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ETHNOPHARMACOLOGICAL RELEVANCE: Solanum torvum Sw. (ST) is used to clear heat toxins, promote blood circulation, and alleviate blood stasis. Therefore, this plant has traditionally been used as an ethnomedicine for common cold, chronic gastritis, and tumors. AIM OF THE STUDY: This study aimed to elucidate the mechanism by which ST induces ferroptosis in hepatocellular carcinoma (HCC), the combination effect with lenvatinib, and the impact on lenvatinib-resistant cells. MATERIALS AND METHODS: Cell viability assays were performed using different hepatoma cell lines treated with ST. Lipid peroxidation and iron assays were performed using flow cytometry. Molecules involved in the ferroptosis pathway were detected by Western blotting. Finally, a lenvatinib-resistant cell line was established to evaluate the antiproliferative effects of ST. RESULTS: ST ethanol extract inhibited the growth of various hepatoma cell lines. A significant reduction in glutathione peroxidase 4 (GPX4) expression was observed following ST treatment, which was accompanied by increased lipid peroxidation and Fe2+ accumulation. ST induced ferroptosis mainly through heme oxygenase-1 (HO-1) expression. HO-1 knockdown reduced ST-induced lipid peroxidation and reversed GPX4 suppression. Acyl-CoA synthetase long-chain family member 4 (ACSL4) also participated in ST-induced ferroptosis. ST and lenvatinib combination showed an additive effect, and ST retained its potential anti-HCC efficacy in a lenvatinib-resistant cell line. CONCLUSION: This study demonstrated that the ethanol extract of ST inhibits hepatoma cell growth by inducing ferroptosis. ST displayed an additive effect with lenvatinib in Hep 3B cells and showed remarkable anti-HCC activity in lenvatinib-resistant Hep 3B cells. Collectively, the study shows that ST might have the potential to reduce lenvatinib use in clinical practice and salvage cases of lenvatinib resistance.
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Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for the current coronavirus disease pandemic. With the rapid evolution of variant strains, finding effective spike protein inhibitors is a logical and critical priority. Angiotensin-converting enzyme 2 (ACE2) has been identified as the functional receptor for SARS-CoV-2 viral entry, and thus related therapeutic approaches associated with the spike protein-ACE2 interaction show a high degree of feasibility for inhibiting viral infection. Our computer-aided drug design (CADD) method meticulously analyzed more than 260,000 compound records from the United States National Cancer Institute (NCI) database, to identify potential spike inhibitors. The spike protein receptor-binding domain (RBD) was chosen as the target protein for our virtual screening process. In cell-based validation, SARS-CoV-2 pseudovirus carrying a reporter gene was utilized to screen for effective compounds. Ultimately, compounds C2, C8, and C10 demonstrated significant antiviral activity against SARS-CoV-2, with estimated EC50 values of 8.8 µM, 6.7 µM, and 7.6 µM, respectively. Using the above compounds as templates, ten derivatives were generated and robust bioassay results revealed that C8.2 (EC50 = 5.9 µM) exhibited the strongest antiviral efficacy. Compounds C8.2 also displayed inhibitory activity against the Omicron variant, with an EC50 of 9.3 µM. Thus, the CADD method successfully discovered lead compounds binding to the spike protein RBD that are capable of inhibiting viral infection.
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Enzima de Conversão de Angiotensina 2 , Antivirais , Tratamento Farmacológico da COVID-19 , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Glicoproteína da Espícula de Coronavírus/metabolismo , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Humanos , SARS-CoV-2/efeitos dos fármacos , Antivirais/farmacologia , Antivirais/química , Enzima de Conversão de Angiotensina 2/metabolismo , Enzima de Conversão de Angiotensina 2/química , Enzima de Conversão de Angiotensina 2/antagonistas & inibidores , Simulação de Acoplamento Molecular , Descoberta de Drogas/métodos , Ligação Proteica , COVID-19/virologia , Desenho de Fármacos , Internalização do Vírus/efeitos dos fármacosRESUMO
Anxiety is a pervasive emotional state where, phenomenologically, subjects often report changes in their experience of time and space. However, a systematic and quantified examination of time and space experience in terms of a self-report scale is still missing which eventually could also be used for clinical differential diagnosis. Based on historical phenomenological literature and patients' subjective reports, we here introduce, in a first step, the Scale for Time and Space Experience of Anxiety (STEA) in a smaller sample of 19 subjects with anxiety disorders and, in a second step, validate its shorter clinical version (cSTEA) in a larger sample of 48 anxiety subjects. The main findings are (i) high convergent and divergent validity of STEA with both Beck Anxiety Inventory (BAI) (r = 0.7325; p < 0.001) and Beck Depression Inventory (BDI) (r = 0.7749; p < 0.0001), as well as with spontaneous mind wandering (MWS) (r = 0.7343; p < 0.001) and deliberate mind wandering (MWD) (r = 0.1152; p > 0.05), (ii) statistical feature selection shows 8 key items for future clinical usage (cSTEA) focusing on the experience of temporal and spatial constriction, (iii) the effects of time and space experience (i.e., for both STEA and cSTEA scores) on the level of anxiety (BAI) are mediated by the degree of spontaneous mind wandering (MWS), (iv) cSTEA allows for differentiating high levels of anxiety from the severity of comorbid depressive symptoms, and (v) significant reduction in the cSTEA scores after a therapeutic intervention (breathing therapy). Together, our study introduces a novel fully quantified and highly valid self-report instrument, the STEA, for measuring time-space experiences in anxiety. Further we develop a shorter clinical version (cSTEA) which allows assessing time space experience in a valid, quick, and simple way for diagnosis, differential diagnosis, and therapeutic monitoring of anxiety.
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Transtornos de Ansiedade , Escalas de Graduação Psiquiátrica , Humanos , Masculino , Feminino , Adulto , Transtornos de Ansiedade/diagnóstico , Transtornos de Ansiedade/psicologia , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica/normas , Reprodutibilidade dos Testes , Psicometria , Ansiedade/diagnóstico , Ansiedade/psicologia , Autorrelato , Percepção Espacial , Percepção do Tempo , Adulto Jovem , Relevância ClínicaRESUMO
BACKGROUND: Type 2 diabetes mellitus (DM) is an independent risk factor for hepatocellular carcinoma (HCC), while insulin is a potent mitogen. Identifying a new therapeutic modality for preventing insulin users from developing HCC is a critical goal for researchers. AIM: To investigate whether regular herbal medicine use can decrease HCC risk in DM patients with regular insulin control. METHODS: We used data acquired from the Taiwanese National Health Insurance research database between 2000 and 2017. We identified patients with DM who were prescribed insulin for > 3 months. The herb user group was further defined as patients prescribed herbal medication for DM for > 3 months per annum during follow-up. We matched the herb users to nonusers at a 1:3 ratio according to age, sex, comorbidities and index year by propensity score matching. We analyzed HCC incidence, HCC survival rates, and the herbal prescriptions involved. RESULTS: We initially enrolled 657144 DM patients with regular insulin use from 2000 to 2017. Among these, 46849 patients had used a herbal treatment for DM, and 140547 patients were included as the matched control group. The baseline variables were similar between the herb users and nonusers. DM patients with regular herb use had a 12% decreased risk of HCC compared with the control group [adjusted hazard ratio (aHR) = 0.88, 95%CI = 0.80-0.97]. The cumulative incidence of HCC in the herb users was significantly lower than that of the nonusers. Patients with a herb use of > 5 years cumulatively exhibited a protective effect against development of HCC (aHR = 0.82, P < 0.05). Of patients who developed HCC, herb users exhibited a longer survival time than nonusers (aHR = 0.78, P = 0.0001). Additionally, we report the top 10 herbs and formulas in prescriptions and summarize the potential pharmacological effects of the constituents. Our analysis indicated that Astragalus propinquus (Huang Qi) plus Salvia miltiorrhiza Bunge (Dan Shen), and Astragalus propinquus (Huang Qi) plus Trichosanthes kirilowii Maxim. (Tian Hua Fen) were the most frequent combination of single herbs. Meanwhile, Ji Sheng Shen Qi Wan plus Dan Shen was the most frequent combination of herbs and formulas. CONCLUSION: This large-scale retrospective cohort study reveals that herbal medicine may decrease HCC risk by 12% in DM patients with regular insulin use.
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Prussian blue analogues (PBAs) are promising materials due to their rich active sites and straightforward synthesis. However, their limited conductivity and electron transfer inefficiency hinder practical applications. This study utilizes a simple one-pot synthesis approach to produce a tungsten-disulfide (WS2) and iron-cobalt Prussian blue analogue composite (WS2-PBA), enhancing conductivity and electron transfer rate performance. Through the inclusion of sodium citrate into the solution, the S-edge site concentration of WS2 increases. This augmentation introduces additional active sites and defects into the catalyst, enhancing its catalytic activity. The effectiveness of the WS2-PBA 3D-Origami paper device for lactate detection in sweat is also evaluated for biomedical applications. The device demonstrated a robust relationship between the lactate concentration and current intensity (R2 = 0.997), with a detection limit of 1.83 mM. Additionally, this platform has successfully detected lactate in clinical sweat, correlating with the high-performance liquid chromatography test results, suggesting promising prospects for clinical diagnosis. In the future, the excellent catalytic and Rct performance of the WS2-PBA will enable its use in biomedical applications.
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Técnicas Biossensoriais , Suor , Ferrocianetos , Ácido LácticoRESUMO
In this study, we demonstrate that palladium-platinum bimetallic nanoparticles (Pd@Pt NPs) as the nanozyme, combined with a multi-layer paper-based analytical device and DNA hybridization, can successfully detect Mycobacterium tuberculosis. This nanozyme has peroxidase-like properties, which can increase the oxidation rate of the substrate. Compared with horseradish peroxidase, which is widely used in traditional detection, the Michaelis constants of Pd@Pt NPs are fourteen and seventeen times lower than those for 3,3',5,5'-tetramethylbenzidine and H2O2, respectively. To verify the catalytic efficiency of Pd@Pt NPs, this study will execute molecular diagnosis of Mycobacterium tuberculosis. We chose the IS6110 fragment as the target DNA and divided the complementary sequences into the capture DNA and reporter DNA. They were modified on paper and Pd@Pt NPs, respectively, to detect Mycobacterium tuberculosis on a paper-based analytical device. With the above-mentioned method, we can detect target DNA within 15 minutes with a linear range between 0.75 and 10 nM, and a detection limit of 0.216 nM. These results demonstrate that the proposed platform (a DNA-nanozyme integrated paper-based analytical device, dnPAD) can provide sensitive and on-site infection prognosis in areas with insufficient medical resources.
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Nanopartículas Metálicas , Mycobacterium tuberculosis , Peróxido de Hidrogênio/química , Platina/química , Paládio/química , Nanopartículas Metálicas/química , DNA , ColorimetriaRESUMO
The soil microbiome plays a key role in plant health. Native soil microbiome inoculation, metagenomic profiling, and high-throughput cultivation require efficient microbe extraction. Sonication and oscillation are the most common methods used to extract soil microbiomes. However, the extraction efficiency of these methods has not been investigated in full. In this study, we compared the culturable microbe numbers, community structures, and alpha diversities among the different methods, including sonication, oscillation, and centrifugation, and their processing times. The study results showed that sonication significantly increases the culturable colony number compared with oscillation and centrifugation. Furthermore, the sonication strategy was found to be the main factor influencing extraction efficiency, but increased sonication time can aid in recovery from this impact. Finally, the extraction processing times were found to have a significant negative relationship with α-diversity among the extracted microbiota. In conclusion, sonication is the main factor for enriching in situ microbiota, and increased extraction time significantly decreases the α-diversity of the extracted microbiota. The results of this study provide insights into the isolation and utilization of different microorganism sources.
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BACKGROUND: The COVID-19 pandemic interrupted the organized training of softball players, similar to the abrupt cessation of sports participation that can happen after an injury. Thus, the COVID-19 pandemic offers a unique model to study how sudden detraining influences softball players. METHODS: We recruited a sample of convenience of National Collegiate Athletic Association Division 1 softball players. They participated in three data collections: pre-lockdown (Jan 2020, T1), post-lockdown (Sept 2020, T2), and before the 2021 season (Jan 2021, T3). Between T1 and T2, players received an at-home conditioning and throwing program, but compliance was not strictly monitored. Between T2-T3, players resumed formal fall training (team-organized workouts, on-field practice, and within-team scrimmage games). At each time point, we collected bilaterally: 1) shoulder internal rotation (IR) and external rotation (ER) range of motion (ROM); 2) shoulder IR and ER strength; 3) hip IR and ER ROM; and 4) hip abduction and extension strength. We used four independent (2 Sides × 3 Timepoints) MANOVA with repeated measures; we followed up significant MANOVA main effect of time with Sidak posthoc tests for pairwise comparisons between time points. RESULTS: Fifteen players participated in this study. We found a significant MANOVA main effect of time for shoulder and hip ROM (p < 0.01). Between T1-T2, dominant shoulder ER ROM decreased 6.5°, dominant shoulder IR ROM increased 4.3°, and lead hip IR ROM increased 4.4°. Between T2-T3, dominant shoulder ER ROM increased 6.3° and trail hip ER ROM increased 5.9°. We found a significant MANOVA main effect of time for shoulder strength (p = 0.03) but not for hip strength (p = 0.18). Between T2-T3, non-dominant shoulder IR and ER increased 1.8 kg and 1.5 kg, respectively. CONCLUSION: A sudden and prolonged cessation of organized training generated changes in shoulder and hip ROM but affected strength to a lesser extent. The loss of shoulder ER and increased lead hip IR ROM are maladaptive as they are associated with injury in overhead athletes. Resuming team-organized training and scrimmage reversed some (shoulder ER), but not all of these changes. Practitioners should monitor clinical variables regularly and be aware of potential changes due to unexpected and prolonged interruptions in training, such as when players suffer sports-related injuries.
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BACKGROUND: Chronic lymphocytic leukaemia (CLL) is the most common lymphoproliferative disease in adults and currently remains incurable. As the progression-free period shortens after each successive treatment, strategies such as maintenance therapy are needed to improve the degree and duration of response to previous therapies. Monoclonal antibodies, immunomodulatory agents, and targeted therapies are among the available options for maintenance therapy. People with CLL who achieve remission after previous therapy may choose to undergo medical observation or maintenance therapy to deepen the response. Even though there is widespread use of therapeutic maintenance agents, the benefits and harms of these treatments are still uncertain. OBJECTIVES: To assess the effects and safety of maintenance therapy, including anti-CD20 monoclonal antibody, immunomodulatory drug therapy, anti-CD52 monoclonal antibody, Bruton tyrosine kinase inhibitor, and B-cell lymphoma-2 tyrosine kinase inhibitor, for individuals with CLL. SEARCH METHODS: We conducted a comprehensive literature search for randomised controlled trials (RCTs) with no language or publication status restrictions. We searched CENTRAL, MEDLINE, Embase, and three trials registers in January 2022 together with reference checking, citation searching, and contact with study authors to identify additional studies. SELECTION CRITERIA: We included RCTs with prospective identification of participants. We excluded cluster-randomised trials, cross-over trial designs, and non-randomised studies. We included studies comparing maintenance therapies with placebo/observation or head-to-head comparisons. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. We assessed risk of bias in the included studies using Cochrane's RoB 1 tool for RCTs. We rated the certainty of evidence for the following outcomes using the GRADE approach: overall survival (OS), health-related quality of life (HRQoL), grade 3 and 4 adverse events (AEs), progression-free survival (PFS), treatment-related mortality (TRM), treatment discontinuation (TD), and all adverse events (AEs). MAIN RESULTS: We identified 11 RCTs (2393 participants) that met the inclusion criteria, including seven trials comparing anti-CD20 monoclonal antibodies (mAbs) (rituximab or ofatumumab) with observation in 1679 participants; three trials comparing immunomodulatory drug (lenalidomide) with placebo/observation in 693 participants; and one trial comparing anti-CD 52 mAbs (alemtuzumab) with observation in 21 participants. No comparisons of novel small molecular inhibitors were found. The median age of participants was 54.1 to 71.7 years; 59.5% were males. The type of previous induction treatment, severity of disease, and baseline stage varied among the studies. Five trials included early-stage symptomatic patients, and three trials included advanced-stage patients (Rai stage III/IV or Binet stage B/C). Six trials reported a frequent occurrence of cytogenic aberrations at baseline (69.7% to 80.1%). The median follow-up duration was 12.4 to 73 months. The risk of selection bias in the included studies was unclear. We assessed overall risk of performance bias and detection bias as low risk for objective outcomes and high risk for subjective outcomes. Overall risk of attrition bias, reporting bias, and other bias was low. Anti-CD20 monoclonal antibodies (mAbs): rituximab or ofatumumab maintenance versus observation Anti-CD20 mAbs maintenance likely results in little to no difference in OS (hazard ratio (HR) 0.94, 95% confidence interval (CI) 0.73 to 1.20; 1152 participants; 3 studies; moderate-certainty evidence) and likely increases PFS significantly (HR 0.61, 95% CI 0.50 to 0.73; 1255 participants; 5 studies; moderate-certainty evidence) compared to observation alone. Anti-CD20 mAbs may result in: an increase in grade 3/4 AEs (rate ratio 1.34, 95% CI 1.06 to 1.71; 1284 participants; 5 studies; low-certainty evidence); little to no difference in TRM (risk ratio 0.82, 95% CI 0.39 to 1.71; 1189 participants; 4 studies; low-certainty evidence); a slight reduction to no difference in TD (risk ratio 0.93, 95% CI 0.72 to 1.20; 1321 participants; 6 studies; low-certainty evidence); and an increase in all AEs (rate ratio 1.23, 95% CI 1.03 to 1.47; 1321 participants; 6 studies; low-certainty evidence) compared to the observation group. One RCT reported that there may be no difference in HRQoL between the anti-CD20 mAbs (ofatumumab) maintenance and the observation group (mean difference -1.70, 95% CI -8.59 to 5.19; 480 participants; 1 study; low-certainty evidence). Immunomodulatory drug (IMiD): lenalidomide maintenance versus placebo/observation IMiD maintenance therapy likely results in little to no difference in OS (HR 0.91, 95% CI 0.61 to 1.35; 461 participants; 3 studies; moderate-certainty evidence) and likely results in a large increase in PFS (HR 0.37, 95% CI 0.19 to 0.73; 461 participants; 3 studies; moderate-certainty evidence) compared to placebo/observation. Regarding harms, IMiD maintenance therapy may result in an increase in grade 3/4 AEs (rate ratio 1.82, 95% CI 1.38 to 2.38; 400 participants; 2 studies; low-certainty evidence) and may result in a slight increase in TRM (risk ratio 1.22, 95% CI 0.35 to 4.29; 458 participants; 3 studies; low-certainty evidence) compared to placebo/observation. The evidence for the effect on TD compared to placebo is very uncertain (risk ratio 0.71, 95% CI 0.47 to 1.05; 400 participants; 2 studies; very low-certainty evidence). IMiD maintenance therapy probably increases all AEs slightly (rate ratio 1.41, 95% CI 1.28 to 1.54; 458 participants; 3 studies; moderate-certainty evidence) compared to placebo/observation. No studies assessed HRQoL. Anti-CD52 monoclonal antibodies (mAbs): alemtuzumab maintenance versus observation Maintenance with alemtuzumab may have little to no effect on PFS, but the evidence is very uncertain (HR 0.55, 95% CI 0.32 to 0.95; 21 participants; 1 study; very low-certainty evidence). We did not identify any study reporting the outcomes OS, HRQoL, grade 3/4 AEs, TRM, TD, or all AEs. AUTHORS' CONCLUSIONS: There is currently moderate- to very low-certainty evidence available regarding the benefits and harms of maintenance therapy in people with CLL. Anti-CD20 mAbs maintenance improved PFS, but also increased grade 3/4 AEs and all AEs. IMiD maintenance had a large effect on PFS, but also increased grade 3/4 AEs. However, none of the above-mentioned maintenance interventions show differences in OS between the maintenance and control groups. The effects of alemtuzumab maintenance are uncertain, coupled with a warning for drug-related infectious toxicity. We found no studies evaluating other novel maintenance interventions, such as B-cell receptor inhibitors, B-cell leukaemia-2/lymphoma-2 inhibitors, or obinutuzumab.
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Antineoplásicos , Leucemia Linfocítica Crônica de Células B , Adulto , Idoso , Humanos , Pessoa de Meia-Idade , Alemtuzumab , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/efeitos adversos , Lenalidomida/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Rituximab/efeitos adversosRESUMO
The development of the cerebral cortex involves a series of dynamic events, including cell proliferation and migration, which rely on the motor protein dynein and its regulators NDE1 and NDEL1. While the loss of function in NDE1 leads to microcephaly-related malformations of cortical development (MCDs), NDEL1 variants have not been detected in MCD patients. Here, we identified two patients with pachygyria, with or without subcortical band heterotopia (SBH), carrying the same de novo somatic mosaic NDEL1 variant, p.Arg105Pro (p.R105P). Through single-cell RNA sequencing and spatial transcriptomic analysis, we observed complementary expression of Nde1/NDE1 and Ndel1/NDEL1 in neural progenitors and post-mitotic neurons, respectively. Ndel1 knockdown by in utero electroporation resulted in impaired neuronal migration, a phenotype that could not be rescued by p.R105P. Remarkably, p.R105P expression alone strongly disrupted neuronal migration, increased the length of the leading process, and impaired nucleus-centrosome coupling, suggesting a failure in nucleokinesis. Mechanistically, p.R105P disrupted NDEL1 binding to the dynein regulator LIS1. This study identifies the first lissencephaly-associated NDEL1 variant and sheds light on the distinct roles of NDE1 and NDEL1 in nucleokinesis and MCD pathogenesis.
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Lisencefalia , Humanos , Lisencefalia/genética , Movimento Celular/genética , Proliferação de Células , Córtex Cerebral , Dineínas/genética , Proteínas de Transporte , Proteínas Associadas aos Microtúbulos/genéticaRESUMO
BACKGROUND: Tracing patient-specific tumor mutations in cell-free DNA (cfDNA) for minimal residual disease (MRD) detection is promising but challenging. Assaying more mutations and cfDNA stands to improve MRD detection but requires highly accurate, efficient sequencing methods and proper calibration to prevent false detection with bespoke tests. METHODS: MAESTRO (Minor Allele Enriched Sequencing Through Recognition Oligonucleotides) uses mutation-specific oligonucleotide probes to enrich cfDNA libraries for tumor mutations and enable their accurate detection with minimal sequencing. A new approach, MAESTRO-Pool, which entails pooling MAESTRO probes for all patients and applying these to all samples from all patients, was used to screen for 22 333 tumor mutations from 9 melanoma patients in 98 plasma samples. This enabled quantification of MRD detection in patient-matched samples and false detection in unmatched samples from other patients. To detect MRD, a new dynamic MRD caller was used that computes a probability for MRD detection based on the number of mutations and cfDNA molecules sequenced, thereby calibrating for variations in each bespoke test. RESULTS: MAESTRO-Pool enabled sensitive detection of MRD down to 0.78 parts per million (ppm), reflecting a 10- to 100-fold improvement over existing tests. Of the 8 MRD positive samples with ultra-low tumor fractions <10â ppm, 7 were either in upward-trend preceding recurrence or downward-trend aligning with response. Of 784 patient-unmatched tests, only one was found as MRD positive (tumor fraction = 2.7â ppm), suggesting high specificity. CONCLUSIONS: MAESTRO-Pool enables massively parallel, tumor-informed MRD testing with concurrent benchmarking of bespoke MRD tests. Meanwhile, our new MRD caller enables more mutations and cfDNA molecules to be tested without compromising specificity. These improve the ability for detecting traces of MRD from blood.
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Ácidos Nucleicos Livres , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasia Residual/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Estudos de Coortes , MutaçãoRESUMO
This systematic review and meta-analysis aimed to determine whether Olympic weightlifting (OW) exercises would improve sprint performance when compared to a control intervention, (no training, standard sport-specific training, traditional resistance training, or plyometric training). Medline, Web of Science, SportDiscus, CINAHL, and Biological Science from inception to September 2022 was searched. Two authors independently selected the included studies, extracted data, and appraised the risk of bias. Certainty of the evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation methodology. The primary meta-analysis combined the results of the sprint performance over the full length of each sprint test. The secondary meta-analyses combined the results of the sprint performance at 5, 10, and 20 m distance to capture information about the acceleration phase of the sprint tests. Eight studies with 206 athletes (female n=10, age range: 18.9-24.2 years) were identified. Sprint performance did not differ significantly comparing OW to the control intervention, nor at the full length (standardized mean difference=-0.07, 95% CI=-0.47 to 0.34, p=0.75, I2=46%) or during the acceleration phase (p≥0.26) of the sprint test. OW training does not improve sprint performance to a greater extent than comparator interventions.
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The continuous emergence of SARS-CoV-2 variants has led to a protracted global COVID-19 pandemic with significant impacts on public health and global economy. While there are currently available SARS-CoV-2 vaccines and therapeutics, most of the FDA-approved antiviral agents directly target viral proteins. However, inflammation is the initial immune pathogenesis induced by SARS-CoV-2 infection, there is still a need to find additional agents that can control the virus in the early stages of infection to alleviate disease progression for the next pandemic. Here, we find that both the spike protein and its receptor CD147 are crucial for inducing inflammation by SARS-CoV-2 in THP-1 monocytic cells. Moreover, we find that 3-epi-betulin, isolated from Daphniphyllum glaucescens, reduces the level of proinflammatory cytokines induced by SARS-CoV-2, consequently resulting in a decreased viral RNA accumulation and plaque formation. In addition, 3-epi-betulin displays a broad-spectrum inhibition of entry of SARS-CoV-2 pseudoviruses, including Alpha (B.1.1.7), Eplison (B.1.429), Gamma (P1), Delta (B.1.617.2) and Omicron (BA.1). Moreover, 3-epi-betulin potently inhibits SARS-CoV-2 infection with an EC50 of <20 µM in Calu-3 lung epithelial cells. Bioinformatic analysis reveals the chemical interaction between the 3-epi-betulin and the spike protein, along with the critical amino acid residues in the spike protein that contribute to the inhibitory activity of 3-epi-betulin against virus entry. Taken together, our results suggest that 3-epi-betulin exhibits dual effect: it reduces SARS-CoV-2-induced inflammation and inhibits virus entry, positioning it as a potential antiviral agent against SARS-CoV-2.
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COVID-19 , Daphniphyllum , Humanos , SARS-CoV-2 , Vacinas contra COVID-19 , Pandemias , Glicoproteína da Espícula de Coronavírus , Internalização do Vírus , Antivirais/farmacologia , Inflamação/tratamento farmacológicoRESUMO
Existing methods for voxelwise transient dopamine (DA) release detection rely on explicit kinetic modeling of the [11C]raclopride PET time activity curve, which at the voxel level is typically confounded by noise, leading to poor performance for detection of low-amplitude DA release-induced signals. Here we present a novel data-driven, task-informed method-referred to as Residual Space Detection (RSD)-that transforms PET time activity curves to a residual space where DA release-induced perturbations can be isolated and processed. Using simulations, we demonstrate that this method significantly increases detection performance compared to existing kinetic model-based methods for low-magnitude DA release (simulated +100% peak increase in basal DA concentration). In addition, results from nine healthy controls injected with a single bolus of [11C]raclopride performing a finger tapping motor task are shown as proof-of-concept. The ability to detect relatively low magnitudes of dopamine release in the human brain using a single bolus injection, while achieving higher statistical power than previous methods, may additionally enable more complex analyses of neurotransmitter systems. Moreover, RSD is readily generalizable to multiple tasks performed during a single PET scan, further extending the capabilities of task-based single-bolus protocols.
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The mustard aphid (L. erysimi) is a pest that infests various cruciferous crops and transmits plant viruses. To achieve eco-friendly pest management, entomopathogenic fungi (EPF) are potential microbial control agents for controlling this pest. Therefore, virulence screening of EPF isolates under Petri dish conditions is necessary before field application. However, the mustard aphid is a parthenogenetic insect, making it difficult to record data during Petri dish experiments. A modified system for detached-leaf bioassays was developed to address this issue, using a micro-sprayer to inoculate conidia onto aphids and prevent drowning by facilitating air-drying after spore suspension. The system maintained high relative humidity throughout the observation period, and the leaf disc remained fresh for over ten days, allowing parthenogenetic reproduction of the aphids. To prevent offspring buildup, a process of daily removal using a painting brush was implemented. This protocol demonstrates a stable system for evaluating the virulence of EPF isolates against mustard aphids or other aphids, enabling the selection of potential isolates for aphid control.
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Afídeos , Animais , Mostardeira , Fungos , Esporos Fúngicos , InsetosRESUMO
Non-alcoholic fatty liver disease (NAFLD) is a type of steatosis caused by excess lipids accumulating in the liver. The prevalence of NAFLD has increased annually due to modern lifestyles and a lack of adequate medical treatment. Thus, we were motivated to investigate the bioactive components of Formosan plants that could attenuate lipid droplet (LD) accumulation. In a series of screenings of 3000 methanolic extracts from the Formosan plant extract bank for anti-LD accumulation activity, the methanolic extract of aerial parts of Elaeagnus glabra Thunb. showed excellent anti-LD accumulation activity. E. glabra is an evergreen shrub on which only a few phytochemical and biological studies have been conducted. Here, one new flavonoid (1), two new triterpenoids (2 and 3), and 35 known compounds (4-38) were isolated from the ethyl acetate layer of aerial parts of E. glabra via a bioassay-guided fractionation process. Their structures were characterized by 1D and 2D NMR, UV, IR, and MS data. Among the isolated compounds, methyl pheophorbide a (37) efficiently reduced the normalized LD content to 0.3% with a concentration of 20 µM in AML12 cell lines without significant cytotoxic effects. 3-O-(E)-Caffeoyloleanolic acid (13) and methyl pheophorbide a (37) showed inhibitory effects on superoxide anion generation or elastase release in fMLP/CB-treated human neutrophils (IC50 < 3.0 µM); they displayed effects similar to those of the positive control, namely, LY294002. These findings indicate that E. glabra can be used for developing a new botanical drug for managing LD accumulation and against inflammation-related diseases.
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Small-molecule compounds with rich sources have diverse structures and activities. The active ingredients in traditional Chinese medicine(TCM) provide new sources for the discovery of new antitumor drugs. Aconitum plants as Chinese medicinal plants have the effects of dispelling wind, removing dampness, warming meridian, and relieving pain. They are mainly used to treat inflammation, pain, rheumatism, and tumors, improve heart function, and dilate blood vessels in clinical practice. Diterpenoid alkaloids are the main active components of Aconitum plants, including C20-, C19-, C18-diterpenoid alkaloids and bis-diterpenoid alkaloids. Stu-dies have demonstrated that diterpenoid alkaloids can effectively treat lung cancer, liver cancer, breast cancer, colon cancer and other cancers. Diterpenoid alkaloids are considered as the most promising natural compounds against cancers. In this review, we summarized the chemical structures and antitumor activities of C20-, C19-, C18-diterpenoid alkaloids and bis-diterpenoid alkaloids extracted from plants of Aconitum, aiming to provide reference for further development of diterpenoid alkaloids from Aconitum as antitumor drugs.
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Aconitum , Alcaloides , Antineoplásicos , Diterpenos , Humanos , Aconitum/química , Estrutura Molecular , Alcaloides/análise , Diterpenos/química , Antineoplásicos/farmacologia , Antineoplásicos/química , Raízes de Plantas/químicaRESUMO
Introduction: Osteosarcoma (OS), the primary malignant bone tumor, has a low survival rate for recurrent patients. Latest reports indicated that cancer-associated fibroblasts (CAFs) were the main component of tumor microenvironment, and would generate a variable role in the progression of tumors. However, the role of CAFs is still few known in osteosarcoma. Methods: The processed RNA-seq data and the corresponding clinical and molecular information were retrieved from the Cancer Genome Atlas Program (TCGA) database and processed data of tumor tissue was obtained from Gene Expression Omnibus (GEO) database. Xcell method was used in data processing, and Gene set variation analysis (GSVA) was used to calculates enrichment scores. Nomogram was constructed to evaluate prognostic power of the predictive model. And the construction of risk scores and assessment of prognostic predictive were based on the LASSO model. Results: This study classified Cancer Genome Atlas (TCGA) cohort into high and low CAFs infiltrate phenotype with different CAFs infiltration enrichment scores. Then TOP 9 genes were screened as prognostic signatures among 2,488 differentially expressed genes between the two groups. Key prognostic molecules were CGREF1, CORT and RHBDL2 and the risk score formula is: Risk-score = CGREF1*0.004 + CORT*0.004 + RHBDL2*0.002. The signatures were validated to be independent prognostic factors to predict tumor prognosis with single-factor COX and multi-factor COX regression analyses and Norton chart. The risk score expression of risk score model genes could predict the drug resistance, and significant differences could be found between the high and low scoring groups for 17-AAG, AZD6244, PD-0325901 and Sorafenib. Discussion: To sum up, this article validated the prediction role of CAF infiltration in the prognosis of OS, which might shed light on the treatment of OS.
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BACKGROUND: Cardiac allograft vasculopathy (CAV) is an obliterative and diffuse form of vasculopathy and is the most common cause of long-term cardiovascular mortality in heart transplant patients. This study aimed to investigate the diagnostic performance of 99mTc and 201Tl tracers in the assessment of CAV using cadmium-zinc-telluride (CZT) single-photon emission computed tomography (SPECT) for myocardial blood flow (MBF) and myocardial flow reserve (MFR) quantification, which was further validated using 13 N-NH3 positron emission tomography (PET). METHODS: Thirty-eight patients with prior heart transplantation who underwent CZT SPECT and 13 N-NH3 PET dynamic scans were included in this study. CZT SPECT with 99mTc-sestamibi was used in the first 19 patients and 201Tl-chloride for the remaining patients. To determine the diagnostic accuracy of angiographically defined moderate-to-severe CAV, the analysis included patients who underwent angiographic examinations within 1 year of their second scan. RESULTS: There were no significant differences in the patient characteristics between the 201Tl and 99mTc tracer groups. Both 201Tl and 99mTc CZT SPECT-derived stress MBF and MFR values globally and in 3 coronary territories showed good correlations with 13 N-NH3 PET. The 201Tl and 99mTc cohorts did not differ significantly in the correlation coefficients of CZT SPECT versus PET for MBF and MFR, except for stress MBF (201Tl:0.95 versus 99mTc:0.80, P=0.03). 201Tl and 99mTc CZT SPECT were satisfactory for detecting PET MFR <2.0 (201Tl area under the curve, 0.92 [0.71-0.99], 99mTc area under the curve, 0.87 [0.64-0.97]) and angiographically defined moderate-to-severe CAV, and CZT SPECT results were comparable to that of 13 N-NH3 PET (CZT area under the curve, 0.90 [0.70-0.99], PET area under the curve, 0.86 [0.64-0.97]). CONCLUSIONS: This small study suggests that CZT SPECT using 201Tl and 99mTc tracers showed comparable MBF and MFR, and the results correlated well with those of 13 N-NH3 PET. Hence, CZT SPECT with 201Tl or 99mTc tracers can be used to detect moderate-to-severe CAV in patients with prior heart transplantation. However, validation using larger studies is warranted.