograft tumors with persistent STAT3 activation without causing significant weight loss. These results clearly indicate that compound 25 could be a potential antitumor agent by inhibiting STAT3 activation.