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BACKGROUND: Bepirovirsen is an antisense oligonucleotide that targets all hepatitis B virus (HBV) messenger RNAs and acts to decrease levels of viral proteins. METHODS: We conducted a phase 2b, randomized, investigator-unblinded trial involving participants with chronic HBV infection who were receiving or not receiving nucleoside or nucleotide analogue (NA) therapy. Participants were randomly assigned (in a 3:3:3:1 ratio) to receive weekly subcutaneous injections of bepirovirsen at a dose of 300 mg for 24 weeks (group 1), bepirovirsen at a dose of 300 mg for 12 weeks then 150 mg for 12 weeks (group 2), bepirovirsen at a dose of 300 mg for 12 weeks then placebo for 12 weeks (group 3), or placebo for 12 weeks then bepirovirsen at a dose of 300 mg for 12 weeks (group 4). Groups 1, 2, and 3 received loading doses of bepirovirsen. The composite primary outcome was a hepatitis B surface antigen (HBsAg) level below the limit of detection and an HBV DNA level below the limit of quantification maintained for 24 weeks after the planned end of bepirovirsen treatment, without newly initiated antiviral medication. RESULTS: The intention-to-treat population comprised 457 participants (227 receiving NA therapy and 230 not receiving NA therapy). Among those receiving NA therapy, a primary-outcome event occurred in 6 participants (9%; 95% credible interval, 0 to 31) in group 1, in 6 (9%; 95% credible interval, 0 to 43) in group 2, in 2 (3%; 95% credible interval, 0 to 16) in group 3, and 0 (0%; post hoc credible interval, 0 to 8) in group 4. Among participants not receiving NA therapy, a primary-outcome event occurred in 7 participants (10%; 95% credible interval, 0 to 38), 4 (6%; 95% credible interval, 0 to 25), 1 (1%; post hoc credible interval, 0 to 6), and 0 (0%; post hoc credible interval, 0 to 8), respectively. During weeks 1 through 12, adverse events, including injection-site reactions, pyrexia, fatigue, and increased alanine aminotransferase levels, were more common with bepirovirsen (groups 1, 2, and 3) than with placebo (group 4). CONCLUSIONS: In this phase 2b trial, bepirovirsen at a dose of 300 mg per week for 24 weeks resulted in sustained HBsAg and HBV DNA loss in 9 to 10% of participants with chronic HBV infection. Larger and longer trials are required to assess the efficacy and safety of bepirovirsen. (Funded by GSK; B-Clear ClinicalTrials.gov number, NCT04449029.).
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Antivirales , Hepatitis B Crónica , Oligonucleótidos Antisentido , ARN Viral , Humanos , Antivirales/efectos adversos , Antivirales/uso terapéutico , ADN Viral/sangre , Antígenos e de la Hepatitis B/sangre , Antígenos de Superficie de la Hepatitis B/sangre , Virus de la Hepatitis B/genética , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/virología , Oligonucleótidos Antisentido/administración & dosificación , Oligonucleótidos Antisentido/efectos adversos , Oligonucleótidos Antisentido/uso terapéutico , Resultado del Tratamiento , ARN Viral/efectos de los fármacos , ARN Mensajero/efectos de los fármacos , Inyecciones SubcutáneasRESUMEN
BACKGROUND AND AIMS: Simultaneous inhibition of the TGF-ß and PD-L1 pathways provides a potential novel treatment approach. Bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of TGF-ßRII (a TGF-ß "trap") fused to a human IgG1 monoclonal antibody blocking PD-L1, was evaluated in patients with advanced HCC. APPROACH AND RESULTS: In this global, open-label, phase 1 study (NCT02517398), patients with PD-L1-unselected HCC who failed or were intolerant to ≥1 line of sorafenib received bintrafusp alfa 1200 mg every 2 weeks in a dose-escalation (n=38) or dose-expansion (n=68) cohort until confirmed progression, unacceptable toxicity, or trial withdrawal. Primary endpoint was best overall response (BOR) per Response Evaluation Criteria in Solid Tumors 1.1 by independent review committee. Secondary endpoints included investigator-assessed BOR, safety, and pharmacokinetics. Median follow-up times (range) were 41.4 (39.8-44.2) and 38.6 (33.5-39.7) months in the dose-escalation and dose-expansion cohorts, respectively. The objective response rate (ORR) was below the prespecified 20% ORR threshold set to evaluate efficacy of bintrafusp alfa in both cohorts (10.5% and 8.8%, respectively). Median overall survival and progression-free survival, respectively, were 13.8 and 1.5 months in the dose-escalation cohort and 13.5 and 1.4 months in the dose-expansion cohort. Treatment-related adverse events occurred in 78.9% and 64.7% of patients in the respective cohorts (grade ≥3 in 18.4% and 25.0% of patients). CONCLUSIONS: Bintrafusp alfa showed moderate clinical activity and a safety profile consistent with previous studies of bintrafusp alfa in patients with advanced HCC.
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BACKGROUND: No adjuvant treatment has been established for patients who remain at high risk for hepatocellular carcinoma recurrence after curative-intent resection or ablation. We aimed to assess the efficacy of adjuvant atezolizumab plus bevacizumab versus active surveillance in patients with high-risk hepatocellular carcinoma. METHODS: In the global, open-label, phase 3 IMbrave050 study, adult patients with high-risk surgically resected or ablated hepatocellular carcinoma were recruited from 134 hospitals and medical centres in 26 countries in four WHO regions (European region, region of the Americas, South-East Asia region, and Western Pacific region). Patients were randomly assigned in a 1:1 ratio via an interactive voice-web response system using permuted blocks, using a block size of 4, to receive intravenous 1200 mg atezolizumab plus 15 mg/kg bevacizumab every 3 weeks for 17 cycles (12 months) or to active surveillance. The primary endpoint was recurrence-free survival by independent review facility assessment in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT04102098. FINDINGS: The intention-to-treat population included 668 patients randomly assigned between Dec 31, 2019, and Nov 25, 2021, to either atezolizumab plus bevacizumab (n=334) or to active surveillance (n=334). At the prespecified interim analysis (Oct 21, 2022), median duration of follow-up was 17·4 months (IQR 13·9-22·1). Adjuvant atezolizumab plus bevacizumab was associated with significantly improved recurrence-free survival (median, not evaluable [NE]; [95% CI 22·1-NE]) compared with active surveillance (median, NE [21·4-NE]; hazard ratio, 0·72 [adjusted 95% CI 0·53-0·98]; p=0·012). Grade 3 or 4 adverse events occurred in 136 (41%) of 332 patients who received atezolizumab plus bevacizumab and 44 (13%) of 330 patients in the active surveillance group. Grade 5 adverse events occurred in six patients (2%, two of which were treatment related) in the atezolizumab plus bevacizumab group, and one patient (<1%) in the active surveillance group. Both atezolizumab and bevacizumab were discontinued because of adverse events in 29 patients (9%) who received atezolizumab plus bevacizumab. INTERPRETATION: Among patients at high risk of hepatocellular carcinoma recurrence following curative-intent resection or ablation, recurrence-free survival was improved in those who received atezolizumab plus bevacizumab versus active surveillance. To our knowledge, IMbrave050 is the first phase 3 study of adjuvant treatment for hepatocellular carcinoma to report positive results. However, longer follow-up for both recurrence-free and overall survival is needed to assess the benefit-risk profile more fully. FUNDING: F Hoffmann-La Roche/Genentech.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Adulto , Humanos , Bevacizumab/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/cirugía , Espera Vigilante , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/cirugíaRESUMEN
BACKGROUND: Pectolinarigenin (PEC) is a flavone extracted from Cirsium, and because it has anti-inflammatory properties, anti-cancer research is also being conducted. The objective of this work was to find out if PEC is involved in tumor control and which pathways it regulates in vivo and in vitro. METHODS: AGS cell lines were xenografted into BALB/c nude mice to create tumors, and PEC was administered intraperitoneally to see if it was involved in tumor control. Once animal testing was completed, tumor proteins were isolated and identified using LC-MS analysis, and gene ontology of the found proteins was performed. RESULTS: Body weight and hematological measurements on the xenograft mice model demonstrated that PEC was not harmful to non-cancerous cells. We found 582 proteins in tumor tissue linked to biological reactions such as carcinogenesis and cell death signaling. PEC regulated 6 out of 582 proteins in vivo and in vitro in the same way. CONCLUSION: Our findings suggested that PEC therapy may inhibit tumor development in gastric cancer (GC), and proteomic research gives fundamental information about proteins that may have great promise as new therapeutic targets in GC.
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Apoptosis , Cromonas , Neoplasias Gástricas , Humanos , Animales , Ratones , Ratones Desnudos , Xenoinjertos , Proteómica , Línea Celular Tumoral , Neoplasias Gástricas/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proliferación CelularRESUMEN
OBP-301 is an oncolytic adenovirus modified to replicate within cancer cells and lyse them. This open-label, non-comparative, phase I dose-escalation trial aimed to assess its safety and optimal dosage in 20 patients with advanced hepatocellular carcinoma. Good tolerance was shown with a maximum tolerated dose of 6 × 1012 viral particles. The most common treatment-emergent adverse events were influenza-like illness, pyrexia, fatigue, decreased platelet count, abdominal distension, and anemia. Cohorts 4 and 5 had approximately 50% higher levels of CD8+ T cells in the peripheral blood after injection. The best target response occurred in 14 patients, 4 of whom had progressive disease. Multiple intratumoral injections of OBP-301 were well tolerated in patients with advanced hepatocellular carcinoma. The stable disease rate for the injected tumors was greater than the overall response rate, even with no obvious tumor response. OBP-301 might have a greater impact on local response as histological examination revealed that the presence of OBP-301 was consistent with the necrotic area at the injection site. Increased infiltration of CD8+ T cells and <1% PD-L1 expression were observed in tumors after injection. Improved antitumor efficacy might be achieved in future studies via viral injection with volume adjustment and in combination with other immuno-therapeutics.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Viroterapia Oncolítica , Virus Oncolíticos , Telomerasa , Humanos , Adenoviridae/genética , Carcinoma Hepatocelular/etiología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/terapia , Línea Celular Tumoral , Viroterapia Oncolítica/efectos adversos , Virus Oncolíticos/genéticaRESUMEN
Bisphenol AF (BPAF) is found in high concentrations in aquatic environments due to the increased use of thermal paper and food packaging. However, there have been relatively few toxicological studies and potential risk assessments of BPAF. In this study, the risk quotient (RQ) and hazard quotient (HQ) of BPAF were derived to present the safety standards for environmental risk management and protection in lakes, rivers, bays, and Italian regions. We applied the species sensitivity distribution (SSD) method based on the previous ecotoxicological data and the results of supplementary toxicity tests on BPAF. From the SSD curves, the hazardous concentration for 5â¯% of the species (HC5) values for the acute and chronic toxicity data were 464.75⯵g/L and 3.59⯵g/L, respectively, and the acute- and chronic-based predicted no-effect concentration were derived as 154.92⯵g/L and 1.20⯵g/L, respectively. The acute-based RQ (RQA)values of BPAF in all regions were negligible (RQ < 0.1). The chronic-based RQ (RQC) in the Xitang River (XR) and the Central Italy (CI) showed a considerably high ecological risk (12.77 and 1.29) and the Hangzhou Bay (0.21), the South and North Italy (0.79 and 0.27), and the Tamagawa River (0.13) had a medium ecological risk (0.1 < RQ < 1.0). However, the HQ values based on the tolerable daily intake for BPAF over all age groups in these regions was < 0.1, indicating the low health risk. Nonetheless, the result of this study indicates that BPAF contamination is serious in XR and CI, and their use and emissions require continuous monitoring.
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Compuestos de Bencidrilo , Monitoreo del Ambiente , Fenoles , Contaminantes Químicos del Agua , Medición de Riesgo , Fenoles/toxicidad , Fenoles/análisis , Compuestos de Bencidrilo/toxicidad , Contaminantes Químicos del Agua/análisis , Contaminantes Químicos del Agua/toxicidad , Italia , Humanos , Monitoreo del Ambiente/métodos , Animales , Ríos/química , Adulto , Niño , Exposición a Riesgos Ambientales , FluorocarburosRESUMEN
BACKGROUND & AIMS: Loss-of-function HSD17ß13 mutations protect against the development of chronic liver disease. HSD17ß13 inhibition represents a potential approach to treat liver diseases, such as non-alcoholic steatohepatitis (NASH). ARO-HSD is an RNA interference (RNAi) therapeutic designed to selectively reduce expression of HSD17ß13 mRNA in hepatocytes. In this study, we evaluated the effects of ARO-HSD in normal healthy volunteers (NHVs) and patients with confirmed or clinically suspected NASH. METHODS: The safety, tolerability, and pharmacodynamics of ARO-HSD were evaluated in 32 NHVs and 18 patients with confirmed/clinically suspected NASH. Double-blind NHV cohorts received single escalating doses of ARO-HSD (25, 50, 100, or 200 mg) or placebo subcutaneously on Day 1. Open-label patient cohorts received ARO-HSD (25, 100, or 200 mg) subcutaneously on Days 1 and 29. Liver biopsy was performed pre-dose and on Day 71 to evaluate expression levels of HSD17ß13 mRNA and protein. RESULTS: ARO-HSD treatment was well tolerated with no treatment-related serious adverse events or drug discontinuations. The most frequently reported treatment-emergent adverse events were mild injection site reactions, which were short in duration. Mean changes in hepatic HSD17ß13 mRNA from baseline to Day 71 were: -56.9% (25 mg), -85.5% (100 mg), and -93.4% (200 mg). The mean HSD17ß13 mRNA reduction was 78.6% (p <0.0001) across pooled cohorts. Hepatic HSD17ß13 protein levels were similarly reduced across doses. In patients, mean changes in alanine aminotransferase from baseline to Day 71 were -7.7% (25 mg), -39.3% (100 mg), and -42.3% (200 mg) (p <0.001 for pooled cohorts). CONCLUSIONS: ARO-HSD was well tolerated at doses ≤200 mg. This proof-of-concept study demonstrated that short-term treatment with ARO-HSD reduces hepatic HSD17ß13 mRNA and protein expression, which is accompanied by reductions in alanine aminotransferase. GOV NUMBER: NCT04202354. IMPACTS AND IMPLICATIONS: There is an unmet medical need for new therapies to treat alcohol-related and non-alcoholic liver disease. ARO-HSD is a small-interfering RNA designed to silence HSD17ß13 expression and hence to phenocopy the protective effect seen in individuals with HSD17ß13 loss-of-function. The reductions in HSD17ß13 expression and in transaminases seen with ARO-HSD administration represent an initial step towards clinical validation of HSD17ß13, a drug target with substantial genetic validation, as an important modulator of human liver disease.
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Enfermedad del Hígado Graso no Alcohólico , Humanos , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Interferencia de ARN , Alanina Transaminasa , Hígado/patología , Pruebas de Función Hepática , Método Doble Ciego , Resultado del TratamientoRESUMEN
INTRODUCTION: For the treatment of spontaneous bacterial peritonitis (SBP), cefotaxime, ceftriaxone, and ciprofloxacin were used as first-line agents. However, considering the increasing rate of antibiotic resistance, it is unclear which of these drugs can be initially recommended. This study aimed to compare the current efficacy of the 3 antibiotics, namely cefotaxime, ceftriaxone, and ciprofloxacin, for the treatment of SBP in patients with cirrhosis with ascites, when guided by therapeutic responses. METHODS: This study was a multicenter, prospective, randomized controlled trial. The inclusion criteria were 16- to 75-year-old patients with liver cirrhosis with ascites, having polymorphonuclear cell count of >250/mm 3 . We performed a follow-up paracentesis at 48 hours to decide continuing or changing the assigned antibiotics and then assessed the resolution rates at 120 and 168 hours of treatment. RESULTS: A total of 261 patients with cirrhosis who developed SBP were enrolled. Most of the patients were diagnosed as those with SBP within 48 hours of admission. The resolution rates at 120 hours, which is the primary endpoint, were 67.8%, 77.0%, and 73.6% in the cefotaxime, ceftriaxone, and ciprofloxacin groups, respectively ( P = 0.388), by intension-to-treat analysis. The 1-month mortality was similar among the groups ( P = 0.770). The model for end-stage liver disease score and the SBP resolution were significant factors for survival. CONCLUSION: The efficacy of empirical antibiotics, such as cefotaxime, ceftriaxone, and ciprofloxacin, against SBP was not significantly different. In addition, these antibiotics administered based on response-guided therapy were still efficacious as initial treatment for SBP, especially in those with community-acquired infections.
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Infecciones Bacterianas , Enfermedad Hepática en Estado Terminal , Peritonitis , Humanos , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Cefotaxima/uso terapéutico , Ceftriaxona/uso terapéutico , Ciprofloxacina/uso terapéutico , Ascitis/tratamiento farmacológico , Estudios Prospectivos , Enfermedad Hepática en Estado Terminal/tratamiento farmacológico , Índice de Severidad de la Enfermedad , Antibacterianos/uso terapéutico , Peritonitis/tratamiento farmacológico , Peritonitis/etiología , Peritonitis/diagnóstico , Cirrosis Hepática/terapia , Infecciones Bacterianas/complicaciones , Infecciones Bacterianas/tratamiento farmacológico , Infecciones Bacterianas/microbiologíaRESUMEN
OBJECTIVE: To evaluate the effects of various initiation time points and durations of hormone therapy (HT) on cardiovascular and metabolic parameters of premenarche, primary ovarian insufficiency (POI) mouse model, induced by 4-vinylcyclohexene diepoxide. METHODS: A total of 50 mice at 4 weeks of age were developed into POI mouse model, further randomly categorized into 5 groups: control group without any intervention; no HT group with only high-fat diet (NT); group 1 with delayed estradiol treatment (T1); group 2 with on-time, continuous estradiol treatment (T2); and group 3 with on-time estradiol treatment but early stop (T3). Cardiovascular risk and metabolic parameters were measured. RESULTS: Presenting with similar body weights, blood glucose levels of T1, T2, and T3 were all significantly lower than NT (p < .001). Serum total cholesterol and insulin were also significantly lower in all HT groups than in NT, especially in T2 (p < .001). For serum low-density lipoprotein-cholesterol, only T2 resulted in the statically lower level than those of NT, T1, and T3 (p < .001). Aortic thickness was significantly increased with aggravated fibrotic change of the intima in NT, and such consequence was significantly ameliorated in HT groups, mostly lowered in T2 (p < .05). Last, serum pro-inflammatory cytokines were significantly low in the HT groups than in NT, especially in T2 with the lowest level (p < .05). . CONCLUSIONS: On-time, continuous E2 treatment immediately after a biologic estrogen deprivation event significantly reduced metabolic and cardiovascular risks in young, pre-menarche female mouse models of POI, confirming decreased serum levels of pro-inflammatory cytokines.
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Enfermedades Cardiovasculares , Insuficiencia Ovárica Primaria , Femenino , Animales , Ratones , Humanos , Enfermedades Cardiovasculares/etiología , Insuficiencia Ovárica Primaria/inducido químicamente , Factores de Riesgo , Factores de Riesgo de Enfermedad Cardiaca , Citocinas , Modelos Animales de Enfermedad , Estradiol , ColesterolRESUMEN
This corrects the article on p. e270 in vol. 38, PMID: 37644684.
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BACKGROUND: This study aimed to investigate the prevalence rate of hepatitis C virus (HCV) infection and identify the demographic, and sociological characteristics and changes in awareness of HCV infection by participating the study for North Korean defectors residing in South Korea. METHODS: This study prospectively enrolled participants. Demographic, sociological and clinical data, and questionnaire surveys focused on awareness of HCV infection were collected. RESULTS: In total, 211 North Korean defectors participated in this study from September 2020 until June 2021. There were 174 women (82.5%), and the overall mean age was 48.9 years (range, 20 to 80 years). Of these participants, 112 (53.1%) had immigrated to South Korea since 2011. The overall prevalence of anti-HCV antibody among North Korean defectors was 1.9%. Thirty participants (14.2%) had hepatitis B surface antigens. A huge lack of awareness regarding HCV infection has been observed among North Korean defectors. CONCLUSION: This is the first prospective study to investigate the prevalence rate of HCV infection among North Korean defectors residing in South Korea. As North Korean defectors are a vulnerable group concerning HCV infection, they may benefit from HCV screening policies and educational interventions for HCV infection.
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Hepacivirus , Hepatitis C , Femenino , Humanos , Persona de Mediana Edad , Estudios Seroepidemiológicos , República Popular Democrática de Corea/epidemiología , Estudios Prospectivos , Hepatitis C/epidemiología , República de Corea/epidemiologíaRESUMEN
This systematic review aimed to assess the prognostic significance of programmed cell death-ligand 1 (PDL-1) and programmed cell death protein 1 (PD-1) in hepatocellular carcinoma (HCC). Medline, EMBASE, and Cochrane Library database searches were conducted, revealing nine relevant cohort studies (seven PDL-1 and three PD-1). Our meta-analysis showed that PD-1/PDL-1 was a marker of poor survival, regardless of the assessment method (PD-1 overall survival (OS): hazard ratio (HR) 2.40; 95% confidence interval (CI), 1.30-4.42; disease-free survival (DFS): HR 2.12; 95% CI, 1.45-3.10; PDL-1: OS: HR 3.61; 95% CI, 2.75-4.75; and DFS: HR 2.74; 95% CI, 2.09-3.59). Additionally, high level of PD-1/PDL-1 expression was associated with aging, multiple tumors, high alpha-fetoprotein levels, and advanced Barcelona Clinic Liver Cancer stage. This high level significantly predicted a poor prognosis for HCC, suggesting that anti-PD-1 therapy is plausible for patients with HCC. Furthermore, HIF-1 induces PD-1 expression, and PD1lowSOCS3high is associated with a better prognosis. Taken together, combination therapy may be the key to effective immunotherapy. Thus, exploring other markers, such as HIF-1 and SOCS3, along with PD-1/PDL-1 immunotherapy, may lead to improved outcomes.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Antígeno B7-H1/metabolismo , Biomarcadores de Tumor/metabolismo , Carcinoma Hepatocelular/patología , Inmunoterapia/métodos , Ligandos , Neoplasias Hepáticas/patología , Microambiente Tumoral , Receptor de Muerte Celular Programada 1/metabolismoRESUMEN
Cancer is a widespread but dangerous disease that can strike anyone and is the second 1leading cause of death worldwide. Prostate cancer, in particular, is a prevalent cancer that occurs in men, and much research is being done on its treatment. Although chemical drugs are effective, they have various side effects, and accordingly, anticancer drugs using natural products are emerging. To date, many natural candidates have been discovered, and new drugs are being developed as drugs to treat prostate cancer. Representative candidate compounds that have been studied to be effective in prostate cancer include apigenin, acacetin and tangeretin of the flavone family among flavonoids. In this review, we look at the effects of these three flavones on prostate cancer cells via apoptosis in vitro and in vivo. Furthermore, in addition to the existing drugs, we suggest the three flavones and their effectiveness as natural anticancer agents, a treatment model for prostate cancer.
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Antineoplásicos , Flavonas , Neoplasias de la Próstata , Masculino , Humanos , Flavonas/farmacología , Flavonas/química , Flavonoides/farmacología , Flavonoides/uso terapéutico , Apoptosis , Apigenina/farmacología , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológicoRESUMEN
BACKGROUND & AIMS: Bepirovirsen, an antisense oligonucleotide targeting pregenomic and mRNA transcripts of HBV, has been conjugated to N-acetyl galactosamine (GSK3389404) to enhance hepatocyte delivery. This dose-finding study was the first to assess GSK3389404 for chronic HBV infection. METHODS: This phase IIa, randomised, double-blind, placebo-controlled, 2-part study was conducted in 22 centres in Asia (NCT03020745). Pharmacokinetic findings from Part 1 informed Part 2 dosing. In Part 2, patients with chronic hepatitis B on nucleos(t)ide analogue therapy were randomised 11:2 to GSK3389404 (30, 60, 120 mg weekly or 120 mg bi-weekly) or placebo until Day 85. Coprimary endpoints included HBsAg response (≥1.5 log10 IU/ml reduction from baseline) rate, safety and pharmacokinetics. RESULTS: Parts 1 and 2 included 12 (9 GSK3389404, 3 placebo) and 66 patients (56 GSK3389404, 10 placebo), respectively. In Part 2, one patient each in the 60 mg weekly, 120 mg weekly and 120 mg bi-weekly arms achieved a HBsAg response. HBsAg reductions were dose-dependent (Day 85: mean 0.34 [60 mg weekly] to 0.75 log10 IU/ml [120 mg weekly]) and occurred in hepatitis B e antigen-positive and -negative patients. No patient achieved HBsAg seroclearance. 43/56 (77%) GSK3389404- and 9/10 (90%) placebo-treated patients reported adverse events. No deaths were reported. Alanine aminotransferase flares (>2x upper limit of normal) occurred in 2 GSK3389404-treated patients (120 mg weekly, 120 mg bi-weekly); both were associated with decreased HBsAg, but neither was considered a responder. GSK3389404 plasma concentrations peaked 2-4 hours post dose; mean plasma half-life was 3-5 hours. CONCLUSIONS: GSK3389404 showed an acceptable safety profile and target engagement, with dose-dependent reductions in HBsAg. However, no efficacious dosing regimen was identified. CLINICAL TRIAL NUMBER: NCT03020745. LAY SUMMARY: Hepatitis B virus (HBV) can result in chronic HBV infection, which may ultimately lead to chronic liver disease, primary liver cancer and death; HBV proteins may prevent the immune system from successfully controlling the virus. GSK3389404 is an investigational agent that targets HBV RNA, resulting in reduced viral protein production. This study assessed the safety of GSK3389404 and its ability to reduce the viral proteins in patients with chronic HBV infection. GSK3389404 showed dose-dependent reduction in hepatitis B surface antigen, with an acceptable safety profile. While no clear optimal dose was identified, the findings from this study may help in the development of improved treatment options for patients with chronic HBV infections.
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Hepatitis B Crónica , Alanina Transaminasa , Antivirales/efectos adversos , ADN Viral , Método Doble Ciego , Galactosamina/uso terapéutico , Antígenos de Superficie de la Hepatitis B , Antígenos e de la Hepatitis B , Virus de la Hepatitis B/genética , Humanos , Oligonucleótidos Antisentido/uso terapéutico , ARN , ARN Mensajero , Proteínas ViralesRESUMEN
The present study investigated the potential adverse effects of aluminum chloride (AlCl3) following a 4-week repeated oral administration in Sprague-Dawley rats. The test article was administered once daily by gavage to male and female rats at dose levels of 0, 100, 300, and 900 mg/kg/day for 4 weeks. After administration of AlCl3 at 900 mg/kg/day, treatment-related systemic toxicity manifested as significant increases in salivation incidence, neutrophil percentage, reticulocytes, serum triglyceride, adrenal gland and liver weights, and single-hepatocyte necrosis, as well as significant decreases in body weight gain, food intake, hemoglobin, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration (MCHC), lymphocyte percentage, serum total protein and albumin, and thymus weight in male rats; and significant increases in salivation incidence, serum triglyceride, and liver weight, as well as a significant decrease in lymphocyte percentage in female rats. At 300 mg/kg/day, a significant decrease in MCHC was found in male rats, but not in female rats. However, this finding was not toxicologically significant because the reduction was minimal and was not accompanied by changes in any other parameters. No treatment-related effects were observed in the 100 mg/kg/day group of both genders. Under the experimental conditions of this study, the target organs of AlCl3 were determined to be the blood, liver, and thymus in rats. The no-observed-adverse-effect level was found to be 300 mg/kg/day in rats of both genders.
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Hígado , Administración Oral , Cloruro de Aluminio/toxicidad , Animales , Femenino , Masculino , Nivel sin Efectos Adversos Observados , Ratas , Ratas Sprague-Dawley , TriglicéridosRESUMEN
Kynurenic acid was included in the three compounds (caffeic acid, chlorogenic acid, and kynurenic acid) that showed high antioxidant and anti-inflammatory potential among the phenolic compounds contained in Gynura procumbens. In this study, the mechanism of cancer cell death induced by kynurenic acid (KYNA), which has the highest molecular binding affinity, in the gastric cancer cell line AGS was confirmed in molecular docking analysis. KYNA showed the most cancer cell death effect on AGS cells among several gastric cancer cell lines (MKN, AGS, and SNU). AGS cells were used for later experiments, and KYNA concentrations of 0, 150, 200, and 250 µM were used. KYNA inhibited cell migration and proliferation in AGS cells in a concentration-dependent manner. G2/M phase cell cycle arrest and reduction of related proteins (Cdc25C, CDK1 and CyclinB1) were confirmed in KYNA-treated AGS cells. Apoptosis of KYNA-treated AGS cells was confirmed by Annexin V/propidium iodide (PI) staining flow cytometry analysis. As a result of morphological chromatin condensation through DAPI (4',6-diamidino-2-phenylindole), intense blue fluorescence was confirmed. The mechanism of apoptosis induction of KYNA-treated AGS cells was confirmed by western blotting. In the extrinsic pathway, apoptosis induction markers FasL, Fas, and Caspase-3 and -8 were increased in a concentration-dependent manner upon KYNA treatment. In the intrinsic pathway, the expression of anti-apoptotic factors PI3K, AKT, and Bcl-xL was down-regulated, and the expression of apoptosis-inducing factors BAD, Bak, Bax, Cytochrom C, and Caspase-9 was up-regulated. Therefore, in the present study, we strongly imply that KYNA induces apoptosis in AGS gastric cancer cells. This suggests that KYNA, a natural compound, could be the basis for drug for the treatment of gastric cancer.
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Neoplasias Gástricas , Apoptosis , Línea Celular Tumoral , Proliferación Celular , Humanos , Ácido Quinurénico/farmacología , Ácido Quinurénico/uso terapéutico , Simulación del Acoplamiento Molecular , Neoplasias Gástricas/metabolismoRESUMEN
Cancer is a horrific disease that, to date, has no cure. It is caused by various factors and takes many lives. Apoptosis is a programmed cell death mechanism and if it does not function correctly in cancer cells, it can lead to severe disease. There are various signaling pathways for regulating apoptosis in cancer cells. Flavonoids are non-artificial natural bioactive compounds that are gaining attention as being capable of for inducing apoptosis in cancer cells. Among these, in this study, we focus on flavones. Flavones are a subclass of the numerous available flavonoids and possess several bioactive functions. Some of the most reported and well-known critical flavones, namely apigenin, acacetin, baicalein, luteolin, tangeretin, and wogonin, are discussed in depth in this review. Our main aim is to investigate the effects of the selected flavones on apoptosis and cell signaling pathways that contribute to death due to various types of cancers.
Asunto(s)
Flavonas , Neoplasias , Apigenina/farmacología , Apoptosis , Flavonas/farmacología , Flavonoides/farmacología , Humanos , Luteolina/farmacología , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Transducción de SeñalRESUMEN
Cadmium (Cd), a harmful heavy metal, can lead to various pulmonary diseases, including chronic obstructive pulmonary disease (COPD), by inducing cytotoxicity and disturbing redox homeostasis. The aim of the present study was to investigate Cd-mediated cytotoxicity using human lung fibroblasts and the therapeutic potential of 3,3'-diindolylmethane (DIM). Cadmium significantly reduced the cell viability of human embryonic lung (HEL299) cells accompanied by enhanced oxidative stress as evidenced by the increased expression of autophagy-related proteins such as LC3B and p62. However, treatment with DIM significantly suppressed autophagic cell death in Cd-induced HEL299 fibroblasts. In addition, DIM induced antioxidant enzyme activity and decreased intracellular reactive oxygen species (ROS) levels in Cd-damaged HEL299 cells. This study suggests that DIM effectively suppressed Cd-induced lung fibroblast cell death through the upregulation of antioxidant systems and represents a potential agent for the prevention of various diseases related to Cd exposure.
Asunto(s)
Muerte Celular Autofágica , Cadmio , Antioxidantes/metabolismo , Antioxidantes/farmacología , Apoptosis , Autofagia , Cadmio/toxicidad , Fibroblastos/metabolismo , Humanos , Indoles , Pulmón/metabolismo , Estrés Oxidativo , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Inflammation is a severe topic in the immune system and play a role as pro-inflammatory mediators. In response to such inflammatory substances, immune cells release cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß). Lipopolysaccharide (LPS) is known as an endotoxin in the outer membrane of Gram-negative bacteria, and it catalyzes inflammation by stimulating the secretion of inflammatory-mediated cytokines such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) by stimulated immune cells. Among the pathways involved in inflammation, nuclear factor kappa (NF-кB) and mitogen-activated protein kinases (MAPKs) are important. NF-kB is a diploid composed of p65 and IkBα and stimulates the pro- gene. MAPKs is a family consisting of the extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK), and p38, JNK and p38 play a role as proinflammatory mediators. Thus, we aim to determine the scutellarein (SCU) effect on LPS stimulated RAW264.7 cells. Furthermore, since scutellarein has been shown to inhibit the SARS coronavirus helicase and has been used in Chinese medicine to treat inflammatory disorders like COVID-19, it would be required to examine scutellarein's anti-inflammatory mechanism. We identified inflammation-inducing substances using western blot with RAW264.7 cells and SCU. And we discovered that was reduced by treatment with SCU in p-p65 and p-IκBα. Also, we found that p-JNK and p-ERK were also decreased but there was no effect in p-p38. In addition, we have confirmed that the iNOS was also decreased after treatment but there is no change in the expression of COX-2. Therefore, this study shows that SCU can be used as a compound to treat inflammation.
Asunto(s)
COVID-19 , FN-kappa B , Animales , Apigenina , Ciclooxigenasa 2/metabolismo , Citocinas/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Lipopolisacáridos/efectos adversos , Ratones , FN-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Células RAW 264.7 , Transducción de SeñalRESUMEN
The toxicity of cadmium (Cd) occurs through accumulation in the environment. The precise mechanism underlying Cd toxicity remains unclear. Therefore, in the present study, we studied the effects of Cd on MM55.K cells and investigated the mechanisms underlying Cd-induced cell death. CdCl2 significantly elevated apoptotic cell death, mitochondrial membrane potential (ΔΨm) loss, and caspase-dependent cell death. Moreover, immunoblotting results revealed that CdCl2 down-regulated the inhibitor of apoptotic protein such as survivin and Bcl-2 which led to the activation of caspase-3 and the cleavage of PARP in MM55.K cells. Besides, CdCl2 caused the up-regulation of ROS-related proteins such as HO-1 and ER stress-related proteins such as GRP78 and CHOP in MM55.K cells. CdCl2 toxicity resulted in the down-regulation of the AKT pathway that leads to the up-regulation of phosphorylated JNK and p38 in MM55.K cells. Thus, CdCl2 induce toxicity by AKT/MAPK regulation and causing ROS production, ER stress, ΔΨm loss, and apoptotic cell death in normal mouse renal cells.