Nove spoznaje i napredak u otkrivanju dizajnerskih benzodiazepina – kratak pregled

This review article takes a closer look at a new class of psychoactive substances called designer benzodiazepines (DBZs) and the challenges of their detection. These are adinazolam, clonazolam, deschloroetizolam, diclazepam, etizolam, flualprazolam, flubromazepam, flubromazolam, phenazepam, and pyrazolam. They are central nervous system depressants and sedatives that can cause psychomotor impairment and increase the overdose risk when combined with other sedatives. DBZs undergo phase I and II metabolism similar to traditional benzodiazepines, but their specific metabolic pathways and the influence of genetic polymorphisms are yet to be clarified. Advances in liquid chromatography-tandem mass spectrometry (LC-MS/MS) have enhanced the method’s sensitivity for DBZs and their metabolites in biological samples and coupled with improved blood sampling methods require less blood for drug monitoring. Further research should focus on elucidating their pharmacokinetic properties and metabolism in humans, especially in view of genetic polymorphisms and drug interactions that could inform clinical treatment choices. Even though we have witnessed important advances in DBZ detection and measurement, further refinements are needed to expand the scope of detectable DBZs and their metabolites. All this should help toxicological research to better identify and characterise the risks of chronic and polydrug abuse and facilitate clinical, forensic, and regulatory responses to this growing issue.Svrha je ovoga preglednog članka dati bolji uvid u djelovanje nove skupine psihoaktivnih tvari zvanih dizajnerski benzodiazepini (DBZ) i u izazove njihova otkrivanja. Poimence, to su adinazolam, klonazolam, deskloroetizolam, diklazepam, etizolam, flualprazolam, flubromazepam, flubromazolam, fenazepam i pirazolam. Riječ je o depresivima i sedativima središnjega živčanog sustava koji mogu oslabiti psihomotornu funkciju te povećati rizik od predoziranja u kombinaciji s ostalim sedativima. DBZ-i prolaze fazu I. i II. biorazgradnje na način sličan onomu tradicionalnih benzodiazepina, no tek nam preostaje razjasniti njihove specifične metaboličke putove i kako na njih utječu genski polimorfizmi. Poboljšanja u tekućinskoj kromatografiji s tandemskom masenom spektrometrijom (engl. liquid chromatographytandem mass spectrometry, krat. LC-MS/MS) povećala su osjetljivost metoda na DBZ-e i njihove metabolite u biološkim uzorcima, a poboljšanja u uzorkovanju krvi smanjila su količine potrebne za praćenje razina tvari. Ipak, potrebna su daljnja istraživanja koja će rasvijetliti njihova farmakokinetička svojstva i metabolizam u ljudi, napose u smislu utjecaja genskih polimorfizama i interakcija lijekova, što će pomoći pri odabiru kliničkog liječenja. Premda smo svjedoci važnih pomaka u otkrivanju i mjerenju DBZ-a, potrebna su daljnja poboljšanja kako bi se povećao opseg DBZ-a i njihovih metabolita koji se ovim metodama mogu otkriti. Sve to trebalo bi ne samo pridonijeti toksikološkim istraživanjima radi boljeg prepoznavanja rizika povezanih s kroničnom kombiniranom zloporabom droga nego i olakšati kliničke, forenzičke i regulatorne postupke kao odgovor na ovaj rastući problem

Chaihu Guizhi Ganjiang Decoction Ameliorates Pancreatic Fibrosis via JNK/mTOR Signaling Pathway

Pancreatic fibrosis is a pathological characteristic of chronic pancreatitis (CP) and pancreatic cancer. Chaihu Guizhi Ganjiang Decoction (CGGD) is a traditional Chinese medicine, which is widely used in the clinical treatment of digestive diseases. However, the potential anti-fibrosis mechanism of CGGD in treating CP remains unclear. Here, we conducted a series of experiments to examine the effect of CGGD on the CP rat model and primary isolated pancreatic stellate cells (PSCs). The results revealed that CGGD attenuated pancreatic damage, decreased collagen deposition, and inhibited PSC activation in the pancreas of CP rats. However, compared with the CP group, CGGD had no effect on body weight and serum amylase and lipase. In addition, CGGD suppressed autophagy by downregulating Atg5, Beclin-1, and LC3B and facilitated phosphorylation of mTOR and JNK in pancreatic tissues and PSCs. Moreover, the CGGD-containing serum also decreased LC3B or collagen I expression after rapamycin (mTOR inhibitor) or SP600125 (JNK inhibitor) treatment in PSCs. In conclusion, CGGD attenuated pancreatic fibrosis and PSC activation, possibly by suppressing autophagy of PSCs through the JNK/mTOR signaling pathway

Anti-Inflammatory ent-Kaurane Diterpenoids from Isodon serra

Ten new ent-kaurane diterpenoids, including two pairs of epimers 1/2 and 4/5 and a 6,7-seco-ent-kauranoid 10, were obtained from the aerial parts of Isodon serra. The structures of the new compounds were confirmed by extensive spectroscopic methods and electronic circular dichroism (ECD) data analysis. An anti-inflammatory assay was applied to evaluate their nitric oxide (NO) inhibitory activities by using LPS-stimulated BV-2 cells. Compounds 1 and 9 exhibited notable NO production inhibition with IC50 values of 15.6 and 7.3 μM, respectively. Moreover, the interactions of some bioactive diterpenoids with inducible nitric oxide synthase (iNOS) were explored by employing molecular docking studies.https://pubs.acs.org/journal/jnprdf2021-09-29hj2021Plant Production and Soil Scienc

Src Inhibition Blocks c-Myc Translation and Glucose Metabolism to Prevent the Development of Breast Cancer

Preventing breast cancer will require the development of targeted strategies that can effectively block disease progression. Tamoxifen and aromatase inhibitors are effective in addressing estrogen receptor–positive (ER+) breast cancer development, but estrogen receptor–negative (ER−) breast cancer remains an unmet challenge due to gaps in pathobiologic understanding. In this study, we used reverse-phase protein array to identify activation of Src kinase as an early signaling alteration in premalignant breast lesions of women who did not respond to tamoxifen, a widely used ER antagonist for hormonal therapy of breast cancer. Src kinase blockade with the small-molecule inhibitor saracatinib prevented the disorganized three-dimensional growth of ER− mammary epithelial cells in vitro and delayed the development of premalignant lesions and tumors in vivo in mouse models developing HER2+ and ER− mammary tumors, extending tumor-free and overall survival. Mechanistic investigations revealed that Src blockade reduced glucose metabolism as a result of an inhibition in ERK1/2–MNK1–eIF4E–mediated cap-dependent translation of c-Myc and transcription of the glucose transporter GLUT1, thereby limiting energy available for cell growth. Taken together, our results provide a sound rationale to target Src pathways in premalignant breast lesions to limit the development of breast cancers

The OpenMolcas Web: A Community-Driven Approach to Advancing Computational Chemistry

The developments of the open-source OpenMolcas chemistry software environment since spring 2020 are described, with a focus on novel functionalities accessible in the stable branch of the package or via interfaces with other packages. These developments span a wide range of topics in computational chemistry and are presented in thematic sections: electronic structure theory, electronic spectroscopy simulations, analytic gradients and molecular structure optimizations, ab initio molecular dynamics, and other new features. This report offers an overview of the chemical phenomena and processes OpenMolcas can address, while showing that OpenMolcas is an attractive platform for state-of-the-art atomistic computer simulations

Recent findings and advancements in the detection of designer benzodiazepines: a brief review

This review article takes a closer look at a new class of psychoactive substances called designer benzodiazepines (DBZs) and the challenges of their detection. These are adinazolam, clonazolam, deschloroetizolam, diclazepam, etizolam, flualprazolam, flubromazepam, flubromazolam, phenazepam, and pyrazolam. They are central nervous system depressants and sedatives that can cause psychomotor impairment and increase the overdose risk when combined with other sedatives. DBZs undergo phase I and II metabolism similar to traditional benzodiazepines, but their specific metabolic pathways and the influence of genetic polymorphisms are yet to be clarified. Advances in liquid chromatography-tandem mass spectrometry (LC-MS/MS) have enhanced the method's sensitivity for DBZs and their metabolites in biological samples and coupled with improved blood sampling methods require less blood for drug monitoring. Further research should focus on elucidating their pharmacokinetic properties and metabolism in humans, especially in view of genetic polymorphisms and drug interactions that could inform clinical treatment choices. Even though we have witnessed important advances in DBZ detection and measurement, further refinements are needed to expand the scope of detectable DBZs and their metabolites. All this should help toxicological research to better identify and characterise the risks of chronic and polydrug abuse and facilitate clinical, forensic, and regulatory responses to this growing issue

Isomorphic Insertion of Ce(III)/Ce(IV) Centers into Layered Double Hydroxide as a Heterogeneous Multifunctional Catalyst for Efficient Meerwein–Ponndorf–Verley Reduction

The development of highly active acid-base catalysts for transfer hydrogenations of biomass derived carbonyl compounds is a new, pressing challenge. Solid Frustrated Lewis Pairs (FLP) catalysis is possibly a solution but the development of this concept is still at a very early stage. Herein, by inserting Ce(III)/Ce(IV) centers into layered double hydroxide (MgAlCe–LDH), effective, selective and recyclable solid acid-base catalysts were synthesized, which enabled efficient transfer hydrogenation (MPV reduction) of biomass derived carbonyl compounds to corresponding alcohols. The cooperative, FLP-like interplay between the active sites of Ce(III)/Ce(IV) and the aluminum-containing defect sites formed by the incorporation of cerium into the lattice of LDH is necessary to maximize the catalytic efficiency. Furthermore, the crucial role of the surface hydroxyl groups in the MPV reactions and the negative impact of the interlamellar/adsorbed water molecules on the catalytic activity of MgAlCe-LDH were demonstrated. These solid FLP-like acid-base catalysts exhibited excellent catalytic performance (cyclohexanol yield of 45%; furfuryl alcohol yield of 51%), which is competitive or superior to the benchmark, Sn- and Zr-containing zeolite catalysts, under mild reaction conditions, especially low temperature (T = 65°C in the case of cyclohexanol production). Our research has indicated that Ce-containing LDH is a potentially commercial solid FLP catalysts

Urban River Transformation and the Landscape Garden City Movement in China

The practice of enhancing existing rivers and creating entirely new waterscapes has exploded in China over the past two decades. In our study of 104 randomly selected cities across China, we identified 14 types of river projects based on grey literature reports and their appearance on sequential aerial imagery, falling into three categories: ‘engineering’, ‘waterfront spaces’ and ‘ecological’ projects. ‘Waterfront spaces’ is the most common (60.5%), followed by ‘engineering’ (28.7%) and ‘ecological’ (10.8%). Using multiple stepwise regression, we found that the types of projects undertaken were strongly influenced by factors such as climate, social-economic setting, and ‘Landscape Garden City’ designation. Designation as a ‘Landscape Garden City’ was correlated with ‘waterfront spaces’, but not ‘engineering’ and ‘ecological’ projects. We found that cities in drier climates (as measured by ‘precipitation minus evaporation’) constructed more projects and they included many projects that impounded seasonal rivers to create year-round water bodies. Based on our results, we conclude that Chinese cities are still in the process of ‘decorating’ rivers, and that the ‘Landscape Garden City’ designation promoted such ‘decorating’ projects, especially ‘linear greening’ projects and ‘public spaces along rivers’. The results also demonstrate that the new river projects in China are often at odds with the local climate

Public Attitudes about Urban Lawns : Social Opportunities Provided by Urban Lawns in Lund, Sweden

Since the 19th century, urban lawns have gradually taken center stage to become one of the main sources of greening in many cities around the world. The current published research on planting technology, maintenance techniques, the impact of lawn maintenance, preferences for manicured lawns and the biodiversity protection for historical lawns as topics, has developed and increased over time. However, what has been less researched is the relationship and interplay between the perceptions of urban residents and their use of urban lawns. More specifically, our research focused on the question of how residents view, socialize and utilize city lawns accessible to them. To provide some insight into this area of urban lawn use, our research study was conducted in Lund, Sweden a city that uses lawns as their main form of greening. To accomplish the study’s objectives the city's lawns were grouped into the following categories:(1) park lawns, (2) residential neighborhood lawns, (3) lawns around public buildings, (4) lawns surrounding residential buildings, (5) lawns along greenways and (6) lawns along roads. By means of distributed open-ended questionnaires the researchers discovered two important findings. First, the socialization patterns and utilization of lawns differed between the six categories due to various factors which included the suitability of the land use. The data also showed that the efficiency of planting lawns in certain areas impacts the ability to access areas for socialization activities (i.e. roadsides and greenways). Secondly, the study revealed that the planting collocation and service facilities of lawns greatly influences residents' ability and opportunities for social interaction. Two other study findings were of interest namely that (1) the utilization of lawns among Lund’s working class was somewhat lower than that of students; and (2) that socialization and use of lawns were not necessarily related to the user's accustomed environmental background. Subsequently, this article discusses key themes that include residents’ attitudes, beliefs and opinions about the interaction of socializing and the meaning of those interactions in an urban environment. It is our purpose that this article spurs a more robust international dialogue about pragmatic lessons urban planners may learn about future designing efforts of urban green space in newly developing cities and established ones already confronting modern space and housing challenges