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Experimental Cell Research Jul 2024Bladder cancer(BC) is one of the most prevalent cancers in the urinary tract, with high recurrence and fatality rates. Research indicates that go-ichi-ni-san complex...
Bladder cancer(BC) is one of the most prevalent cancers in the urinary tract, with high recurrence and fatality rates. Research indicates that go-ichi-ni-san complex subunit 1 (GINS1) crucially influences cancer progression by regulating DNA replication through cell cycle modulation. Thus, suppressing the active proliferation of cells in tumor tissues may require silencing GINS1. However, the consequences of GINS1 in bladder cancer aren't to be determined. In this paper, we examine the role and mechanism of GINS1 in the development of bladder cancer. GINS1 expression levels and prognostic relevance in bladder cancer were validated using Western blotting, immunohistochemistry, and Kaplan-Meier survival analysis. The influence of GINS1 on bladder cancer was investigated using a variety of approaches, including cell transfection, cell counts, transwell migrations, colony formation, and flow cytometry. Immunohistochemistry studies demonstrate that GINS1 expression is increased in bladder cancer tissues. GINS1 silencing resulted in an arrest of the cell cycle at the phase of G0/G1, which inhibited BC cell growth both in vitro and in vivo. GINS1 knockdown also hindered the AKT/mTOR pathway. Furthermore, increased GINS1 expression affects the cell cycle and stimulates the AKT/mTOR pathway, allowing BC to develop more quickly. Consequently, GINS1 occurs as a latent therapeutic target, particularly for individuals with BC.
Topics: Urinary Bladder Neoplasms; Humans; Proto-Oncogene Proteins c-akt; TOR Serine-Threonine Kinases; Chromosomal Proteins, Non-Histone; Signal Transduction; Cell Proliferation; Animals; Cell Line, Tumor; Proto-Oncogene Proteins c-myc; Gene Expression Regulation, Neoplastic; Mice; Disease Progression; Mice, Nude; Male; Female; Prognosis; Mice, Inbred BALB C; DNA-Binding Proteins
PubMed: 38880324
DOI: 10.1016/j.yexcr.2024.114125 -
Nature Communications Jun 2024Motor learning relies on experience-dependent plasticity in relevant neural circuits. In four experiments, we provide initial evidence and a double-blinded,...
Motor learning relies on experience-dependent plasticity in relevant neural circuits. In four experiments, we provide initial evidence and a double-blinded, sham-controlled replication (Experiment I-II) demonstrating that motor learning involving ballistic index finger movements is improved by preceding paired corticospinal-motoneuronal stimulation (PCMS), a human model for exogenous induction of spike-timing-dependent plasticity. Behavioral effects of PCMS targeting corticomotoneuronal (CM) synapses are order- and timing-specific and partially bidirectional (Experiment III). PCMS with a 2 ms inter-arrival interval at CM-synapses enhances learning and increases corticospinal excitability compared to control protocols. Unpaired stimulations did not increase corticospinal excitability (Experiment IV). Our findings demonstrate that non-invasively induced plasticity interacts positively with experience-dependent plasticity to promote motor learning. The effects of PCMS on motor learning approximate Hebbian learning rules, while the effects on corticospinal excitability demonstrate timing-specificity but not bidirectionality. These findings offer a mechanistic rationale to enhance motor practice effects by priming sensorimotor training with individualized PCMS.
Topics: Humans; Male; Learning; Female; Adult; Neuronal Plasticity; Young Adult; Motor Neurons; Transcranial Magnetic Stimulation; Pyramidal Tracts; Evoked Potentials, Motor; Double-Blind Method; Motor Cortex; Fingers; Motor Skills; Synapses
PubMed: 38879614
DOI: 10.1038/s41467-024-49478-5 -
Nature Communications Jun 2024The capacity of HIV-1 to replicate during optimal antiretroviral therapy (ART) is challenging to assess directly. To gain greater sensitivity to detect evolution on ART,...
The capacity of HIV-1 to replicate during optimal antiretroviral therapy (ART) is challenging to assess directly. To gain greater sensitivity to detect evolution on ART, we used a nonhuman primate (NHP) model providing precise control over the level of pre-ART evolution and more comprehensive analyses than are possible with clinical samples. We infected 21 rhesus macaques (RMs) with the barcoded virus SIVmac239M and initiated ART early to minimize baseline genetic diversity. RMs were treated for 285-1200 days. We used several tests of molecular evolution to compare 1352 near-full-length (nFL) SIV DNA single genome sequences from PBMCs, lymph nodes, and spleen obtained near the time of ART initiation and those present after long-term ART, none of which showed significant changes to the SIV DNA population during ART in any animal. To investigate the possibility of ongoing replication in unsampled putative tissue sanctuaries during ART, we discontinued treatment in four animals and confirmed that none of the 336 nFL SIV RNA sequences obtained from rebound plasma viremia showed evidence of evolution. The rigorous nature of our analyses reinforced the emerging consensus of a lack of appreciable ongoing replication on effective ART and validates the relevance of this NHP model for cure studies.
Topics: Animals; Simian Immunodeficiency Virus; Simian Acquired Immunodeficiency Syndrome; Macaca mulatta; Virus Replication; Anti-Retroviral Agents; Evolution, Molecular; RNA, Viral; Viral Load; Viremia; DNA, Viral; Male
PubMed: 38877003
DOI: 10.1038/s41467-024-49369-9 -
Oncology Reports Jul 20242',3',4'‑trihydroxyflavone (2‑D08), a SUMO E2 inhibitor, has several biological functions, including anticancer activity, but its effects on uterine leiomyosarcoma...
2',3',4'‑trihydroxyflavone (2‑D08), a SUMO E2 inhibitor, has several biological functions, including anticancer activity, but its effects on uterine leiomyosarcoma (Ut‑LMS) are unknown. The anticancer activity of 2‑D08 was explored in an model using SK‑LMS‑1 and SK‑UT‑1B cells (human Ut‑LMS cells). Treatment with 2‑D08 inhibited cell viability in a dose‑ and time‑dependent manner and significantly inhibited the colony‑forming ability of Ut‑LMS cells. In SK‑UT‑1B cells treated with 2‑D08, flow cytometric analysis revealed a slight increase in apoptotic rates, while cell cycle progression remained unaffected. Western blotting revealed elevated levels of RIP1, indicating induction of necrosis, but LC3B levels remained unchanged, suggesting no effect on autophagy. A lactate dehydrogenase (LDH) assay confirmed increased LDH release, further supporting the induction of apoptosis and necrosis by 2‑D08 in SK‑UT‑1B cells. 2‑D08‑induced production of reactive oxygen species and apoptosis progression were observed in SK‑LMS‑1 cells. Using Ki67 staining and bromodeoxyuridine assays, it was found that 2‑D08 suppressed proliferation in SK‑LMS‑1 cells, while treatment for 48 h led to cell‑cycle arrest. 2‑D08 upregulated p21 protein expression in SK‑LMS‑1 cells and promoted apoptosis through caspase‑3. Evaluation of α‑SM‑actin, calponin 1 and TAGLN expression indicated that 2‑D08 did not directly initiate smooth muscle phenotypic switching in SK‑LMS‑1 cells. Transcriptome analysis on 2‑D08‑treated SK‑LMS‑1 cells identified significant differences in gene expression and suggested that 2‑D08 modulates cell‑cycle‑ and apoptosis‑related pathways. The analysis identified several differentially expressed genes and significant enrichment for biological processes related to DNA replication and molecular functions associated with the apoptotic process. It was concluded that 2‑D08 exerts antitumor effects in Ut‑LMS cells by modulating multiple signaling pathways and that 2‑D08 may be a promising candidate for the treatment of human Ut‑LMS. The present study expanded and developed knowledge regarding Ut‑LMS management and indicated that 2‑D08 represents a notable finding in the exploration of fresh treatment options for such cancerous tumors.
Topics: Humans; Leiomyosarcoma; Female; Uterine Neoplasms; Cell Line, Tumor; Apoptosis; Cell Proliferation; Cell Survival; Gene Expression Regulation, Neoplastic; Reactive Oxygen Species; Signal Transduction; Flavones; Antineoplastic Agents; Cell Cycle; Autophagy
PubMed: 38874019
DOI: 10.3892/or.2024.8756 -
Tobacco Induced Diseases 2024The e-cigarette market is large and diverse. Traditional smoking cessation trials involving a control group and a 6-month observation period are an inefficient...
INTRODUCTION
The e-cigarette market is large and diverse. Traditional smoking cessation trials involving a control group and a 6-month observation period are an inefficient methodology for testing the multiple treatment options e-cigarettes provide for harm reduction in cigarette smokers. We determined when product substitution occurred in the e-cigarette provision arm of an e-cigarette substitution trial for cigarette smokers who were not interested in quitting.
METHODS
We conducted a secondary analysis of 120 cigarette smokers with severe mental illness (recruitment 2017-2020) who were given disposable e-cigarettes for 8 weeks and assessed at weeks 0 (t0), 2, 4, 6, and 8. We explored product substitution through visit-to-visit correlations in change in product use, then developed a dual process growth model for cigarette and e-cigarette use to test the association between increases in e-cigarette use and concurrent decreases in cigarettes smoked.
RESULTS
Mean age of the participants was 45.9 years, and 42.7% smoked ≥20 cigarettes per day. Almost all product substitution occurred between t0 and t2. For the average smoker (18 cigarettes per day), t2 cigarette frequency decreased by 0.39 (95% CI: -0.56 - -0.22) cigarettes for each additional e-cigarette session. There was effect modification (p=0.033), such that baseline light smokers (<10 cigarettes/day) had no significant decrease in t2 cigarette frequency, regardless of their initial increase in e-cigarette use, while heavy smokers (38 cigarettes/day) switched products nearly on a one-to-one basis.
CONCLUSIONS
In this study, most product substitution occurred early, and heavier smokers had larger t2 decreases in cigarettes/day with increased e-cigarette use. If confirmed with replication studies, the findings could suggest establishment of a novel outcome for e-cigarette studies - early product substitution - and support the value of short-term comparative effectiveness trials that compare multiple potentially lower harm tobacco products.
CLINICAL TRIAL REGISTRATION
The study was registered on the official website of ClinicalTrials.gov.
IDENTIFIER
ID NCT03050853.
PubMed: 38873183
DOI: 10.18332/tid/189220 -
Water Research X May 2024The impacts of climate change on hydrology underscore the urgency of understanding watershed hydrological patterns for sustainable water resource management. The...
The impacts of climate change on hydrology underscore the urgency of understanding watershed hydrological patterns for sustainable water resource management. The conventional physics-based fully distributed hydrological models are limited due to computational demands, particularly in the case of large-scale watersheds. Deep learning (DL) offers a promising solution for handling large datasets and extracting intricate data relationships. Here, we propose a DL modeling framework, incorporating convolutional neural networks (CNNs) to efficiently replicate physics-based model outputs at high spatial resolution. The goal was to estimate groundwater head and surface water depth in the Sabgyo Stream Watershed, South Korea. The model datasets consisted of input variables, including elevation, land cover, soil type, evapotranspiration, rainfall, and initial hydrological conditions. The initial conditions and target data were obtained from the fully distributed hydrological model HydroGeoSphere (HGS), whereas the other inputs were actual measurements in the field. By optimizing the training sample size, input design, CNN structure, and hyperparameters, we found that CNNs with residual architectures (ResNets) yielded superior performance. The optimal DL model reduces computation time by 45 times compared to the HGS model for monthly hydrological estimations over five years (RMSE 2.35 and 0.29 m for groundwater and surface water, respectively). In addition, our DL framework explored the predictive capabilities of hydrological responses to future climate scenarios. Although the proposed model is cost-effective for hydrological simulations, further enhancements are needed to improve the accuracy of long-term predictions. Ultimately, the proposed DL framework has the potential to facilitate decision-making, particularly in large-scale and complex watersheds.
PubMed: 38872710
DOI: 10.1016/j.wroa.2024.100228 -
Frontiers in Aging Neuroscience 2024The observational association between cathepsin and Parkinson's disease (PD) has been partially explored in previous research. However, the causal relationship remains...
OBJECTIVE
The observational association between cathepsin and Parkinson's disease (PD) has been partially explored in previous research. However, the causal relationship remains unclear. In this study, our objective is to investigate the causal link between cathepsin and PD using Mendelian randomization (MR) analysis and elucidate the underlying mechanisms governing their interaction.
METHODS
Utilizing bidirectional two-sample MR and multivariable MR, we systematically investigates the causal relationship between nine cathepsins and PD. The data pertaining to cathepsins were obtained from the Integrative Epidemiology Unit (IEU) Open GWAS Project, while data related to PD were sourced from versions R9 and R10 of the FinnGen database. The primary analytical method utilized was the inverse variance weighted (IVW), with MR analysis initially conducted using PD data from R9, complemented by a series of sensitivity analyses. Subsequently, replication analysis was performed on the R10 dataset, and meta-analysis were employed to merge the findings from both datasets. To explore potential mechanisms by which Cathepsins may impact PD, MR analyses were performed on significant Cathepsins with alpha-synuclein. MR analysis and colocalization analysis were conducted on expression quantitative trait loci (eQTL) data of gene related to alpha-synuclein with PD data.
RESULT
Forward MR analyses revealed more cathepsin B (CTSB) associated with less PD risk (OR = 0.898, 95%CI: 0.834-0.966, = 0.004), while more cathepsin H (CTSH) (OR = 1.076, 95%CI: 1.007-1.149, = 0.029) and more cathepsin S (CTSS) (OR = 1.076, 95%CI: 1.007-1.150, = 0.030) associated with increasing PD risk. Meta-analyses validated these associations. Multivariate MR Results were consistent with those before adjustment. No significant results were observed in bidirectional MR analysis. In the investigation of the underlying mechanism, our findings demonstrate that CTSB significantly reduces the levels of alpha-synuclein (OR = 0.909, 95%CI: 0.841-0.983, = 0.017). Concurrently, a genetically determined positive correlation between alpha-synuclein and PD is illuminated by both eQTL MR and colocalization analysis.
CONCLUSION
In conclusion, this MR study yields robust evidence suggesting an association between elevated levels of CTSB and reduced PD risk, mediated by the downregulation of alpha-synuclein levels. Conversely, higher levels of CTSH and CTSS are associated with an increased risk of PD. These findings offer novel insights into the pathophysiological mechanisms of PD and identify potential drug targets for disease prevention and treatment warranting further clinical investigations.
PubMed: 38872630
DOI: 10.3389/fnagi.2024.1394807 -
Cell Host & Microbe Jun 2024Aspects of how Burkholderia escape the host's intrinsic immune response to replicate in the cell cytosol remain enigmatic. Here, we show that Burkholderia has evolved...
Aspects of how Burkholderia escape the host's intrinsic immune response to replicate in the cell cytosol remain enigmatic. Here, we show that Burkholderia has evolved two mechanisms to block the activity of Ring finger protein 213 (RNF213)-mediated non-canonical ubiquitylation of bacterial lipopolysaccharide (LPS), thereby preventing the initiation of antibacterial autophagy. First, Burkholderia's polysaccharide capsule blocks RNF213 association with bacteria and second, the Burkholderia deubiquitylase (DUB), TssM, directly reverses the activity of RNF213 through a previously unrecognized esterase activity. Structural analysis provides insight into the molecular basis of TssM esterase activity, allowing it to be uncoupled from its isopeptidase function. Furthermore, a putative TssM homolog also displays esterase activity and removes ubiquitin from LPS, establishing this as a virulence mechanism. Of note, we also find that additional immune-evasion mechanisms exist, revealing that overcoming this arm of the host's immune response is critical to the pathogen.
Topics: Ubiquitination; Lipopolysaccharides; Humans; Burkholderia; Bacterial Proteins; Esterases; Immune Evasion; Ubiquitin-Protein Ligases; Host-Pathogen Interactions; Autophagy; Virulence
PubMed: 38870903
DOI: 10.1016/j.chom.2024.04.012 -
PloS One 2024This paper presents the initial exploration of the free radical scavenging capabilities of peptides derived from protein hydrolysates (PPH) obtained from Zingiber...
A novel peptide derived from Zingiber cassumunar rhizomes exhibits anticancer activity against the colon adenocarcinoma cells (Caco-2) via the induction of intrinsic apoptosis signaling.
This paper presents the initial exploration of the free radical scavenging capabilities of peptides derived from protein hydrolysates (PPH) obtained from Zingiber cassumunar rhizomes (Phlai). To replicate the conditions of gastrointestinal digestion, a combination of pepsin and pancreatin proteolysis was employed to generate these hydrolysates. Subsequently, the hydrolysate underwent fractionation using molecular weight cut-off membranes at 10, 5, 3, and 0.65 kDa. The fraction with a molecular weight less than 0.65 kDa exhibited the highest levels ABTS, DPPH, FRAP, and NO radical scavenging activity. Following this, RP-HPLC was used to further separate the fraction with a molecular weight less than 0.65 kDa into three sub-fractions. Among these, the F5 sub-fraction displayed the most prominent radical-scavenging properties. De novo peptide sequencing via quadrupole-time-of-flight-electron spin induction-mass spectrometry identified a pair of novel peptides: Asp-Gly-Ile-Phe-Val-Leu-Asn-Tyr (DGIFVLNY or DY-8) and Ile-Pro-Thr-Asp-Glu-Lys (IPTDEK or IK-6). Database analysis confirmed various properties, including biological activity, toxicity, hydrophilicity, solubility, and potential allergy concerns. Furthermore, when tested on the human adenocarcinoma colon (Caco-2) cell line, two synthetic peptides demonstrated cellular antioxidant activity in a concentration-dependent manner. These peptides were also assessed using the FITC Annexin V apoptosis detection kit with PI, confirming the induction of apoptosis. Notably, the DY-8 peptide induced apoptosis, upregulated mRNA levels of caspase-3, -8, and -9, and downregulated Bcl-2, as confirmed by real-time quantitative polymerase chain reaction (RT-qPCR). Western blot analysis indicated increased pro-apoptotic Bax expression and decreased anti-apoptotic Bcl-2 expression in Caco-2 cells exposed to the DY-8 peptide. Molecular docking analysis revealed that the DY-8 peptide exhibited binding affinity with Bcl-2, Bcl-xL, and Mcl-1, suggesting potential utility in combating colon cancer as functional food ingredients.
Topics: Humans; Apoptosis; Rhizome; Caco-2 Cells; Signal Transduction; Peptides; Colonic Neoplasms; Zingiberaceae; Adenocarcinoma; Antineoplastic Agents; Free Radical Scavengers
PubMed: 38870120
DOI: 10.1371/journal.pone.0304701 -
Heliyon Jun 2024Anti-SARS-CoV-2 and immunomodulatory drugs are important for treating clinically severe patients with respiratory distress symptoms. Alpha- and gamma-mangostins (AM and...
BACKGROUND
Anti-SARS-CoV-2 and immunomodulatory drugs are important for treating clinically severe patients with respiratory distress symptoms. Alpha- and gamma-mangostins (AM and GM) were previously reported as potential 3C-like protease (3CL) and Angiotensin-converting enzyme receptor 2 (ACE2)-binding inhibitors .
OBJECTIVE
We aimed to evaluate two active compounds, AM and GM, from for their antivirals against SARS-CoV-2 in live virus culture systems and their cytotoxicities using standard methods. Also, we aimed to prove whether 3CL and ACE2 neutralization were major targets and explored whether any additional targets existed.
METHODS
We tested the translation and replication efficiencies of SARS-CoV-2 in the presence of AM and GM. Initial and subgenomic translations were evaluated by immunofluorescence of SARS-CoV-2 3CL and N expressions at 16 h after infection. The viral genome was quantified and compared with the untreated group. We also evaluated the efficacies and cytotoxicities of AM and GM against four strains of SARS-CoV-2 (wild-type B, B.1.167.2, B.1.36.16, and B.1.1.529) in Vero E6 cells. The potential targets were evaluated using cell-based anti-attachment, time-of-drug addition, 3CL activities, and ACE2-binding using a surrogated viral neutralization test (sVNT). Moreover, additional targets were explored using combinatorial network-based interactions and Chemical Similarity Ensemble Approach (SEA).
RESULTS
AM and GM reduced SARS-CoV-2 3CL and N expressions, suggesting that initial and subgenomic translations were globally inhibited. AM and GM inhibited all strains of SARS-CoV-2 at EC of 0.70-3.05 μM, in which wild-type B was the most susceptible strain (EC 0.70-0.79 μM). AM was slightly more efficient in the variants (EC 0.88-2.41 μM), resulting in higher selectivity indices (SI 3.65-10.05), compared to the GM (EC 0.94-3.05 μM, SI 1.66-5.40). GM appeared to be more toxic than AM in both Vero E6 and Calu-3 cells. Cell-based anti-attachment and time-of-addition suggested that the potential molecular target could be at the post-infection. 3CL activity and ACE2 binding were interfered with in a dose-dependent manner but were insufficient to be a major target. Combinatorial network-based interaction and chemical similarity ensemble approach (SEA) suggested that fatty acid synthase (FASN), which was critical for SARS-CoV-2 replication, could be a target of AM and GM.
CONCLUSION
AM and GM inhibited SARS-CoV-2 with the highest potency at the wild-type B and the lowest at the B.1.1.529. Multiple targets were expected to integratively inhibit viral replication in cell-based system.
PubMed: 38867992
DOI: 10.1016/j.heliyon.2024.e31987