Hasil untuk "Therapeutics. Pharmacology"

S. Sreelatha, P. Padma

E. D. Levin, F. J. McClernon, A. Rezvani

A. Kazantsev, L. Thompson

Marion Peyressatre, C. Prével, M. Pellerano et al.

Cyclin-dependent kinases (CDK/Cyclins) form a family of heterodimeric kinases that play central roles in regulation of cell cycle progression, transcription and other major biological processes including neuronal differentiation and metabolism. Constitutive or deregulated hyperactivity of these kinases due to amplification, overexpression or mutation of cyclins or CDK, contributes to proliferation of cancer cells, and aberrant activity of these kinases has been reported in a wide variety of human cancers. These kinases therefore constitute biomarkers of proliferation and attractive pharmacological targets for development of anticancer therapeutics. The structural features of several of these kinases have been elucidated and their molecular mechanisms of regulation characterized in depth, providing clues for development of drugs and inhibitors to disrupt their function. However, like most other kinases, they constitute a challenging class of therapeutic targets due to their highly conserved structural features and ATP-binding pocket. Notwithstanding, several classes of inhibitors have been discovered from natural sources, and small molecule derivatives have been synthesized through rational, structure-guided approaches or identified in high throughput screens. The larger part of these inhibitors target ATP pockets, but a growing number of peptides targeting protein/protein interfaces are being proposed, and a small number of compounds targeting allosteric sites have been reported.

David P. Burns, Sarah E. Drummond, Stefanie Wölfel et al.

Obstructive sleep apnoea (OSA) involves impaired upper airway muscle function and is linked to several pathologies including systemic hypertension, daytime somnolence and cognitive decline. Selenium is an essential micronutrient that exerts many of its effects through selenoproteins. Evidence indicates that either deficient or excessive dietary selenium intake can result in impaired muscle function, termed nutritional myopathy. To investigate the effects of selenium on an upper airway muscle, the sternohyoid, rats were fed on diets containing deficient, normal (0.5 ppm sodium selenite) or excessive (5 ppm selenite) selenium for a period of two weeks. Sternohyoid contractile function was assessed ex vivo. Serum selenium levels and activity of the glutathione antioxidant system were determined by biochemical assays. The abundance of three key muscle selenoproteins (selenoproteins -N, -S and -W (SELENON, SELENOS and SELENOW)) in sternohyoid muscle were quantified by immunoblotting. Levels of these selenoproteins were also compared between rats exposed to chronic intermittent hypoxia, a model of OSA, and sham treated animals. Although having no detectable effect on selected organ masses and whole-body weight, either selenium-deficient or -excessive diets severely impaired sternohyoid contractile function. These changes did not involve altered fibre size distribution. These dietary interventions resulted in corresponding changes in serum selenium concentrations but did not alter the activity of glutathione-dependent antioxidant systems in sternohyoid muscle. Excess dietary selenium increased the abundance of SELENOW protein in sternohyoid muscles but had no effect on SELENON or SELENOS. In contrast, chronic intermittent hypoxia increased SELENON, decreased SELENOW and had no significant effect on SELENOS in sternohyoid muscle. These findings indicate that two-week exposure to selenium-deficient or -excessive diets drastically impaired upper airway muscle function. In the sternohyoid, SELENON, SELENOS and SELENOW proteins show distinct alterations in level following exposure to different dietary selenium intakes, or to chronic intermittent hypoxia. Understanding how alterations in Se and selenoproteins impact sternohyoid muscle function has the potential to be translated into new therapies for prevention or treatment of OSA.

Christiano dos Santos, Aline Thais Bruni

Novel psychoactive substances (NPSs) are compounds plotted to modify the chemical structures of prohibited substances, offering alternatives for consumption and evading legislation. The prompt emergence of these substances presents challenges in health concerns and forensic assessment because of the lack of analytical standards. A viable alternative for establishing these standards involves leveraging in silico methods to acquire spectroscopic data. This study assesses the efficacy of utilizing infrared spectroscopy (IRS) data derived from density functional theory (DFT) for analyzing NPSs. Various functionals were employed to generate infrared spectra for five distinct NPS categories including the following: amphetamines, benzodiazepines, synthetic cannabinoids, cathinones, and fentanyls. PRISMA software was conceived to rationalize data management. Unsupervised learning techniques, including Hierarchical Cluster Analysis (HCA), Principal Component Analysis (PCA), and t-distributed stochastic neighbor embedding (t-SNE), were utilized to refine the assessment process. Our findings reveal no significant disparities among the different functionals used to generate infrared spectra data. Additionally, the application of unsupervised learning demonstrated adequate segregation of NPSs within their respective groups. In conclusion, integrating theoretical data and dimension reduction techniques proves to be a powerful strategy for evaluating the spectroscopic characteristics of NPSs. This underscores the potential of this combined methodology as a diagnostic tool for distinguishing IR spectra across various NPS groups, facilitating the evaluation of newly unknown compounds.

Zhu L, Zhou J, Yu C et al.

Lujian Zhu,1,* Jing Zhou,1,* Chen Yu,2 Lei Gu,3 Qin Wang,1 Hanglu Xu,1 Yin Zhu,4 Maodong Guo,5 Minli Hu,5 Wei Peng,6 Hao Fang,7 Haizhen Wang8 1Department of Infectious Diseases, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, People’s Republic of China; 3Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China; 4Department of Infectious Diseases, Taizhou Enze Medical Center (Group), Enze Hospital, Taizhou, People’s Republic of China; 5Department of Gastroenterology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, People’s Republic of China; 6Department of Intensive Care Unit, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, People’s Republic of China; 7Department of Trauma Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, People’s Republic of China; 8Department of Health Management Center, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, People’s Republic of China*These authors contributed equally to this workCorrespondence: Haizhen Wang, Department of Health Management Center, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, People’s Republic of China, Email whz002012@sina.comAbstract: Ferroptosis, a type of programmed cell death that relies on iron, is distinct in terms of its morphological, biochemical and genetic features. Unlike other forms of cell death, such as autophagy, apoptosis, necrosis, and pyroptosis, ferroptosis is primarily caused by lipid peroxidation. Cells that die due to iron can potentially trigger an immune response which intensifies inflammation and causes severe inflammatory reactions that eventually lead to multiple organ failure. In recent years, ferroptosis has been identified in an increasing number of medical fields, including neurological pathologies, chronic liver diseases and sepsis. Ferroptosis has the potential to cause an inflammatory tempest, with many of the catalysts and pathological indications of respiratory ailments being linked to inflammatory reactions. The growing investigation into ferroptosis in respiratory disorders has also garnered significant interest to better understand the mechanism of ferroptosis in these diseases. In this review, the recent progress in understanding the molecular control of ferroptosis and its mechanism in different respiratory disorders is examined. In addition, this review discusses current challenges and prospects for understanding the link between respiratory diseases and ferroptosis.Keywords: respiratory system, ferroptosis, iron metabolism, oxidative stress, treatment

Eric S. Wang, Alyssa L Verano, R. Nowak et al.

The zinc-finger transcription factor Helios is critical for maintaining the identity, anergic phenotype and suppressive activity of regulatory T (Treg) cells. While it is an attractive target to enhance the efficacy of currently approved immunotherapies, no existing approaches can directly modulate Helios activity or abundance. Here, we report the structure-guided development of small molecules that recruit the E3 ubiquitin ligase substrate receptor cereblon to Helios, thereby promoting its degradation. Pharmacological Helios degradation destabilized the anergic phenotype and reduced the suppressive activity of Treg cells, establishing a route towards Helios-targeting therapeutics. More generally, this study provides a framework for the development of small-molecule degraders for previously unligandable targets by reprogramming E3 ligase substrate specificity. Two degraders targeting zinc finger transcription factor IKZF2 (Helios) were developed by reprogramming CRL4CRBN E3 ligase, and the pharmacologic degradation of Helios results in Treg destabilization.

P. Hagedorn, R. Persson, E. Funder et al.

Over the past 20 years, the field of RNA-targeted therapeutics has advanced based on discoveries of modified oligonucleotide chemistries, and an ever-increasing understanding of how to apply cellular assays to identify oligonucleotides with improved pharmacological properties in vivo. Locked nucleic acid (LNA), which exhibits high binding affinity and potency, is widely used for this purpose. Our understanding of RNA biology has also expanded tremendously, resulting in new approaches to engage RNA as a therapeutic target. Recent observations indicate that each oligonucleotide is a unique entity, and small structural differences between oligonucleotides can often lead to substantial differences in their pharmacological properties. Here, we outline new principles for drug discovery exploiting oligonucleotide diversity to identify rare molecules with unique pharmacological properties.

A. Mathew, Saji Uthaman, Ki-Hyun Cho et al.

Sabine Raab-Westphal, J. Marshall, S. Goodman

Integrins are transmembrane receptors that are central to the biology of many human pathologies. Classically mediating cell-extracellular matrix and cell-cell interaction, and with an emerging role as local activators of TGFβ, they influence cancer, fibrosis, thrombosis and inflammation. Their ligand binding and some regulatory sites are extracellular and sensitive to pharmacological intervention, as proven by the clinical success of seven drugs targeting them. The six drugs on the market in 2016 generated revenues of some US$3.5 billion, mainly from inhibitors of α4-series integrins. In this review we examine the current developments in integrin therapeutics, especially in cancer, and comment on the health economic implications of these developments.

Marziyeh Hajialyani, Devesh Tewari, E. Sobarzo-Sánchez et al.

Wound healing process is an intricate sequence of well-orchestrated biochemical and cellular phenomena to restore the integrity of the skin and subcutaneous tissue. Several plant extracts and their phytoconstituents are known as a promising alternative for wound healing agents due to the presence of diverse active components, ease of access, and their limited side effects. The development of nanotechnological methods can help to improve the efficacy of different therapeutics as well as herbal-based products. Here, we present a review of the efficacy of the plant based-nanomaterials in the management of wounds and discuss the involved therapeutic targets. For this purpose, a profound search has been conducted on in vitro, in vivo, and/or clinical evidences evaluating the efficacy and pharmacological mechanisms of natural product-based nanostructures on different types of wounds. Different pharmacological targets are involved in the wound healing effects of herbal-based nanostructures, including suppressing the production of inflammatory cytokines and inflammatory transduction cascades, reducing oxidative factors and enhancing antioxidative enzymes, and promoting neovascularization and angiogenic pathways through increasing the expression of vascular endothelial growth factor, fibroblast growth factor, and platelet-derived growth factor. Moreover, nanostructure of plant extracts and their phytochemicals can enhance their bioavailability, control their release in the form of sustained delivery systems to the wound site, and enhance the permeability of these therapeutics to the underlying skin layers, which are all necessary for the healing process. Overall, various plant extracts and their natural compounds, used in nanoformulations, have demonstrated high activity in the management of wounds and thus can be assumed as future pharmaceutical drugs.

Miao Song, Naiyue Hu, Sumei Zhou et al.

Drought poses a significant challenge to global wheat production, and the application of exogenous phytohormones offers a convenient approach to enhancing drought tolerance of wheat. However, little is known about the molecular mechanism by which strigolactones (SLs), newly discovered phytohormones, alleviate drought stress in wheat. Therefore, this study is aimed at elucidating the physiological and molecular mechanisms operating in wheat and gaining insights into the specific role of SLs in ameliorating responses to the stress. The results showed that SLs application upregulated the expression of genes associated with the antioxidant defense system (<i>Fe/Mn-SOD</i>, <i>PER1</i>, <i>PER22</i>, <i>SPC4</i>, <i>CAT2</i>, <i>APX1</i>, <i>APX7</i>, <i>GSTU6</i>, <i>GST4</i>, <i>GOR</i>, <i>GRXC1</i>, and <i>GRXC15</i>), chlorophyll biogenesis (<i>CHLH</i>, and <i>CPX</i>), light-harvesting chlorophyll A-B binding proteins (<i>WHAB1.6</i>, and <i>LHC Ib-21</i>), electron transfer (<i>PNSL2</i>), E3 ubiquitin-protein ligase (<i>BB</i>, <i>CHIP</i>, and <i>RHY1A</i>), heat stress transcription factor (<i>HSFA1</i>, <i>HSFA4D</i>, and <i>HSFC2B</i>), heat shock proteins (<i>HSP23.2</i>, <i>HSP16.9A</i>, <i>HSP17.9A</i>, <i>HSP21</i>, <i>HSP70</i>, <i>HSP70-16</i>, <i>HSP70-17</i>, <i>HSP70-8</i>, <i>HSP90-5</i>, and <i>HSP90-6</i>), DnaJ family members (<i>ATJ1</i>, <i>ATJ3</i>, and <i>DJA6</i>), as well as other chaperones (<i>BAG1</i>, <i>CIP73</i>, <i>CIPB1</i>, and <i>CPN60I</i>). but the expression level of genes involved in chlorophyll degradation (<i>SGR</i>, <i>NOL</i>, <i>PPH</i>, <i>PAO</i>, <i>TIC55</i>, and <i>PTC52</i>) as well as photorespiration (<i>AGT2</i>) was found to be downregulated by SLs priming. As a result, the activities of superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT) were enhanced, and chlorophyll content and photosynthetic rate were increased, which indicated the alleviation of drought stress in wheat. These findings demonstrated that SLs alleviate drought stress by promoting photosynthesis through enhancing chlorophyll levels, and by facilitating ROS scavenging through modulation of the antioxidant system. The study advances understandings of the molecular mechanism underlying SLs-mediated drought alleviation and provides valuable insights for implementing sustainable farming practice under water restriction.

O. A. Belova, V. A. Kurkin, M. V. Egorov

Licorice herb (Glycyrrhiza glabra L.) is a promising herbal raw material, which can be comprehensively used to develop drugs with an anti-inflammatory action.The aim of the article was to development a quantitative determination method of total flavonoids in Glycyrrhiza glabra L. herbs.Materials and methods. The subjects of research were 5 samples of licorice herb harvested in summer in various places of growing and cultivation. Pinostrobin was used as a standard sample. The registration of the electronic spectra was carried out with a spectrophotometer (Analytik Jena AG, Germany) by differential spectrophotometry, 96% ethanol was used as a solvent.Results. The methods for quantitative determination of total flavonoids in Glycyrrhiza glabra L. was carried out at an analytical wavelength of 310 nm equivalent to pinocembrin. The optimum parameters for the extraction of total flavonoids from Glycyrrhiza glabra L. were as follows: the extractant – 90% ethanol; the «raw material-extractant» ratio was 1:50; the extraction time was 60 min; the degree of atomization was 2 mm. The content of total flavonoids for the Glyccyrhiza glabra L. herb has been determined, it varies from 0.39±0.002 to 3.41±0.015% with the humidity of the vegetative raw material from 9.97±0.003 to 10.03±0.003% depending on the place of the vegetation, cultivation and year of the raw material collection. The error of the single determination with a 95% confidence level was ±0.73%.Conclusion. The developed methods for the quantitative determination of total flavonoids in Glycyrrhiza glabra L. herbs can be used to solve the issues of standardization of these medicinal plant raw materials.

Florian Westphal, Ulrich Jehn, Dennis Görlich et al.

M. Mithoefer, C. Grob, T. Brewerton

J. Franco, U. Balaji, Elizaveta Freinkman et al.

Due to loss of p16ink4a in pancreatic ductal adenocarcinoma (PDA), pharmacological suppression of CDK4/6 could represent a potent target for treatment. In PDA models, CDK4/6 inhibition had a variable effect on cell cycle but yielded accumulation of ATP and mitochondria. Pharmacological CDK4/6 inhibitors induce cyclin D1 protein levels; however, RB activation was required and sufficient for mitochondrial accumulation. CDK4/6 inhibition stimulated glycolytic and oxidative metabolism and was associated with an increase in mTORC1 activity. MTOR and MEK inhibitors potently cooperate with CDK4/6 inhibition in eliciting cell-cycle exit. However, MTOR inhibition fully suppressed metabolism and yielded apoptosis and suppression of tumor growth in xenograft models. The metabolic state mediated by CDK4/6 inhibition increases mitochondrial number and reactive oxygen species (ROS). Concordantly, the suppression of ROS scavenging or BCL2 antagonists cooperated with CDK4/6 inhibition. Together, these data define the impact of therapeutics on PDA metabolism and provide strategies for converting cytostatic response to tumor cell killing.

Shaherin Basith, Minghua Cui, Sunhye Hong et al.

Capsaicin is the most predominant and naturally occurring alkamide found in Capsicum fruits. Since its discovery in the 19th century, the therapeutic roles of capsaicin have been well characterized. The potential applications of capsaicin range from food flavorings to therapeutics. Indeed, capsaicin and few of its analogues have featured in clinical research covered by more than a thousand patents. Previous records suggest pleiotropic pharmacological activities of capsaicin such as an analgesic, anti-obesity, anti-pruritic, anti-inflammatory, anti-apoptotic, anti-cancer, anti-oxidant, and neuro-protective functions. Moreover, emerging data indicate its clinical significance in treating vascular-related diseases, metabolic syndrome, and gastro-protective effects. The dearth of potent drugs for management of such disorders necessitates the urge for further research into the pharmacological aspects of capsaicin. This review summarizes the historical background, source, structure and analogues of capsaicin, and capsaicin-triggered TRPV1 signaling and desensitization processes. In particular, we will focus on the therapeutic roles of capsaicin and its analogues in both normal and pathophysiological conditions.

Fettucciari K, Fruganti A, Marchegiani A et al.

Katia Fettucciari,1 Alessandro Fruganti,2 Andrea Marchegiani,2 Stefano Brancorsini,1 Pierfrancesco Marconi,1 Gabrio Bassotti3,4 1Department of Experimental Medicine, University of Perugia Medical School, Perugia, Italy; 2School of Biosciences and Veterinary Medicine, University of Camerino, Macerata, Italy; 3Gastroenterology, Hepatology &amp; Digestive Endoscopy Section, Department of Medicine, University of Perugia Medical School, Perugia, Italy; 4Gastroenterology &amp; Hepatology Unit, Santa Maria della Misericordia Hospital, Perugia, ItalyCorrespondence: Katia FettucciariDepartment of Experimental Medicine, University of Perugia Medical School, Piazza Lucio Severi 1, Edificio B IV Piano, Sant&rsquo;Andrea delle Fratte, Perugia 06132, ItalyTel +39755858124Email katia.fettucciari@unipg.itAbstract: Clostridioides difficile infection (CDI) has a serious impact on the healthcare system, and most of its pathogenic effects are mainly due to the activity of toxins A and B (TcdA and TcdB, respectively). The molecular mechanisms of their cytotoxic activity are well known, especially in the colon, where the infection occurs and normally remains localized. However, the mechanisms causing toxic effects on various systemic organs (extraintestinal manifestations) with frequent lethal outcomes in some patients affected by CDI are still poorly understood. Few studies are available that demonstrate low serum levels of Tcds in both experimental animal models and patients with CDI. Until now, it has remained unclear how low levels of circulating Tcds could lead to serious toxic effects. On the basis of our previous in vitro studies, in which the proinflammatory cytokines TNF-alpha and IFN-gamma strongly potentiated the toxic activity of low doses of TcdB, we hypothesize that the presence of both TcdB in the circulation and a systemic proinflammatory cytokine storm may be responsible for the selective severe effects of TcdB in some patients. This may occur in patients with severe CDI and systemic Tcds, in whom proinflammatory cytokines such as TNF-alpha and IFN-gamma reach a significant concentration in the circulation. This hypothesis could identify therapeutic interventions based on the reduction or neutralization of the indirect toxic action of these cytokines.Keywords: Clostridioides difficile, toxin B, proinflammatory cytokines, TNF-alpha, IFN-gamma, systemic effects