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The growing field of computational chemistry and artificial intelligence is drawing unprecedented attention in drug discovery. However, the underrepresentation of female scientists persists in the field. While the gender disparity is acknowledged in academic settings, the issue is less addressed and intensifies in the pharmaceutical and biotech industry both at the entry-level and leadership positions. At Viva Biotech, we challenge this norm: over 60% of the full-time employees in our computational chemistry group are women, a testament of our commitment to the pursuit of gender equality. We share our vision of the evolving role of computational chemistry in drug discovery and where women stand and rise in the field. In this article, we discuss how we engage female empowerment with tactical approaches and from personal experiences. The intention is to offer actionable guidance for female computational chemists at early career stages to bring visibility to their impacts, and ascent to senior positions.
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Química Computacional , Femenino , Humanos , Biotecnología , Descubrimiento de Drogas , Inteligencia ArtificialRESUMEN
BACKGROUND: Nipah virus is a zoonotic paramyxovirus responsible for disease outbreaks with high fatality rates in south and southeast Asia. However, knowledge of the potential geographical extent and risk patterns of the virus is poor. We aimed to establish an integrated spatiotemporal and phylogenetic database of Nipah virus infections in humans and animals across south and southeast Asia. METHODS: In this geospatial modelling analysis, we developed an integrated database containing information on the distribution of Nipah virus infections in humans and animals from 1998 to 2021. We conducted phylodynamic analysis to examine the evolution and migration pathways of the virus and meta-analyses to estimate the adjusted case-fatality rate. We used two boosted regression tree models to identify the potential ecological drivers of Nipah virus occurrences in spillover events and endemic areas, and mapped potential risk areas for Nipah virus endemicity. FINDINGS: 749 people and eight bat species across nine countries were documented as being infected with Nipah virus. On the basis of 66 complete genomes of the virus, we identified two clades-the Bangladesh clade and the Malaysia clade-with the time of the most recent common ancestor estimated to be 1863. Adjusted case-fatality rates varied widely between countries and were higher for the Bangladesh clade than for the Malaysia clade. Multivariable meta-regression analysis revealed significant relationships between case-fatality rate estimates and viral clade (p=0·0021), source country (p=0·016), proportion of male patients (p=0·036), and travel time to health-care facilities (p=0·036). Temperature-related bioclimate variables and the probability of occurrence of Pteropus medius were important contributors to both the spillover and the endemic infection models. INTERPRETATION: The suitable niches for Nipah virus are more extensive than previously reported. Future surveillance efforts should focus on high-risk areas informed by updated projections. Specifically, intensifying zoonotic surveillance efforts, enhancing laboratory testing capacity, and implementing public health education in projected high-risk areas where no human cases have been reported to date will be crucial. Additionally, strengthening wildlife surveillance and investigating potential modes of transmission in regions with documented human cases is needed. FUNDING: The Key Research and Development Program of China.
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Infecciones por Henipavirus , Virus Nipah , Virus Nipah/fisiología , Infecciones por Henipavirus/epidemiología , Infecciones por Henipavirus/transmisión , Humanos , Animales , Quirópteros/virología , Asia Sudoriental/epidemiología , Filogenia , Zoonosis/epidemiología , Zoonosis/virologíaRESUMEN
[This corrects the article DOI: 10.1371/journal.pone.0278354.].
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Na3MnTi(PO4)3 (NMTP) emerges as a promising cathode material with high-performance for sodium-ion batteries (SIBs). Nevertheless, its development has been limited by several challenges, including poor electronic conductivity, the Mn3+ Jahn-Teller effect, and the presence of a Na+/Mn2+ cation mixture. To address these issues, we have developed a cation/anion-dual regulation strategy to activate the redox reactions involving manganese, thereby significantly enhancing the performance of NMTP. This strategy simultaneously enhances the structural dynamics and facilitates rapid ion transport at high rates by inducing the formation of sodium vacancy. The combined effects of these modifications lead to a substantial improvement in specific capacity (79.1 mAh/g), outstanding high-rate capabilities (35.9 mAh/g at 10C), and an ultralong cycle life (only 0.040 % capacity attenuation per cycle over 250 cycles at 1C for Na3.34Mn1.2Ti0.8(PO3.98F0.02)3) when used as a cathode material in SIBs. Furthermore, its performance in full cell demonstrates impressive rate capability (44.4 mAh/g at 5C) and exceptional cycling stability (with only 0.116 % capacity decay per cycle after 150 cycles at 1C), suggesting its potential for practical applications. This work presents a dual regulation strategy targeting different sites, offering a significant advancement in the development of NASICON phosphate cathodes for SIBs.
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Bach2 was initially discovered in B cells, where it was revealed to control the transcription involved in cell differentiation. Bach2 is intimately connected to CD8 + T lymphocytes in various differentiation states and subsets according to recent findings. Bach2 can regulate primitive T cells, stimulate the development and differentiation of memory CD8 + T cells, inhibit the differentiation of effector CD8 + T cells, and play a significant role in the exhaustion of CD8 + T cells. The appearance and development of diseases are tightly linked to irregular CD8 + T cell differentiation and function. Accordingly, Bach2 offers novel approaches and possible targets for the clinical treatment of associated disorders based on research on these pathways. Here, we summarize the role of Bach2 in the function and differentiation of CD8 + T cells and its potential clinical applications.
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Linfocitos B , Linfocitos T CD8-positivos , Diferenciación Celular , Activación de Linfocitos , HumanosRESUMEN
During multivalent ions insertion processes, intense electrostatic interaction between charge carriers and host makes the high-performance reversible Al3+ storage remains an elusive target. On account of the strong electrostatic repulsion and poor robustness, Prussian Blue analogues (PBAs) suffer severely from the inevitable and large strain and phase change during reversible Al3+ insertion. Herein, we demonstrate an entropy-driven strategy to realize ultralong life aqueous Al-ion batteries (AIBs) based on medium entropy PBAs (ME-PBAs) host. By multiple redox active centers introduction, the intrinsic poor conductivity can be enhanced simultaneously, resulting in outstanding capabilities of electrochemical Al3+ storage. Meanwhile, the co-occupation at metal sites in PBA frameworks can also increase the M-N bond intensity, which is beneficial for constraining the phase change during consecutive Al3+ reversible insertion, to realize an extended lifespan over 10,000 cycles. Based on the calculation at different operation states, the fluctuation of ME-PBA lattice parameters is only 1.2 %. Assembled with MoO3 anodes, the full cells can also deliver outstanding electrochemical properties. The findings highlight that, the entropy regulation strategy could uncover the isochronous constraint on both strain and phase transition for long-term reversible Al3+ storage, providing a promising design for advanced electrode materials for aqueous multivalent ions batteries.
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The suppression of tumor proliferation via cellular senescence has emerged as a promising approach for anti-tumor therapy. Tumor necrosis factor receptor-associated factor 2 (TRAF2), an adaptor protein involved in the NF-κB signaling pathway and reactive oxygen species (ROS) production, has been implicated in hepatocellular carcinoma (HCC) proliferation. However, little is currently known about whether TRAF2 promotes HCC development by inhibiting cellular senescence. Replicative senescence model and IR-induced mouse model demonstrated that TRAF2 expression was decrease in senescence cells or liver tissues. Depletion of TRAF2 could inhibit proliferation and arrest the cell cycle via activating p53/p21WAF1 and p16INK4a/pRb signaling pathways in HCC cells and eventually lead to cellular senescence. Mechanistically, TRAF2 deficiency increased the expression of mitochondrial protein reactive oxygen species modulator 1 (ROMO1) and subsequently activated the NAD+/SIRT3/SOD2 pathway to promote the production of ROS and cause mitochondrial dysfunction, which eventually contributed to DNA damage response (DDR). Our findings demonstrate that TRAF2 deficiency inhibits the proliferation of HCC by promoting senescence. Therefore, targeting TRAF2 through various approaches holds therapeutic potential for treating HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Sirtuina 3 , Animales , Ratones , Carcinoma Hepatocelular/patología , Senescencia Celular/genética , Neoplasias Hepáticas/patología , NAD/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Sirtuina 3/genética , Sirtuina 3/metabolismo , Factor 2 Asociado a Receptor de TNF/genéticaRESUMEN
Deuterium Metabolic Imaging (DMI) is a novel method that can complement traditional anatomical magnetic resonance imaging (MRI) of the brain. DMI relies on the MR detection of metabolites that become labeled with deuterium (2H) after administration of a deuterated substrate and can provide images with highly specific metabolic information. However, clinical adoption of DMI is complicated by its relatively long scan time. Here, we demonstrate a strategy to interleave DMI data acquisition with MRI that results in a comprehensive neuro-imaging protocol without adding scan time. The interleaved MRI-DMI routine includes four essential clinical MRI scan types, namely T1-weighted MP-RAGE, FLAIR, T2-weighted Imaging (T2W) and susceptibility weighted imaging (SWI), interwoven with DMI data acquisition. Phantom and in vivo human brain data show that MR image quality, DMI sensitivity, as well as information content are preserved in the MRI-DMI acquisition method. The interleaved MRI-DMI technology provides full flexibility to upgrade traditional MRI protocols with DMI, adding unique metabolic information to existing types of anatomical image contrast, without extra scan time.
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Calcipotriol (CAL) has been widely studied as a fibrosis inhibitor and used to treat plaque psoriasis via transdermal administration. The clinical application of CAL to treat liver fibrosis is bottlenecked by its unsatisfactory pharmacokinetics, biodistribution, and side effects, such as hypercalcemia in patients. The exploration of CAL as a safe and effective antifibrotic agent remains a major challenge. Therefore, we rationally designed and synthesized a self-assembled drug nanoparticle encapsulating CAL in its internal hydrophobic core for systematic injection (termed NPs/CAL) and further investigated the beneficial effect of the nanomaterial on liver fibrosis. C57BL/6 mice were used as the animal model, and human hepatic stellate cell line LX-2 was used as the cellular model of hepatic fibrogenesis. Immunofluorescence staining, flow cytometry, western blotting, immunohistochemical staining, and in vitro imaging were used for evaluating the efficacy of NPs/CAL treatment. We found NPs/CAL can be quickly internalized in vitro, thus potently deactivating LX-2 cells. In addition, NPs/CAL improved blood circulation and the accumulation of CAL in liver tissue. Importantly, NPs/CAL strongly contributed to the remission of liver fibrosis without inducing hypercalcemia. Overall, our work identifies a promising paradigm for the development of nanomaterial-based agents for liver fibrosis therapy.
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BACKGROUND: Outbreaks of monkeypox have been ongoing in non-endemic countries since May 2022. A thorough assessment of its global zoonotic niche and potential transmission risk is lacking. METHODS: We established an integrated database on global monkeypox virus (MPXV) occurrence during 1958 - 2022. Phylogenetic analysis was performed to examine the evolution of MPXV and effective reproductive number (Rt) was estimated over time to examine the dynamic of MPXV transmissibility. The potential ecological drivers of zoonotic transmission and inter-regional transmission risks of MPXV were examined. RESULTS: As of 24 July 2022, a total of 49 432 human patients with MPXV infections have been reported in 78 countries. Based on 525 whole genome sequences, two main clades of MPXV were formed, of which Congo Basin clade has a higher transmissibility than West African clade before the 2022-monkeypox, estimated by the overall Rt (0.81 vs. 0.56), and the latter significantly increased in the recent decade. Rt of 2022-monkeypox varied from 1.14 to 4.24 among the 15 continuously epidemic countries outside Africa, with the top three as Peru (4.24, 95% CI: 2.89-6.71), Brazil (3.45, 95% CI: 1.62-7.00) and the United States (2.44, 95% CI: 1.62-3.60). The zoonotic niche of MPXV was associated with the distributions of Graphiurus lorraineus and Graphiurus crassicaudatus, the richness of Rodentia, and four ecoclimatic indicators. Besides endemic areas in Africa, more areas of South America, the Caribbean States, and Southeast and South Asia are ecologically suitable for the occurrence of MPXV once the virus has invaded. Most of Western Europe has a high-imported risk of monkeypox from Western Africa, whereas France and the United Kingdom have a potential imported risk of Congo Basin clade MPXV from Central Africa. Eleven of the top 15 countries with a high risk of MPXV importation from the main countries of 2022-monkeypox outbreaks are located at Europe with the highest risk in Italy, Ireland and Poland. CONCLUSIONS: The suitable ecological niche for MPXV is not limited to Africa, and the transmissibility of MPXV was significantly increased during the 2022-monkeypox outbreaks. The imported risk is higher in Europe, both from endemic areas and currently epidemic countries. Future surveillance and targeted intervention programs are needed in its high-risk areas informed by updated prediction.
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Mpox , Humanos , Mpox/epidemiología , Filogenia , Brotes de Enfermedades , Estudios Retrospectivos , BrasilRESUMEN
Mesenchymal stem cells (MSCs) have emerged as a promising alternative treatment for liver disease due to their roles in regeneration, fibrosis inhibition, and immunoregulation. Mitochondria are crucial in maintaining hepatocyte integrity and function. Mitochondrial dysfunction, such as impaired synthesis of adenosine triphosphate (ATP), decreased activity of respiratory chain complexes, and altered mitochondrial dynamics, is observed in most liver diseases. Accumulating evidence has substantiated that the therapeutic potential of MSCs is mediated not only through their cell replacement and paracrine effects but also through their regulation of mitochondrial dysfunction in liver disease. Here, we comprehensively review the involvement of mitochondrial dysfunction in the development of liver disease and how MSCs can target mitochondrial dysfunction. We also discuss recent advances in a novel method that modifies MSCs to enhance their functions in liver disease. A full understanding of MSC restoration of mitochondrial function and the underlying mechanisms will provide innovative strategies for clinical applications. Video Abstract.
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Hepatopatías , Células Madre Mesenquimatosas , Humanos , Hepatopatías/terapia , Mitocondrias , Membranas Mitocondriales , Adenosina TrifosfatoRESUMEN
Layered transition metal oxides have the greatest potential for commercial application as cathode materials for sodium-ion batteries. However, transition metal oxides inevitably undergo an irreversible oxygen loss process during cycling, which leads to structural changes in the material and ultimately to severe capacity degradation. In this work, using density function theory (DFT) calculations, the Ni-O bond is revealed to be the weakest of the M-O bonds, which may lead to structural failure. Herein, the synergistic surface CeO2 modification and the trace doping of Ce elements stimulate oxygen redox and improve its reversibility, thus improving the structural stability and electrochemical performance of the material. Theoretical calculations prove that Na0.67Mn0.7Ni0.2Co0.1O2 (MNC) obtains electrons from CeO2, avoiding destruction of the Ni-O bond by over-energy released during the charging process and inhibiting oxygen loss. The capacity retention was 77.37% for 200 cycles at 500 mA g-1, compared to 33.84% for the unmodified Na0.67Mn0.7Ni0.2Co0.1O2. Overall, the present work demonstrates that the synergistic effect of surface coating and doping is an effective strategy for realizing tuning oxygen release and high electrochemical performance.
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Aging and replicative cellular senescence are associated with the reduced therapeutic potential of mesenchymal stem cells (MSCs) on a variety of diseases. This study aimed to determine the mechanism in MSC senescence and further explore a modification strategy to reverse senescence-associated cell dysfunction to improve the therapeutic efficacy of MSCs on acute liver failure (ALF). We found that the adipose tissue-derived MSCs from old mice (oAMSCs) exhibited senescence phenotypes and showed reduced therapeutic efficacy in lipopolysaccharide and D-galactosamine-induced ALF, as shown by the increased hepatic necrosis, liver histology activity index scores, serum liver function indicator levels, and inflammatory cytokine levels. The expression of miR-17-92 cluster members, especially miR-17 and miR-20a, was obviously decreased in oAMSCs and replicatively senescent AMSCs, and was consistent with the decreased oncogene c-Myc level during AMSC senescence and may mediate c-Myc stemness addiction. Further experiments revealed that c-Myc-regulated miR-17-92 expression contributed to increased p21 expression and redox system dysregulation during AMSC senescence. Furthermore, modification of AMSCs with the two key miRNAs in the miR-17-92 cluster mentioned above reversed the senescence features of oAMSCs and restored the therapeutic effect of senescent AMSCs on ALF. In conclusion, the cellular miR-17-92 cluster level is correlated with AMSC senescence and can be used both as an index for evaluating and as a modification target for improving the therapeutic potential of AMSCs.NEW & NOTEWORTHY We reported for the first time that c-Myc-regulated miR-17-92 contributed to increased p21 expression and redox system dysregulation during AMSC senescence and was associated with the reduced therapeutic effects of senescent AMSCs on ALF. Moreover, modifying the expression of the miR-17-92 cluster members, especially miR-17 and/or miR-20a, could reverse AMSC senescence. Thus, miR-17-92 cluster can be used both as an index for evaluating and as a modification strategy for improving the therapeutic potential of AMSCs.
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Células Madre Mesenquimatosas , MicroARNs , Ratones , Animales , MicroARNs/genética , MicroARNs/metabolismo , Células Madre Mesenquimatosas/metabolismo , Envejecimiento/genética , Oxidación-Reducción , Estrés Oxidativo , Senescencia CelularRESUMEN
The first epidemiologic study was conducted to prospectively examine the association between Food Environment Index (FEI) and gastric cancer (GC) risk in the US. Surveillance, Epidemiology, and End Results provided information on GC incident cases diagnosed between 2000 and 2015 from 16 population-based cancer registries across the US. The county-level food environment was assessed using the FEI, an indicator of access to healthy foods (0 is worst, 10 is best). Poisson regression was used to calculate incidence rate ratios (IRRs) and 95% confidence intervals (CIs) for the association between FEI and GC risk adjusting for individual-level and county-level covariates. Higher levels of FEI were associated with a statistically significant reduced risk for GC (n = 87,288 cases; adjusted IRR for every score increase = 0.50, 95% CI 0.35, 0.70; P < 0.001; adjusted IRR for the medium vs. low category = 0.87, 95% CI 0.81, 0.94; and adjusted IRR for the high vs. low category = 0.89, 95% CI 0.82, 0.95). These results suggest that a healthy food environment, as measured by FEI, may be a protective factor for GC in the US. To reduce the GC incidence, further strategies to improve food environment at the county level are warranted.
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Neoplasias Gástricas , Humanos , Estados Unidos/epidemiología , Factores de Riesgo , Incidencia , Neoplasias Gástricas/epidemiología , Neoplasias Gástricas/etiologíaRESUMEN
TRAF2 (Tumor necrosis factor receptor-associated factor 2) is a dual function protein, acting as an adaptor protein and a ubiquitin E3 ligase, which plays an essential role in mediating the TNFα-NFκB signal pathway. Dysregulated expression of TRAF2 has been reported in a variety of human cancers. Whether and how TRAF2 regulates the growth of liver cancer cells remains elusive. The goal of this study is to investigate potential dysregulation of TRAF2 and its biological function in liver cancer, and to elucidate the underlying mechanism, leading to validation of TRAF2 as an attractive liver cancer target. Here, we reported TRAF2 is up-regulated in human liver cancer cell lines and tissues, and high TRAF2 expression is associated with a poor prognosis of HCC patients. Proteomics profiling along with Co-immunoprecipitation analysis revealed that p62 is a new substrate of TRAF2, which is subjected to TRAF2-induced polyubiquitination via the K63 linkage at the K420 residue. A strong negative correlation was found between the protein levels of p62 and TRAF2 in human HCC samples. TRAF2 depletion inhibited growth and survival of liver cancer cells both in vitro and in vivo by causing p62 accumulation, which is partially rescued by simultaneous p62 knockdown. Mechanistically, TRAF2-mediated p62 polyubiquitylation activates the mTORC1 by forming the p62-mTORC1-Rag complex, which facilitates the lysosome localization of mTORC1. TRAF2 depletion inhibited mTORC1 activity through the disruption of interaction between p62 and the mTORC1 complex. In conclusion, our study provides the proof-of-concept evidence that TRAF2 is a valid target for liver cancer.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Proliferación Celular , Neoplasias Hepáticas/genética , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Factor 2 Asociado a Receptor de TNF/metabolismo , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
This study examines childhood cancer survival rates and prognostic factors related to survival in the majority Hispanic population of South Texas. The population-based cohort study used Texas Cancer Registry data (1995-2017) to examine survival and prognostic factors. Cox proportional hazard models and Kaplan-Meier survival curves were used for survival analyses. The 5-year relative survival rate for 7,999 South Texas cancer patients diagnosed at 0-19 years was 80.3% for all races/ethnicities. Hispanic patients had statistically significant lower 5-year relative survival rates than non-Hispanic White (NHW) patients for male and female together diagnosed at age≥5 years. When comparing survival among Hispanic and NHW patients for the most common cancer, acute lymphocytic leukemia (ALL), the difference was most significant in the 15-19 years age range, with 47.7% Hispanic patients surviving at 5 years compared to 78.4% of NHW counterparts. The multivariable-adjusted analysis showed that males had statistically significant 13% increased mortality risk than females [hazard ratio (HR): 1.13, 95% confidence interval (CI):1.01-1.26] for all cancer types. Comparing to patients diagnosed at ages 1-4 years, patients diagnosed at age < 1 year (HR: 1.69, 95% CI: 1.36-2.09), at 10-14 year (HR: 1.42, 95% CI: 1.20-1.68), or at 15-19 years (HR: 1.40, 95% CI: 1.20-1.64) had significant increased mortality risk. Comparing to NHW patients, Hispanic patients showed 38% significantly increased mortality risk for all cancer types, 66% for ALL, and 52% for brain cancer. South Texas Hispanic patients had lower 5-year relative survival than NHW patients especially for ALL. Male gender, diagnosis at age<1 year or 10-19 years were also associated with decreased childhood cancer survival. Despite advances in treatment, Hispanic patients lag significantly behind NHW patients. Further cohort studies in South Texas are warranted to identify additional factors affecting survival and to develop interventional strategies.
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Neoplasias , Poblaciones Vulnerables , Humanos , Masculino , Niño , Femenino , Persona de Mediana Edad , Preescolar , Lactante , Estudios de Cohortes , Texas/epidemiología , Neoplasias/epidemiología , BlancoRESUMEN
BACKGROUND: Severe community-acquired pneumonia (SCAP) is associated with a substantial number of hospitalisations and deaths worldwide. Infection or co-infection patterns, along with their age dependence and clinical effects are poorly understood. We aimed to explore the causal and epidemiological characteristics by age, to better describe patterns of community-acquired pneumonia (CAP) and their association with severe disease. METHODS: National surveillance of CAP was conducted through a network of hospitals in 30 provinces in China from 2009-20 inclusive. Patients with CAP were included if they had evidence of acute respiratory tract, had evidence of pneumonia by chest radiography, diagnosis of pneumonia within 24 h of hospital admission, and resided in the study catchment area. For the enrolled patients with CAP, nasopharyngeal and oral swabs were taken and tested for eight viral pathogens; and blood, urine, or expectorated sputum was tested for six bacterial pathogens. Clinical outcomes, including SCAP, were investigated with respect to age and patterns of infections or co-infections by performing binary logistic regression and multivariate analysis. FINDINGS: Between January, 2009, and December, 2020, 18 807 patients with CAP (3771 [20·05%] with SCAP) were enrolled. For both children (aged ≤5 years) and older adults (aged >60 years), a higher overall rate of viral and bacterial infections, as well as viral-bacterial co-infections were seen in patients with SCAP than in patients with non-SCAP. For adults (aged 18-60 years), however, only a higher rate of bacterial-bacterial co-infection was observed. The most frequent pathogens associated with SCAP were respiratory syncytial virus (RSV; 21·30%) and Streptococcus pneumoniae (12·61%) among children, and influenza virus (10·94%) and Pseudomonas aeruginosa (15·37%) among older adults. Positive rates of detection of most of the tested pathogens decreased during 2020 compared with the 2009-19 period, except for RSV, P aeruginosa, and Klebsiella pneumoniae. Multivariate analyses showed SCAP was significantly associated with infection with human adenovirus, human rhinovirus, K pneumoniae, or co-infection of RSV and Haemophilus influenzae or RSV and Staphylococcus aureus in children and adolescents (aged <18 years), and significantly associated with infection with P aeruginosa, K pneumoniae, or S pneumoniae, or co-infection with P aeruginosa and K pneumoniae in adults (aged ≥18 years). INTERPRETATION: Both prevalence and infection pattern of respiratory pathogens differed between patients with SCAP and patients with non-SCAP in an age-dependent manner. These findings suggest potential advantages to age-related strategies for vaccine schedules, as well as clinical diagnosis, treatment, and therapy. FUNDING: China Mega-Project on Infectious Disease Prevention and The National Natural Science Funds of China. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.
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Coinfección , Infecciones Comunitarias Adquiridas , Neumonía , Virus Sincitial Respiratorio Humano , Virosis , Niño , Adolescente , Humanos , Adulto , Anciano , Coinfección/epidemiología , Coinfección/complicaciones , Coinfección/microbiología , Neumonía/diagnóstico , Neumonía/epidemiología , Neumonía/etiología , Streptococcus pneumoniae , Virosis/complicaciones , Klebsiella pneumoniae , Infecciones Comunitarias Adquiridas/epidemiología , Infecciones Comunitarias Adquiridas/diagnóstico , Infecciones Comunitarias Adquiridas/microbiologíaRESUMEN
Acetaminophen (APAP) is the major cause of drug-induced liver injury, with limited treatment options. APAP overdose invokes excessive oxidative stress that triggers mitochondria-to-nucleus retrograde pathways, contributing to APAP-induced liver injury (AILI). Mesenchymal stem cell therapy is a promising tool for acute liver failure. Therefore, the purpose of this study was to investigate the beneficial effects of adipose-derived mesenchymal stem cell (AMSC) therapy on AILI and reveal the potential therapeutic mechanisms. C57BL/6 mice were used as the animal model and AML12 normal murine hepatocytes as the cellular model of APAP overdose. Immunohistochemical staining, Western blotting, immunofluorescence staining, and RNA sequencing assays were used for assessing the efficacy and validating mechanisms of AMSC therapy. We found AMSC therapy effectively ameliorated AILI, while delayed AMSC injection lost its efficacy related to the c-Jun N-terminal kinase (JNK)-mediated mitochondrial retrograde pathways. We further found that AMSC therapy inhibited JNK activation and mitochondrial translocation, reducing APAP-induced mitochondrial damage. The downregulation of activated ataxia telangiectasia-mutated (ATM) and DNA damage response proteins in AMSC-treated mouse liver indicated AMSCs blocked the JNK-ATM pathway. Overall, AMSCs may be an effective treatment for AILI by inhibiting the JNK-ATM mitochondrial retrograde pathway, which improves APAP-induced mitochondrial dysfunction and liver injury.
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ASK1, also known as MAP3K5, plays a vital role in the MAPK pathway. The MAPK pathway has a variety of biological functions and plays an important role in regulating cell proliferation, differentiation, and apoptosis. Studies have shown that ASK1 is involved in apoptosis, inflammation, oxidative stress, and other processes and plays an essential role in various liver diseases. Therefore, ASK1 can be a therapeutic target for treating liver disease. Here, we initially summarized the effect of ASK1 on liver disease and described the differential regulation of ASK1, including phosphorylation, ubiquitination and methylation, by which the effects of ASK1 on some liver diseases can be inhibited. Although much has been discovered about the phosphorylation of ASK1, the effects of other post-transcriptional modifications on the activity of ASK1 require further exploration. We hope that by summarizing the existing regulatory mechanism we can shed new light on the research and provide new ideas for finding ASK1-targeting drugs.
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Apoptosis , Hepatopatías , Humanos , Apoptosis/genética , Ubiquitinación , Fosforilación , Proliferación Celular , Hepatopatías/genética , MAP Quinasa Quinasa Quinasa 5/genéticaRESUMEN
There is no effective treatment for acute liver failure (ALF) except for an artificial liver support system (ALSS) and liver transplant. Bruton tyrosine kinase (Btk) plays important immunoregulatory roles in the inflammatory diseases, but its possible function in ALF remains to be characterized. In this study, we detected the phosphorylation level of Btk in ALF mouse liver and analyzed the protective effects of Btk inhibitor on survival rate and liver damage in ALF mouse models. We measured the expression levels of various inflammatory cytokines in the ALF mouse liver and primary human monocytes. In addition, we examined the expression of the NLRP3 inflammasome in mouse models with or without Btk inhibition. Clinically, we observed the dynamic changes of Btk expression in PBMCs of ALSS-treated patients. Our results showed that Btk was upregulated significantly in the experimental ALF mouse models and that Btk inhibition alleviated liver injury and reduced the mortality in these models. The protective effect of Btk inhibitors on ALF mice partially depended on the suppression of NLRP3 inflammasome signaling. Clinical investigations revealed that the dynamic changes of Btk expression in PBMCs could predict the effect of ALSS treatment. Our work shows that Btk inhibition is an effective therapeutic strategy for ALF. Moreover, Btk is a useful indicator to predict the therapeutic effect of ALSS on liver failure, which might have great value in clinical practice.