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Colorectal cancer is among the deadliest cancers in the world. Due to the occurrence of side effects related to current standard therapy, researchers are seeking better alternative treatments. For many years, herbs have been a promising source for discovering therapeutic compounds. Therefore, the primary objective of this research was to examine the distinctive apoptotic and anti-inflammatory properties exhibited by Levisticum officinale Koch (lovage) on HT-29 and Caco-2 cell lines. The maceration method was used to prepare different extracts (ethanol, dichloromethane, petroleum, and residues) from the plant. These extracts were then tested on two colon cancer cell lines - HT-29 and Caco-2 - using the MTT assay to determine the half-maximal inhibitory concentration (IC50) values. In addition, we evaluated the expression levels of several inflammatory genes (IKKb, IKKa, and REIB) using real-time PCR. We also assessed Cox-2 protein expression using western blot analysis. The western blot was also used to analyze apoptosis-related proteins, including Caspase-3, BAX, and Bcl-2. The dichloromethane extract of Levisticum officin (DELO) exhibited a high cytotoxic effect on Caco-2 and HT-29 cell lines, with IC50 values of 106.0±2 μg/mL in HT-29 cells and 175.3±4 μg/mL in Caco-2 cells after 72 hours. None of the lovage extracts showed a significant cytotoxic effect on non-cancerous cells (3T3 cell line). Furthermore, the group treated with DELO showed a lower expression level of inflammatory genes and COX-2 protein compared to the control group. Notably, treatment with DELO resulted in an increase in Caspase-3 protein and BAX/Bcl-2 ratio in both HT-29 and Caco-2 cells. According to this study, DELO has the potential to act as an anti-inflammatory and anti-cancer agent. Further research on the compounds present in DELO and their effect on various signaling pathways could help in the development of new drugs for diseases where inflammation or cells escape from apoptosis play a crucial role.

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Intracellular alkalosis and extracellular acidosis are two pathological features associated with malignant cells. They offer advantages in terms of invasiveness and proliferation. Extracellular acidification is the consequence of intracellular metabolic changes associated with a higher metabolic rate of cancer cells, potentially inducing dangerous intracellular acidification. To overcome this menace, malignant cells adapt themselves to export hydrogen ions. Therefore, it is reasonable that targeting intracellular alkalinization and extracellular acidification to prompt the reversal of such a pH gradient towards a condition comparable to normal, untransformed cells may represent a strategy helping to contrast malignant behavior. In the present study, we investigated in vitro, in prostate cancer cell models, the biological activity towards intracellular, extracellular and organelle pH of systems of molecules of vegetal origin. A few of these systems were shown to promote intracellular acidification in vitro, whereas others were shown to prevent extracellular acidification and promote lysosomal alkalinization in a cell type-dependent manner. This result clearly indicates that these systems may function as agents interfering with malignant cells inverted pH gradient. Further analysis would be necessary to unravel the cell type specificity of their effects, as well as their mechanism of action. Nevertheless, our proof-of-principle study provides evidence that such systems of molecules can be considered interesting agents in co-adjuvating anti-cancer therapies.

Mesalazine is a 5-aminosalicylate commonly used in the treatment of ulcerative colitis. It has been very rarely associated with neutropenia. We report a woman in her 30s who developed neutropenia 2 years after starting mesalazine. She had not been started on any other medications and extensive investigation for alternative causes of neutropenia were unremarkable. Mesalazine was discontinued and her neutrophil count normalised within 2 weeks.

Scorpion antipredator behavior incorporates risk assessment that informs decision-making and venom usage. We quantified antipredator behaviors of the clinically significant Arizona bark scorpion (Centruroides sculpturatus) in their natural environment using exposure to two stimuli: a freshly thawed laboratory mouse (Mus musculus) and a membrane-covered glass beaker. We videotaped and compared envenomation behaviors between sexes (females, gravid females, and males), across sizes, and between animal orientations (on vertical or horizontal substrates). Results failed to show consistent support for any of our four hypotheses. Females (especially gravid females) were no more likely than males to exhibit higher levels of stinging and venom expenditure. Scorpions on horizontal surfaces compared to those on vertical surfaces, and larger scorpions compared to smaller ones, were likewise no more likely to exhibit higher levels of responsiveness. Mice were more likely to be stung than the membrane-covered beaker, but with fewer and briefer stings, suggesting the scorpions did not attempt to deliver more venom into the mice. Thus, we discerned no clear patterns in risk assessment, stinging, and venom use associated with sex, substrate orientation, body size, or threat stimuli. These findings contrasted with those of several prior laboratory studies. Variation from unaccounted environmental variables may have obfuscated divergent behavioral tactics. Nevertheless, the behaviors we document here provide insights on the range of defensive behaviors exhibited by C. sculpturatus under natural environmental conditions, including the frequency of dry stings (11.8%) to the membrane-covered beakers.

Respiratory viruses such as rhinovirus and respiratory syncytial virus (RSV) are common triggers of asthma exacerbations in children. The COVID-19 pandemic introduced non-pharmaceutical interventions (NPIs) that altered viral circulation; however, their long-term effects on pediatric asthma outcomes remain unclear. To evaluate how the epidemiology and severity of respiratory viral infections in children with asthma changed before, during, and after COVID-19-related NPIs. We conducted a cross-sectional analysis of pediatric asthma patients (ages 4-18) with laboratory-confirmed respiratory viral infections from 2018 to 2024 at Arkansas Children's (AC) and AC Northwest (ACNW). Viral detection was performed using the BioFire&#xae; Respiratory Panel. Clinical severity was evaluated using a modified World Health Organization Ordinal Scale for Clinical Improvement (mWHO OSI). Patients were categorized by period (pre-NPI, NPI, post-NPI), viral type, rurality, and Childhood Opportunity Index (COI). This study included 9,391 pediatric asthma patients with laboratory-confirmed viral infections. RV/EV was the most common virus during all periods. Viral incidence decreased during NPIs but rebounded post-NPI with unusual seasonality. mWHO OSI scores declined over time (pre-NPI: 2.98; NPI: 2.49; post-NPI: 2.28), with significant reductions in hospitalizations, PICU admissions, and oxygen use (p&#x2009;<&#x2009;0.0001). Severe disease (mWHO OSI 6-8) was infrequent. Rural and low-COI patients exhibited higher severity, although disparities narrowed post-NPI. NPIs were associated with sustained reductions in asthma-related illness severity, even with increased viral detection post-pandemic. These findings highlight the long-term impact of public health measures on pediatric asthma outcomes and emphasize the need for ongoing surveillance of respiratory viruses and health disparities.

Plants release extracellularly lipid bilayer-enclosed vesicles of nanometric size that can be retrieved in their fluids. Plant-derived extracellular vesicles (PDEVs) have mostly been involved in modulating host-pathogen interaction, making them a tool for cross-kingdom communication with a key role in plant immunity. In addition, PDEVs have demonstrated promising therapeutic features, not only in terms of intrinsic nutraceutical properties but also of active molecules' delivery. Transgenic plants have been developed for a variety of purposes, i.e., to improve their functional properties like crops, but also to produce therapeutic molecules. However, it is unclear whether transgenes can end up in PDEVs, thus making them a vehicle for their cross-kingdom diffusion into the environment. Here, we investigated the association of transgenic DNA and RNA with PDEVs secreted by tobacco (Nicotiana tabacum) engineered to express the neomycine phosphotransferase II (Npt-II) gene. PDEVs were isolated from leaf apoplastic fluid by ultracentrifugation and characterized for their morphology and size. The association of DNA and RNA was assessed by qRT-PCR and their immunomodulatory properties by assaying PDEVs-induced IL1&#x3b2; and IL10 on THP1 monocytes. Npt-II RNA, but not DNA, could be amplified from PDEVs, whereas no differences were observed between wt and transgenic tobacco PDEVs in terms of immunomodulatory properties. Although a different behaviour by other types of RNAs or DNAs could still be possible, our findings indicate that in this model, PDEVs are not associated with transgenic DNA, but they can protect RNA, including transgenic RNA, from degradation, contributing to their cross-kingdom spreading.

Extracellular vesicles (EVs) can be isolated from biological fluids and cell culture medium. Their nanometric dimension, relative stability, and biocompatibility have raised considerable interest for their therapeutic use as delivery vehicles of macromolecules, namely nucleic acids and proteins. Deficiency in lysosomal enzymes and associated proteins is at the basis of a group of genetic diseases known as lysosomal storage disorders (LSDs), characterized by the accumulation of undigested substrates into lysosomes. Among them, GM2 gangliosidoses are due to a deficiency in the activity of lysosomal enzyme &#x3b2;-hexosaminidase, leading to the accumulation of the GM2 ganglioside and severe neurological symptoms. Current therapeutic approaches, including enzyme replacement therapy (ERT), have proven unable to significantly treat these conditions. Here, we provide evidence that the lysosomal &#x3b2;-hexosaminidase enzyme is associated with EVs released by HEK cells and that the EV-associated activity can be increased by overexpressing the &#x3b1;-subunit of &#x3b2;-hexosaminidase. The delivery of EVs to &#x3b2;-hexosaminidase-deficient fibroblasts results in a partial cross-correction of the enzymatic defect. Overall findings indicate that EVs could be a source of &#x3b2;-hexosaminidase that is potentially exploitable for developing therapeutic approaches for currently untreatable LSDs.

Extracting spin system parameters from 1D high resolution 1H-NMR spectra can be an intricate task requiring sophisticate methods. With a few exceptions methods to perform such a total line shape analysis commonly rely on local optimization techniques which for increasing complexity of the underlying spin system tend to reveal local solutions. In this work we propose a full Bayesian modeling approach based on a quantum mechanical model of the spin system. The Bayesian formalism provides a global optimization strategy which allows to efficiently include prior knowledge about the spin system or to incorporate additional constraints concerning the parameters of interest. The proposed algorithm has been tested on synthetic and real 1D 1H-NMR data for various spin systems with increasing complexity. The results show that the Bayesian algorithm provides accurate estimates even for complex spectra with many overlapping regions, and that it can cope with symmetry induced local minima. By providing an unbiased estimate of the model evidence the proposed algorithm furthermore offers a way to discriminate between different spin system candidates.

Liver disease is within the top five causes of premature death in adults. Deaths caused by complications of cirrhosis continue to rise, whilst deaths related to other non-liver disease areas are declining. Portal hypertension is the primary sequelae of cirrhosis and is associated with the development of variceal haemorrhage, ascites, hepatic encephalopathy and infection, collectively termed hepatic decompensation, which leads to hospitalisation and mortality. It remains uncertain whether administering a non-selective beta-blocker (NSBB), specifically carvedilol, at an earlier stage, i.e. when oesophageal varices are small, can prevent VH and reduce all-cause decompensation (ACD). The BOPPP trial is a pragmatic, multicentre, placebo-controlled, triple-blinded, randomised controlled trial (RCT) in England, Scotland, Wales and Northern Ireland. Patients aged 18&#xa0;years or older with cirrhosis and small oesophageal varices that have never bled will be recruited, subject to exclusion criteria. The trial aims to enrol 740 patients across 55 hospitals in the UK. Patients are allocated randomly on a 1:1 ratio to receive either carvedilol 6.25&#xa0;mg (a NSBB) or a matched placebo, once or twice daily, for 36&#xa0;months, to attain adequate power to determine the effectiveness of carvedilol in preventing or reducing ACD. The primary outcome is the time to first decompensating event. It is a composite primary outcome made up of variceal haemorrhage (VH, new or worsening ascites, new or worsening hepatic encephalopathy (HE), spontaneous bacterial peritonitis (SBP), hepatorenal syndrome, an increase in Child-Pugh grade by 1 grade or MELD score by 5 points, and liver-related mortality. Secondary outcomes include progression to medium or large oesophageal varices, development of gastric, duodenal, or ectopic varices, participant quality of life, healthcare costs and transplant-free survival. The BOPPP trial aims to investigate the clinical and cost-effectiveness of carvedilol in patients with cirrhosis and small oesophageal varices to determine whether this non-selective beta-blocker can prevent or reduce hepatic decompensation. There is clinical equipoise on whether intervening in cirrhosis, at an earlier stage of portal hypertension, with NSBB therapy is beneficial. Should the trial yield a positive result, we anticipate that the administration and use of carvedilol will become widespread with pathways developed to standardise the administration of the medication in primary care. The trial has been approved by the National Health Service (NHS) Research Ethics Committee (REC) (reference number: 19/YH/0015). The results of the trial will be submitted for publication in a peer-reviewed scientific journal. Participants will be informed of the results via the BOPPP website ( www.boppp-trial.org ) and partners in the British Liver Trust (BLT) organisation. EUDRACT reference number: 2018-002509-78. ISRCTN reference number: ISRCTN10324656.&#xa0;Registered on April 24 2019.

We investigated the novel recombinant oncolytic adenovirus Ad-delo-sr39TK-RGD, armed with a mutant herpes simplex virus type 1 thymidine kinase (HSV1-sr39TK) as a suicide gene, and explored its antitumor efficacy in combination with HSV1-sr39TK/ganciclovir (GCV) gene therapy and temozolomide (TMZ). Ad-delo-sr39TK-RGD is an E1-mutated conditionally replicating adenovirus dependent on the human Y-box binding protein 1 (YB-1). Thus, we utilized the YB-1 dependency of the vector to target human glioma cells in vitro, using two-dimensional cell culture and three-dimensional multicellular spheroids, and demonstrated the strong replication competence and oncolytic potential of the virus. The cytotoxicity mediated by HSV1-sr39TK and its prodrug GCV enhanced the oncolytic effect even at <0.1&#x2009;&#x3bc;g&#x2009;ml(-1) GCV and induced cell killing of > 95% after adding GCV 0-1 days following infection. An increased bystander effect of viral replication and GCV in co-cultured infected and uninfected cells was observed. Co-administrating Ad-delo-sr39TK-RGD with TMZ and GCV, spheroid growth was reduced drastically. Gamma counting of infected spheroids demonstrated successful accumulation of the radiotracer (18)F-labeled 9-[4-fluoro-3-(hydroxymethyl)butyl]guanine mediated by HSV1-sr39TK. Hence, our results show that the combination of YB-1-dependent virotherapy with suicide genes and TMZ effectively induces glioma cell killing and may allow for in vivo non-invasive imaging within a limited time frame.

A novel way to analyze the boron clusters is proposed in which the cluster is partitioned as inner and outer rings. Fragment molecular orbital analysis, based on this fragmentation, reveals that the delocalized valence electrons in B(12) and B(13)(+) clusters can be trifurcated as 6pi-6sigma(delo)-6sigma(3-ring), leading to triple aromaticity, which is unique to these clusters.

Polyphenon E (Poly E) is a standardized, caffeine-free green tea extract with defined polyphenol content. Poly E is reported to confer chemoprotective activity against prostate cancer (PCa) progression in the TRAMP model of human PCa, and has shown limited activity against human PCa in human trials. The molecular mechanisms of the observed Poly E chemopreventive activity against PCa are not fully understood. We hypothesized that Poly E treatment of PCa cells induces gene expression changes, which could underpin the molecular mechanisms of the limited Poly E chemoprevention activity against PCa. PC-3 cells were cultured in complete growth media supplemented with varied Poly E concentrations for 24 h, then RNA was isolated for comparative DNA microarray (0 vs. 200 mg/L Poly E) and subsequent TaqMan qRT-PCR analyses. Microarray data for 54,613 genes were filtered for >2-fold expression level changes, with 8319 genes increased and 6176 genes decreased. Eight genes involved in key signaling or regulatory pathways were selected for qRT-PCR. Two genes increased expression significantly, MXD1 (13.98-fold; p = 0.0003) and RGS4 (21.98-fold; p = 0.0011), by qRT-PCR. MXD1 and RGS4 significantly increased gene expression in Poly E-treated PC-3 cells, and the MXD1 gene expression increases were Poly E dose-dependent.

An imaginary but realistic scenario is presented in order to stimulate thought and discussion about ethical dilemmas faced by those responsiblefor psychiatric cases. The method is designed to achieve greater consistency in two areas: in professional discussions of ethical problems and in public accountability for these problems. It is proposed in this paper that arguments for and against intervention can be evaluated by attributing to each argument a 'telo' and/or 'delo' value, depending on the possible consequences of intervention and the degree to which intervention would infringe or safeguard the rights of the individual concerned. The main purpose of the proposed method is to 'objectify' existing intuitive ideas and personal viewsfor the purpose of arriving at a balanced quantitative and qualitative evaluation of the decisions that are often required in psychiatric care.

Prof. Dr. Dimitar T. Hrisoho was born on June 11, 1924 in Bitola, R. Macedonia. He died in Struga on September 22, 1986, and was buried in Skopje. He completed primary and secondary education in Bitola. He graduated from the Medical Faculty in Belgrade in 1951 as one of the best students of his generation (average grade of 9.75). In 1953 he was employed at the Internal Clinic of the Medical Faculty in Skopje, where in 1955 he passed the specialist exam in internal medicine. He successfully defended his habilitation "Polyarthritis chronica evolutiva" and his doctoral dissertation "Clinical features of Vitina nephropathy". The doctoral dissertation indicates that Vitina nephropathy is a new site of the Balkan Endemic Nephropathy entity and that more genetic testing of patients were needed. Based on numerous clinical and scientific researches published in over 200 papers, he was elected a Full Professor of internal medicine at the Medical Faculty of the Ss. Cyril and Methodius University in Skopje in 1971. In 1970, he formed the nephrology section of the Macedonian Medical Association (MMA), which grew into the nephrology Association of MMA. Through the Association, the education of the medical staff from the field of nephrology was performed. He also set up a bio-cybernetics association. He achieved his vision and desire to transfer and apply the achievements of modern nephrology in the diagnosis and treatment of kidney patients in Macedonia at the Clinic of Nephrology of the Medical Faculty in Skopje, which was the first specialized institution established for examination and treatment of kidney patients in the former Yugoslavia and the Balkans. The Clinic educated nephrological staff and examined and treated kidney patients with new methods and drugs that positively affected the development of nephrology as a subspecialty of the internal medicine. D. Hrisoho was actively involved in the introduction of new methods for examination of kidney patients, as well as in the treatment of patients with acute and chronic renal insufficiency with dialysis since 1965. He also participated in the first two kidney transplantations from living donors performed in 1977. He wrote a chapter on "kidney examination", printed in the book of Prof. A. J. Ignjatovski "Fundamentals of Internal Propedeutics" Part III, published by "Prosvetno delo", 1963, in Skopje. This is the first text to investigate a patient with kidney disease published in a textbook in R. Macedonia. In 1984 he published the textbook "Clinical Nephrology" printed by the University of the Ss. Cyril and Methodius University in Skopje. Prof. D. Hrisoho organized the First Scientific Meeting of Yugoslav Nephrologists with international participation, from 26 to 28 September 1977, in Struga, R. Macedonia. The meeting was attended by prominent nephrologists from the former Yugoslavia, the Balkans, Europe and the United States, among them: J.S. Cameron from UK, J.L. Funck-Brentano from France, M. Burg and P. Ivanovich from the USA, R. Kluthe from Germany and A. Puchlev from Bulgaria. The scientific meeting was the largest nephrology event until then organized in the former Yugoslavia. The meeting provided an exchange of experiences with world-renowned nephrologists. D. Hrisoho presented the paper Artificial intelligence in nephrology. The author tried to apply bio-cybernetics in nephrology. Prof. D. Hrisoho was Vice Dean of the Medical Faculty in Skopje in the period 1963-1965 and Vice Rector of the University of the Ss. Cyril and Methodius University in Skopje in the period 1974-1975. Prof. Hrisoho was also active in socio-political organizations. For his medical, educational and scientific activities he received several awards and recognitions in the country and abroad. Thus, the work of Prof. D. Hrisoho was permanently embedded in the nephrology of R. Macedonia.

Coordination of public communication has become a key issue in management of complex emergencies, and is a matter of debate between nuclear emergency management professionals. A particular problem is when inconsistent information is sent to the media and public by official sources from different levels, which has led to calls for a more coordinated approach. The IAEA created guidelines recommending a one-voice communication approach that provides clear, consistent and coordinated information by relevant stakeholders. The reviewed theory on the emergency communication coordination and the empirical results in this paper demonstrate some challenges regarding the feasibility of the above stated goal. This paper explores the communication process in the two-month period of the Fukushima nuclear emergency by using a quantitative comparative content and discourse analysis of 1340 printed media articles on the Fukushima nuclear disaster from two major newspapers in Spain ('El Pa&#xed;s' and 'El Mundo'), Italy ('Corriere della Sera' and 'La Repubblica'), Norway ('Aftenposten' and 'Dagsavisen'), Slovenia ('Delo' and 'Ve&#x10d;er'), Belgium ('Le Soir' and 'De Standaard') and Russia ('Komsomolskaya Pravda' and 'Izvestiya'). The results show that it will be difficult to achieve a truly coordinated approach and one-voice communication in severe nuclear and radiological emergency due to the communication difficulties created by the dispersion of information sources, a broad and dispersed focus of the reported information, partially subjective and conflicting media reporting. The paper suggests ways to improve public communication coordination in nuclear and radiological disasters.

The article presents data concerning clinical and laboratory diagnostics of different diseases and the importance of determination of the erythrocyte sedimentation rate in it. In 1924 (80 years ago) the first work of T. P. Panchenko about the macromethod of the determination Erythrocyte sedimentation rate and its importance in clinical and laboratory diagnostics was published in the medical journal "Vrachebnoe Delo". Although this method is not specific, it integrally reflects general derangements of the organism's homeostasis in patients with acute and chronic diseases and allows controlling sanogenese and completing recovery processes. Nowadays this method is still actual in physician's practice.