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Microplastics (MPs), an emerging pollutant of global concern, have been studied in the Hongyingzi sorghum production base. In this study, we investigated MPs in the surface soil (0-10 cm) and deeper soil (10-20 cm) in the Hongyingzi sorghum production base. Pollution characterization and ecological risk evaluation were conducted. The results revealed that the MP abundance ranged from 1.31 × 102 to 4.27 × 103 particles/kg, with an average of 1.42 ± 1.22 × 103 particles/kg. There was no clear correlation between the MP abundance and soil depth, and the ordinary kriging method predicted a range of 1.26 × 103-1.28 × 103 particles/kg in most of the study area, indicating a relatively uniform distribution. Among the 12 types of MPs detected, acrylates copolymer (ACR), polypropylene (PP), polyurethane (PU), and polymethyl methacrylate (PMMA) were the most frequently detected. These MPs primarily originated from packaging and advertising materials made from polyurethane and polyester used by Sauce Wine enterprises, as well as plastic products made from polyolefin used in daily life and agricultural activities. The particle size of MPs was primarily 20-100 µm. Overall, the proportion of the 20-100 µm MPs was 95.1% in the surface soil layer and 86.7% in the deeper soil layer. Based on the pollution load index, the MP pollution level in the study area was classified as class I. Polymer hazard index evaluation revealed that the risk levels at all of the sampling sites ranged from IV to V, and ACR, PU, and PMMA were identified as significant sources of polymer hazard. Potential ecological index evaluation revealed that most of the soil samples collected from the study area were dangerous or extremely dangerous, and the surface soil posed a greater ecological risk than the deeper soil. These findings provide a scientific foundation for the prevention, control, and management of MP pollution in the Hongyingzi sorghum production base.
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Neovascular age-related macular degeneration (nvAMD) is the leading cause of blindness in the elderly population. Although it is known that nvAMD is associated with focal inflammation, understanding of the precise immune components governing this process remains limited. Here, we identified natural killer (NK) cells as a prominent lymphocyte population infiltrating the perivascular space of choroidal neovascularization (CNV) lesions in patients with nvAMD and in mouse models. Olink proteomic analysis and single-cell RNA sequencing combined with knockout studies demonstrated the involvement of C-C chemokine receptor 5 (CCR5) in NK cell recruitment and extravasation at the CNV sites of mice. Depletion of NK cells or inhibition of activating receptor NK group 2, member D (NKG2D) inhibited the formation of neutrophil extracellular traps, increased vascular leakage, and exacerbated pathological angiogenesis, indicating that NK cells restrain pathogenesis in this mouse model. Age is the strongest risk factor for AMD, and we show that NK cells from aged human donors exhibited a less cytotoxic phenotype. NK cells from old mice exhibited compromised protective effects in the CNV mouse model. In addition, interleukin-2 complex-mediated expansion of NK cells improved CNV formation in mice. Collectively, our study highlights NK cells as a potential therapeutic target for patients with nvAMD.
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Trampas Extracelulares , Células Asesinas Naturales , Degeneración Macular , Animales , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Degeneración Macular/patología , Humanos , Trampas Extracelulares/metabolismo , Neovascularización Coroidal/patología , Neovascularización Coroidal/metabolismo , Modelos Animales de Enfermedad , Ratones , Ratones Endogámicos C57BL , Neutrófilos/metabolismo , Neutrófilos/inmunología , Masculino , Anciano , FemeninoRESUMEN
The chip-scale hybrid optical pumping spin-exchange relaxation-free (SERF) atomic magnetometer with a single-beam arrangement has prominent applications in biomagnetic measurements because of its outstanding features, including ultrahigh sensitivity, an enhanced signal-to-noise ratio, homogeneous spin polarization and a much simpler optical configuration than other devices. In this work, a miniaturized single-beam hybrid optical pumping SERF atomic magnetometer based on a microfabricated atomic vapor cell is demonstrated. Although the optically thin Cs atoms are spin-polarized, the dense Rb atoms determine the experimental results. The enhanced signal strength and narrowed resonance linewidth are experimentally proven, which shows the superiority of the proposed magnetometer scheme. By using a differential detection scheme, we effectively suppress optical noise with an approximate five-fold improvement. Moreover, the cell temperature markedly affects the performance of the magnetometer. We systematically investigate the effects of temperature on the magnetometer parameters. The theoretical basis for these effects is explained in detail. The developed miniaturized magnetometer has an optimal magnetic sensitivity of 20 fT/Hz1/2. The presented work provides a foundation for the chip-scale integration of ultrahighly sensitive quantum magnetometers that can be used for forward-looking magnetocardiography (MCG) and magnetoencephalography (MEG) applications.
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Prostate cancer bone metastasis is a predominant cause of death for prostate cancer (PCa) patients. However, the underlying mechanisms are poorly understood. Here, we report that high levels of RNF41 are associated with metastatic human prostate cancer. RNF41 silencing inhibits prostate cancer cell growth, cell migration and invasion in vitro and in vivo. Mechanistically, we identify that RNF41 induces K27- and K63-linked noncanonical polyubiquitination of MYO1C to enhance its stability and induce actin remodeling, which promotes PCa bone metastasis. RNF41 was significantly upregulated in metastatic prostate cancer tissues and positively associated with MYO1C expression. Furthermore, we show in intraarterial injected-bone metastasis xenograft model that targeting MYO1C stability by inhibition of RNF41 markedly suppressed PCa bone metastasis. Collectively, our findings identify RNF41 is an important regulator of prostate cancer cell growth and metastasis and targeting RNF41/MYO1C could be a valuable strategy to ameliorate prostate cancer progression and metastasis.
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Neoplasias Óseas , Miosina Tipo I , Neoplasias de la Próstata , Ubiquitina-Proteína Ligasas , Masculino , Humanos , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/genética , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Animales , Miosina Tipo I/metabolismo , Miosina Tipo I/genética , Ratones , Línea Celular Tumoral , Neoplasias Óseas/secundario , Neoplasias Óseas/metabolismo , Neoplasias Óseas/genética , Neoplasias Óseas/patología , Actinas/metabolismo , Movimiento Celular/genética , Proliferación Celular/genética , Ubiquitinación , Metástasis de la Neoplasia , Regulación Neoplásica de la Expresión Génica , Estabilidad ProteicaRESUMEN
OBJECTIVE: The underlying mechanisms of Overactive Bladder (OAB) remain unclear. This research is designed to investigate the correlation between the intake of dietary live microorganisms and OAB. METHODS: This analysis encompasses a cross-sectional study of broad population information gathered from the National Health and Nutrition Examination Surveys (NHANES) spanning the years 2007 to 2018. Participants were categorized into three groups-low, medium, and high-according to their consumption of dietary live microorganisms, as per the Sanders Dietary Active Microbiota Classification System. We utilized a weighted logistic regression model, restricted cubic spline (RCS), and subgroup analyses to investigate the relationship between dietary live microorganism intake and OAB. RESULTS: This research encompassed 16,795 subjects. The incidence of OAB was reduced in the group consuming a high amount of live dietary microbes compared to the groups with low and medium intake of such microbes. After detailed adjustments for covariates, analysis revealed that participants in the high live dietary microbe group had notably reduced odds of OAB compared to those in the low live dietary microbe group (OR: 0.84, 95% CI: 0.71-0.99, p = 0.03). RCS analysis indicated a nonlinear correlation between high dietary active microbiota intake and the incidence of OAB. CONCLUSION: This research emphasizes the potential advantages of a high dietary intake of active microbiota for preventing OAB. These findings support incorporating active microbiota into dietary guidelines, demonstrating their connection with a decreased incidence of OAB.
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Dieta , Encuestas Nutricionales , Vejiga Urinaria Hiperactiva , Humanos , Vejiga Urinaria Hiperactiva/epidemiología , Estudios Transversales , Masculino , Femenino , Adulto , Persona de Mediana Edad , Estados Unidos/epidemiología , Dieta/estadística & datos numéricos , Incidencia , AncianoRESUMEN
OBJECTIVES: To evaluate the effectiveness and safety of Qishen Yiqi Dripping Pill (QSYQ) in patients with acute coronary syndrome (ACS) after percutaneous coronary intervention (PCI). METHODS: This multicentre prospective cohort study was conducted at 40 centers in China. Patients with ACS after PCI entered either the QSYQ or Western medicine (WM) groups naturally based on whether they had received QSYQ before enrollment. QSYQ group received QSYQ (0.52 g, 3 times a day for 12 months) in addition to WM. The primary endpoint included cardiac death, non-fatal myocardial infarction, and urgent revascularization. The secondary endpoint included rehospitalization due to ACS, heart failure, stroke, and other thrombotic events. Quality of life was assessed by the Seattle Angina Questionnaire (SAQ). RESULTS: A total of 936 patients completed follow-up of the primary endpoint from February 2012 to December 2018. Overall, 487 patients received QSYQ and WM. During a median follow-up of 566 days (inter quartile range, IQR, 517-602), the primary endpoint occurred in 46 (9.45%) and 65 (14.48%) patients in QSYQ and WM groups respectively [adjusted hazard ratio (HR) 0.60, 95% confidence interval (CI) 0.41-0.90; P=0.013]. The secondary endpoint occurred in 61 (12.53%) and 74 (16.48%) patients in QSYQ and WM groups, respectively (adjusted HR 0.76, 95% CI 0.53-1.09; P=0.136). In sensitivity analysis, the results still demonstrated that WM combined with QSYQ reduced the risk of the primary endpoint (HR 0.67, 95% CI 0.46-0.98; P=0.039). Moreover, QSYQ improved the disease perception domain of the SAQ (P<0.05). CONCLUSION: In patients with ACS after PCI, QSYQ combined with WM reduced the incidence of the primary endpoint. These findings provide a promising option for managing ACS after PCI and suggest the potential treatment for reducing the risk of primary endpoint included cardiac death, non-fatal myocardial infarction, and urgent revascularization through intermittent administration of QSYQ (Registration No. ChiCTR-OOC-14005552).
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High levels of hepatitis B virus (HBV) surface antigen (HBsAg) in the blood of chronic HBV carriers are considered to drive the exhaustion of antigen-specific T and B lymphocytes and thus responsible for the persistence of infection. Accordingly, therapeutic elimination of HBsAg may facilitate the activation of adaptive antiviral immune responses against HBV and achieve a functional cure of chronic hepatitis B. We discovered recently that an amphipathic alpha helix spanning W156 to R169 of HBV small envelope (S) protein plays an essential role in the morphogenesis of subviral particles (SVPs) and metabolism of S protein. We thus hypothesized that pharmacological disruption of SVP morphogenesis may induce intracellular degradation of S protein and reduce HBsAg secretion. To identify inhibitors of SVP biogenesis, we screened 4417 bioactive compounds with a HepG2-derived cell line expressing HBV S protein and efficiently secreting small spherical SVPs. The screen identified 24 compounds that reduced intracellular SVPs and secreted HBsAg in a concentration-dependent manner. However, 18 of those compounds inhibited the secretion of HBsAg and HBeAg in HBV replicon transfected HepG2 cells at similar efficiency, suggesting each of those compounds may disrupt a common cellular function required for the synthesis and/or secretion of these viral proteins. Interestingly, lycorine more efficiently inhibited the secretion of HBsAg in HepG2 cells transfected with HBV replicons, HepG2.2.15 cells and HBV infected - HepG2 cells expressing sodium taurocholate cotransporting polypeptide (NTCP). The structure activity relationship and antiviral mechanism of lycorine against HBV have been determined.
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Antivirales , Antígenos de Superficie de la Hepatitis B , Virus de la Hepatitis B , Humanos , Virus de la Hepatitis B/efectos de los fármacos , Antivirales/farmacología , Antígenos de Superficie de la Hepatitis B/metabolismo , Células Hep G2 , Ensamble de Virus/efectos de los fármacos , Virión/efectos de los fármacos , Descubrimiento de Drogas , Replicación Viral/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/farmacología , Proteínas del Envoltorio Viral/metabolismo , Antígenos e de la Hepatitis B/metabolismoRESUMEN
[This retracts the article DOI: 10.3892/br.2015.527.].
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Chronic hepatitis B virus (HBV) infection is due to the failure of host immune system to resolve the viral infection. Accordingly, restoration or reconstitution of a functional antiviral immune response to HBV is essential to achieve durable control of HBV replication leading to a functional cure of chronic hepatitis B (CHB). Noninfectious subviral particles (SVPs), comprised of HBV surface antigen (HBsAg), are the predominant viral products secreted by HBV-infected hepatocytes. The high levels of SVPs in the circulation induce immune tolerance and contribute to the establishment of chronic HBV infection. The current standard-of-care medications for CHB efficiently suppress HBV replication but fail to reduce the levels of HBsAg in majority of treated patients. Further understanding the mechanisms underlying SVP morphogenesis, secretion and regulation by viral and host cellular factors are critical for the discovery of therapeutics that can inhibit SVP production and/or induce the degradation of HBV envelope proteins. We describe herein a protocol for intracellular SVP detection by a native agarose gel electrophoresis-based particle gel assy. The method is suitable for quantitative detection of intracellular HBV SVPs and can be applied in dissecting the molecular mechanism of SVP morphogenesis and the discovery of antiviral agents targeting SVP formation in hepatocytes.
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Virus de la Hepatitis B , Virión , Virus de la Hepatitis B/fisiología , Virus de la Hepatitis B/efectos de los fármacos , Humanos , Hepatocitos/virología , Hepatocitos/metabolismo , Antígenos de Superficie de la Hepatitis B/metabolismo , Replicación Viral/efectos de los fármacos , Electroforesis en Gel de Agar/métodos , Células Cultivadas , Hepatitis B Crónica/virología , Hepatitis B Crónica/tratamiento farmacológicoRESUMEN
BACKGROUND: Despite numerous risk factors being associated with hypertension, the breadth of research remains constrained, with a notable absence of systematic, data-driven exploration into established and novel factors across a broad spectrum of exposures. This study aims to construct an atlas on known and emerging factors for hypertension through comprehensive epidemiological and genetic analyses. METHODS: We conducted exposome-wide association studies (ExWAS) via Cox regression models on two equally sized datasets for discovery and replication in UK Biobank, a large prospective cohort study. A maximum of 10,806 exposome variables were included in ExWAS and were grouped into 13 categories: genomics, sociodemographic, lifestyle, physical measure, biomarkers, medical history, imaging markers, sex-specific factors, psychosocial factors, cognitive function indicators, local environment, family history, and early life factors. The credibility of epidemiological associations was assessed through meta-analyses. The genetic underpinnings were explored through linkage-disequilibrium score regression (LDSC), quantifying global genetic correlation. Two-sample Mendelian randomization (MR) studies were conducted to investigate the causal effects of each exposure on hypertension, with co-analyses undertaken to identify associations supported by both epidemiological and genetic evidence. RESULTS: This study included 214,957 UK Biobank participants, hypertension-free at baseline. In our ExWAS analyses, 964 significant exposome variables were replicated. In meta-analyses, 462 were backed by convincing and highly suggestive evidence. Among 10,765 exposures in LDSC, 1923 had global genetic correlations with hypertension. The MR analyses yielded robust evidence for a causal relationship with 125 phenotypes, probable evidence for 270 phenotypes, and suggestive evidence for 718 phenotypes. Co-analyses identified 146 associations supported by strong epidemiological and genetic evidence. These primarily encompassed traits like anthropometry, lung function, lipids, and factors such as urate and walking pace. This coverage further extended from well-studied factors (like BMI and physical activity) to less explored exposures (including high light scatter reticulocyte count and age at first live). All study results are compiled in a webserver for user-friendly exploration of exposure-hypertension associations. CONCLUSION: This study provides an atlas on established and novel risk factors for hypertension, underpinned by epidemiological and causal evidence. Our findings present a multiple perspective to prioritize hypertension prevention strategies, encompassing modifiable risk factors like television watching time and walking pace. The study also emphasized the roles of urate in hypertension pathogenesis. Consequently, our study may serve as a critical guide for hypertension prevention and bear significant clinical implications.
Researchers have created a comprehensive map that identifies and analyses a wide array of risk factors linked to the development of high blood pressure, using extensive data from the UK Biobank. The study revealed 964 significant factors related to lifestyle, environment, and genetics that could influence the risk of developing hypertension, with 462 of these factors showing strong evidence of a link.Key lifestyle-related findings include the impact of behaviors such as television watching and walking pace on hypertension risk, suggesting that modifiable habits can be targeted for prevention strategies.
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BACKGROUND: Cyclin-dependent kinase 12 (CDK12)-deficient prostate cancer defines a subtype of castration-resistant prostate cancer (CRPC) with a poor prognosis. Current therapy, including PARP inhibitors, shows minimal treatment efficacy for this subtype of CRPC, and the underlying mechanism remains elusive. METHODS: Based on bioinformatics analysis, we evaluated the relationship between CDK12 deficiency and prostate cancer patient's prognosis and treatment resistance. Furthermore, we used CRISPR-Cas9 technology and mass spectrometry-based metabolomic profiling to reveal the metabolic characteristics of CDK12-deficient CRPC. To elucidate the specific mechanisms of CDK12 deficiency-mediated CRPC metabolic reprogramming, we utilized cell RNA-seq profiling and other molecular biology techniques, including cellular reactive oxygen species probes, mitochondrial function assays, ChIP-qPCR and RNA stability analyses, to clarify the role of CDK12 in regulating mitochondrial function and its contribution to ferroptosis. Finally, through in vitro drug sensitivity testing and in vivo experiments in mice, we identified the therapeutic effects of the electron transport chain (ETC) inhibitor IACS-010759 on CDK12-deficient CRPC. RESULTS: CDK12-deficient prostate cancers reprogramme cellular energy metabolism to support their aggressive progression. In particular, CDK12 deficiency enhanced the mitochondrial respiratory chain for electronic transfer and ATP synthesis to create a ferroptosis potential in CRPC cells. However, CDK12 deficiency downregulated ACSL4 expression, which counteracts the lipid oxidation stress, leading to the escape of CRPC cells from ferroptosis. Furthermore, targeting the ETC substantially inhibited the proliferation of CDK12-deficient CRPC cells in vitro and in vivo, suggesting a potential new target for the therapy of CDK12-deficient prostate cancer. CONCLUSIONS: Our findings show that energy and lipid metabolism in CDK12-deficient CRPC work together to drive CRPC progression and provide a metabolic insight into the worse prognosis of CDK12-deficient prostate cancer patients. KEY POINTS: CDK12 deficiency promotes castration-resistant prostate cancer (CRPC) progression by reprogramming cellular metabolism. CDK12 deficiency in CRPC leads to a more active mitochondrial electron transport chain (ETC), ensuring efficient cell energy supply. CDK12 phosphorylates RNA Pol II to ensure the transcription of ACSL4 to regulate ferroptosis. Mitochondrial ETC inhibitors exhibit better selectivity for CDK12-deficient CRPC cells, offering a promising new therapeutic approach for this subtype of CRPC patients.
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Quinasas Ciclina-Dependientes , Ferroptosis , Neoplasias de la Próstata Resistentes a la Castración , Animales , Humanos , Masculino , Ratones , Línea Celular Tumoral , Quinasas Ciclina-Dependientes/metabolismo , Quinasas Ciclina-Dependientes/genética , Progresión de la Enfermedad , Ferroptosis/genética , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/patología , Oxadiazoles/farmacología , Piperidinas/farmacologíaRESUMEN
Using the aldehyde amine condensation procedure and the triphenylamine group as the skeleton structure, the new triphenylamine-aromatic aldehyde-succinylhydrazone probe molecule DHBYMH was created. A newly created acylhydrazone probe was structurally characterized by mass spectrometry (MS), NMR, and infrared spectroscopy (FTIR). Fluorescence and UV spectroscopy were used to examine DHBYMH's sensing capabilities for metal ions. Notably, DHBYMH achieved a detection limit of 1.62 × 10-7 M by demonstrating exceptional selectivity and sensitivity towards Cu2+ ions in an optimum sample solvent system (DMSO/H2O, (v/v = 7/3); pH = 7.0; cysteine (Cys) concentration: 1 × 10-4 M). NMR titration, high-resolution mass spectrometry analysis, and DFT computation were used to clarify the response mechanism. Ultimately, predicated on DHBYMH's reversible identification of Cu2+ ions in the presence of EDTA, a molecular logic gate was successfully designed.
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Objective: Change of femoral neck ante-version angle postoperatively due to inadequate reduction could result in unsatisfying treatment outcome of intertrochanteric fracture. However, the influence of increased or decreased femoral neck ante-version on the biomechanical stability of the bone-implant complex has rarely been studied. Methods: A finite element model of a complete normal human femur with normal femoral neck ante-version as 13° was established accurately by scanning a 64 year old female femur. The models of 31-A1.1 intertrochanteric fractures with different femoral neck ante-version angles of 3°, 5.5°, 8°, 10.5°, 13°, 15.5°, 18°, 20.5°, 23° were created. They were assembled with a proximal femoral nail anti-rotation (PFNA) device. The biomechanical differences with varying femoral neck ante-version angles were compared using finite element analysis method. Results: As the femoral neck ante-version angle gradually increased from 13° to 23°with a gradient of 2.5°, the peak von Mises stress was gradually increased from 137.82 MPa to 276.02 MPa. Similarly, the peak von Mises stress was gradually increased from 137.82 MPa to 360.12 MPa with the femoral neck ante-version angle decreased from 13° to 3°. When decreased ante-version angle of 7.5° and increased ante-version angle of 10° will exceed the yield strength of femoral (240.32 MPa), the risk of femoral fracture will increase significantly. The maximum displacement of the femur was significantly reduced for increased ante-version models than for decreased ante-version models, whether the changes of ante-version angles were 2.5°, 5°, 7.5° or 10°. The maximum stress of PFNA was found in the intersection of main nail and helical blade, and became greater gradually as the ante-version angle increased or decreased with a gradient of 2.5°. The maximum stress of PFNA was presented in the model 5.5° with the maximum stress of 724.42 MPa (near to the yield strength of titanium alloy of 700-1000 MPa), producing the breakage risk of PFNA. The maximum displacement of the PFNA was significantly reduced for increased ante-version models than for decreased ante-version models, whether the changes of ante-version angles were 2.5°, 5°, 7.5° or 10°. Conclusion: Based on the results of present study, it was demonstrated that the anatomical reduction of femoral neck ante-version was vital to secure the optimal stability. Abnormal femoral ante-version could increase the potential risk of failure for intertrochanteric fracture after PFNA. The stability of increased femoral ante-version (less than 10°) was superior to the stability of decreased ante-version (less than 5°) for the cases of difficulty to acquire anatomical reduction. The clinical implication of the finding was that increased femoral neck ante-version had an advantage of mechanical stability towards the decreased femoral neck ante-version for the cases of comminuted intertrochanteric fracture and failure of anatomical reduction.
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Hepatitis B virus (HBV) integration exists throughout the clinical course of chronic hepatitis B (CHB). This study investigated the effects of long-term antiviral therapy on the level and profiles of transcriptionally active HBV integration. Serial liver biopsies and paired blood samples were obtained from 16, 16, and 22 patients with CHB at baseline, 78, and 260 weeks of entecavir monotherapy or combined with pegylated interferon alfa, respectively. Serum HBV biomarkers were longitudinally assessed. RNA-seq and HIVID2 program was used to identify HBV-host chimeric RNAs transcribed from integrated DNA. The counts of HBV integration reads were positively related to both serum HBV DNA levels (r = 0.695, p = 0.004) and HBeAg titers (r = 0.724, p = 0.021) at baseline, but the positive correlation exited only to the serum HBsAg levels after 260 weeks of antiviral therapy (r = 0.662, p = 0.001). After 78 weeks of antiviral therapy, the levels of HBV integration expression decreased by 12.25 folds from baseline. The viral junction points were enriched at the S and HBx genes after the long-term antiviral therapy. HBs-FN1 became one of the main transcripts, with the mean proportion of HBs-FN1 in all integrated expression increased from 2.79% at baseline to 10.54% at Week 260 of antiviral treatment. Antiviral therapy may reduce but not eliminate the HBV integration events and integration expression. Certain integration events, such as HBs-FN1 can persist in long-term antiviral treatment.
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Antivirales , ADN Viral , Virus de la Hepatitis B , Hepatitis B Crónica , Hígado , Integración Viral , Humanos , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/virología , Antivirales/uso terapéutico , Masculino , Virus de la Hepatitis B/genética , Virus de la Hepatitis B/efectos de los fármacos , Adulto , Femenino , Hígado/virología , Persona de Mediana Edad , ADN Viral/sangre , ADN Viral/genética , Guanina/análogos & derivados , Guanina/uso terapéutico , Interferón-alfa/uso terapéutico , Antígenos e de la Hepatitis B/sangre , Antígenos de Superficie de la Hepatitis B/sangre , Estudios LongitudinalesRESUMEN
BACKGROUND: Recent interest in the Non-High Density to High Density Lipoprotein Cholesterol ratio (NHHR) has emerged due to its potential role in metabolic disorders. However, the connection between NHHR and the development of kidney stones still lacks clarity. The primary goal of this research is to explore how NHHR correlates with kidney stone incidence. METHODS: An analysis was conducted on the data collected by the National Health and Nutrition Examination Survey (NHANES) between 2007 and 2018, focusing on adults over 20 years diagnosed with kidney stones and those with available NHHR values. Employing weighted logistic regression and Restricted Cubic Spline (RCS) models, NHHR levels' correlation with kidney stone risk was examined. Extensive subgroup analyses were conducted for enhanced reliability of the findings. RESULTS: The findings indicate a heightened kidney stone risk for those at the highest NHHR levels relative to those at the lowest (reference group). A notable non-linear correlation of NHHR with kidney stone incidence has been observed, with a significant P-value (< 0.001), consistent across various subgroups. CONCLUSION: A clear link exists between high NHHR levels and increased kidney stone risk in the American adult population. This study highlights NHHR's significance as a potential indicator in kidney stone formation.
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Cálculos Renales , Encuestas Nutricionales , Humanos , Cálculos Renales/sangre , Cálculos Renales/epidemiología , Adulto , Masculino , Femenino , Persona de Mediana Edad , Estudios Transversales , Factores de Riesgo , HDL-Colesterol/sangre , Estados Unidos/epidemiología , Incidencia , Anciano , Modelos LogísticosRESUMEN
BACKGROUND: Kidney stones exhibit a robust correlation with cardiovascular disease (CVD). The objective of this research is to investigate the correlation between kidney stones and Life's Essential 8 (LE8), a newly updated assessment of cardiovascular health (CVH), among adults in the United States. METHODS: In this study, which analyzed data from the 2007-2018 National Health and Nutrition Examination Survey, we employed LE8 scores (ranging from 0 to 100) as the independent variable, classifying them into low, moderate, and high CVH categories. The research examined the relationship between LE8 scores and kidney stones by using multivariate logistic regression and restricted cubic spline models, with kidney stones as the dependent variable. RESULTS: Out of the 14,117 participants in this research, the weighted mean LE8 score was 69.70 ± 0.27. After accounting for confounding factors, there was an inverse association between higher LE8 scores and the likelihood of developing kidney stones (OR of 0.81 per 10-point increase, with a 95% confidence interval of 0.77-0.85), demonstrating a non-linear dose-response pattern. Similar patterns were observed for health behaviors, health factor scores, and kidney stones. Stratified analyses demonstrated a stable negative correlation between LE8 scores and kidney stones across different subgroups. CONCLUSION: LE8 and its subscale scores exhibited a robust and inverse correlation with the occurrence of kidney stones. Encouraging adherence to optimal CVH levels has the potential to serve as an effective strategy in preventing and minimizing the occurrence of kidney stones.
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Cálculos Renales , Humanos , Cálculos Renales/epidemiología , Masculino , Femenino , Persona de Mediana Edad , Adulto , Encuestas Nutricionales , Estados Unidos/epidemiología , Anciano , Enfermedades Cardiovasculares/epidemiología , Estudios TransversalesRESUMEN
Hepatitis B virus (HBV) chronically infects 296 million people worldwide and causes more than 820,000 deaths annually due to cirrhosis and hepatocellular carcinoma. Current standard-of-care medications for chronic hepatitis B (CHB) include nucleos(t)ide analogue (NA) viral DNA polymerase inhibitors and pegylated interferon alpha (PEG-IFN-α). NAs can efficiently suppress viral replication and improve liver pathology, but not eliminate or inactivate HBV covalently closed circular DNA (cccDNA). CCC DNA is the most stable HBV replication intermediate that exists as a minichromosome in the nucleus of infected hepatocyte to transcribe viral RNA and support viral protein translation and genome replication. Consequentially, a finite duration of NA therapy rarely achieves a sustained off-treatment suppression of viral replication and life-long NA treatment is most likely required. On the contrary, PEG-IFN-α has the benefit of finite treatment duration and achieves HBsAg seroclearance, the indication of durable immune control of HBV replication and functional cure of CHB, in approximately 5% of treated patients. However, the low antiviral efficacy and poor tolerability limit its use. Understanding how IFN-α suppresses HBV replication and regulates antiviral immune responses will help rational optimization of IFN therapy and development of novel immune modulators to improve the rate of functional cure. This review article highlights mechanistic insight on IFN control of HBV infection and recent progress in development of novel IFN regimens, small molecule IFN mimetics and combination therapy of PEG-IFN-α with new direct-acting antivirals and therapeutic vaccines to facilitate the functional cure of CHB.
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Hepatitis B Crónica , Hepatitis B , Hepatitis C Crónica , Neoplasias Hepáticas , Humanos , Antivirales/farmacología , Antivirales/uso terapéutico , Antígenos de Superficie de la Hepatitis B , Hepatitis C Crónica/tratamiento farmacológico , Virus de la Hepatitis B , Interferón-alfa/uso terapéutico , Hepatitis B/tratamiento farmacológico , ADN Viral , Neoplasias Hepáticas/tratamiento farmacológicoRESUMEN
Musashi1 and Musashi2 are RNA-binding proteins originally found in drosophila, in which they play a crucial developmental role. These proteins are pivotal in the maintenance and differentiation of stem cells in other organisms. Research has confirmed that the Musashi proteins are highly involved in cell signal-transduction pathways such as Notch and TGF-ß. These signaling pathways are related to the induction and development of cancers, such as breast cancer, leukemia, hepatoma and liver cancer. In this review we focus on how Musashi proteins interact with molecules in different signaling pathways in various cancers and how they affect the physiological functions of these pathways. We further illustrate the status quo of Musashi proteins-targeted therapies and predict the target RNA regions that Musashi proteins interact with, in the hope of exploring the prospect of the design of Musashi protein-targeted medicines.
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Química Farmacéutica , Neoplasias , Humanos , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Proteínas de Unión al ARN/metabolismo , Neoplasias/tratamiento farmacológico , ARNRESUMEN
Ecteinascidin 743 (Et-743), also known by the trade name Yondelis®, is the pioneering marine natural product to be successfully developed as an antitumor drug. Moreover, it is the first tetrahydroisoquinoline natural product used clinically for antitumor therapy since Kluepfel, a Canadian scientist, discovered the tetrahydroisoquinoline alkaloid (THIQ) naphthyridinomycin in 1974. Currently, almost a hundred natural products of bistetrahydroisoquinoline type have been reported. Majority of these bistetrahydroisoquinoline alkaloids exhibit diverse pharmacological activities, with some family members portraying potent antitumor activities such as Ecteinascidins, Renieramycins, Saframycins, Jorumycins, among others. Due to the unique chemical structure and exceptional biological activity of these natural alkaloids, coupled with their scarcity in nature, research seeking to provide material basis for further bioactivity research through total synthesis and obtaining compound leads with medicinal value through structural modification, remains a hot topic in the field of antitumor drug R&D. Despite the numerous reviews on the total synthesis of bistetrahydroisoquinoline natural products, comprehensive reviews on their structural modification are apparently scarce. Moreover, structural modification of bioactive natural products to acquire lead compounds with improved pharmaceutical characteristics, is a crucial approach for innovative drug discovery. This paper presents an up-to-date review of both structural modification and activity of bistetrahydroisoquinoline natural products. It highlights how such alkaloids can be used as antitumor lead compounds through careful chemical modifications. This review offers valuable scientific references for pharmaceutical chemists engaged in developing novel antitumor agents based on such alkaloid modifications, as well as those with such a goal in future.
Asunto(s)
Alcaloides , Antineoplásicos , Productos Biológicos , Tetrahidroisoquinolinas , Alcaloides/química , Antineoplásicos/química , Productos Biológicos/farmacología , Productos Biológicos/química , Canadá , Preparaciones Farmacéuticas , Tetrahidroisoquinolinas/químicaRESUMEN
Heart failure with preserved ejection fraction (HFpEF) represents a multifaceted syndrome related to complex pathologic mechanisms. Sacubitril/valsartan (Sac/val) has demonstrated therapeutic efficacy in HFpEF treatment. However, additional research is required to elucidate its pharmacological mechanisms. Accordingly, this study aimed to explore the potential therapeutic effects of Sac/val in HFpEF rats and the underlying molecular mechanisms. In this study, rats with HFpEF were induced by subjecting spontaneously hypertensive rats to a diet rich in fats, salts, and sugars, along with administering streptozotocin. Subsequently, they were administered Sac/val at a daily dosage of 18 mg/kg. Finally, cardiac structure and function were assessed using echocardiography; Hematoxylin and eosin staining and Masson's trichrome staining were employed to evaluate the pathological changes; Quantitative real-time polymerase chain reaction and Western blot analysis were conducted to determine the expression of pertinent mRNA and proteins. Sac/val treatment attenuated left ventricular (LV) remodeling and diastolic dysfunction in HFpEF rats, possibly related to its anti-inflammatory, anti-hypertrophic, and anti-fibrotic efficacy. Mechanistically, Sac/val might inhibit inflammation by down-regulating cell adhesion molecule (intercellular adhesion molecule-1 (ICAM-1) and vascular endothelial cell adhesion molecule-1 (VCAM-1)) expression. Additionally, it blocked the phosphorylation of glycogen synthase kinase 3ß (GSK-3ß) to prevent cardiomyocyte hypertrophy. Furthermore, it effectively suppressed myocardial fibrosis by inhibiting the transforming growth factor-beta1 (TGF-ß1)/Smads pathway. Our findings suggest that Sac/val improved LV remodeling and diastolic dysfunction, potentially attributed to its anti-inflammatory, anti-hypertrophic, and anti-fibrotic effects. These results provide a sound theoretical rationale for the clinical application of Sac/val in patients with HFpEF.