Borupmartinez7936
Atherosclerosis is a chronic inflammatory disease in which the members of S100 family proteins (calgranulins) bind with their receptors, particularly receptor for advanced glycation end products (RAGE) and toll-like receptor-4 (TLR-4) and play a key role in the pathogenesis and progression of disease. Thus, these proteins could be considered as potential biomarkers and therapeutic targets in the treatment of atherosclerotic inflammation.
This review summarizes the pathology of S100A8, S100A9, and S100A12 in the development of atherosclerosis and reveals key structural features of these proteins which are potentially critical in their pathological effects. This article focuses on the translational significance of antagonizing these proteins by using small molecules in patent literature, clinical and preclinical studies and also discusses future approaches that could be employed to block these proteins in the treatment of atherosclerosis.
Based on the critical role of S100/calgranulins in the regulation of atherosclerosis, these proteins are potential targets to develop better therapeutic options in the treatment of inflammatory diseases. However, further research is still needed to clarify their exact molecular mechanism by analyzing their detailed structural features that can expedite future research to develop novel therapeutics against these proteins to treat atherosclerotic inflammation.
Based on the critical role of S100/calgranulins in the regulation of atherosclerosis, these proteins are potential targets to develop better therapeutic options in the treatment of inflammatory diseases. However, further research is still needed to clarify their exact molecular mechanism by analyzing their detailed structural features that can expedite future research to develop novel therapeutics against these proteins to treat atherosclerotic inflammation.Herein, a new wave of bis([1, 2, 4]triazolo)[4,3-a3',4'-c]quinoxaline derivatives have been successfully designed and synthesised. The synthesised derivatives were biologically investigated for their cytotoxic activities against HepG2 and MCF-7. Also, the tested compounds were further examined in vitro for their VEGFR-2 inhibitory activity. The most promising derivative 23j was further investigated for its apoptotic behaviour in HepG2 cell lines using flow cytometric and western-plot analyses. Additional in-silico studies were performed to predict how the synthesised compounds can bind to VEGFR-2 and to determine the drug-likeness profiling of these derivatives. The results revealed that compounds 23a, 23i, 23j, 23l, and 23n displayed the highest antiproliferative activities against the two cell lines with IC50 values ranging from 6.4 to 19.4 µM. Furthermore, compounds 23a, 23d, 23h, 23i, 23j, 23l, 23 m, and 23n showed the highest VEGFR-2 inhibitory activities with IC50 values ranging from 3.7 to 11.8 nM, comparing to sorafenib (IC50 = 3.12 nM). Moreover, compound 23j arrested the HepG2 cell growth at the G2/M phase and induced apoptosis by 40.12% compared to the control cells (7.07%). As well, such compound showed a significant increase in the level of caspase-3 (1.36-fold), caspase-9 (2.80-fold), and BAX (1.65-fold), and exhibited a significant decrease in Bcl-2 level (2.63-fold).
Gastrointestinal (GI) cancers account for the second leading cause of cancer-related deaths in the United States. Guanylyl cyclase C (GUCY2C) is an intestinal signaling system that regulates intestinal fluid and electrolyte secretion as well as intestinal homeostasis. In recent years, it has emerged as a promising target for chemoprevention and therapy for GI malignancies.
The loss of GUCY2C signaling early in colorectal tumorigenesis suggests it could have a significant impact on tumor initiation. Recent studies highlight the importance of GUCY2C signaling in preventing colorectal tumorigenesis using agents such as linaclotide, plecanatide, and sildenafil. Furthermore, GUCY2C is a novel target for immunotherapy and a diagnostic marker for primary and metastatic diseases.
There is an unmet need for prevention and therapy in GI cancers. In that context, GUCY2C is a promising target for prevention, although the precise mechanisms by which GUCY2C signaling affects tumorigenesis remain to be defined. Furthermore, clinical trials are exploring its role as an immunotherapeutic target for vaccines to prevent metastatic disease. Indeed, GUCY2C is an emerging target across the disease continuum from chemoprevention, to diagnostic management, through the treatment and prevention of metastatic diseases.
There is an unmet need for prevention and therapy in GI cancers. CORT125134 In that context, GUCY2C is a promising target for prevention, although the precise mechanisms by which GUCY2C signaling affects tumorigenesis remain to be defined. Furthermore, clinical trials are exploring its role as an immunotherapeutic target for vaccines to prevent metastatic disease. Indeed, GUCY2C is an emerging target across the disease continuum from chemoprevention, to diagnostic management, through the treatment and prevention of metastatic diseases.Pathogenic bacteria resistant to most antibiotics, including the methicillin-resistant Staphylococcus aureus (MRSA) represent a serious medical problem. The search for new antiinfectives, possessing a diverse mechanism of action compared to the clinically used antibiotics, has become an attractive research field. S. aureus DNA encodes a β-class carbonic anhydrase, SauBCA. It is a druggable target that can be inhibited by certain aromatic and heterocyclic sulphonamides. Here we investigated inorganic anions and some other small molecules for their inhibition of SauBCA. The halides, nitrite, nitrate, bicarbonate, carbonate, bisulphite, sulphate, stannate, and N,N-diethyldithiocarbamate were submillimolar SauBCA inhibitors with KIs in the range of 0.26 - 0.91 mM. The most effective inhibitors were sulfamide, sulfamate, phenylboronic acid, and phenylarsonic acid with KIs of 7 - 43 µM. Several interesting inhibitors detected here may be considered lead compounds for the development of even more effective derivatives, which should be investigated for their bacteriostatic effects.Ischaemic stroke is a leading cause of death and disability. One of the major pathogenic mechanisms after ischaemia includes the switch to the glycolytic pathway, leading to tissue acidification. Carbonic anhydrase (CA) contributes to pH regulation. A new generation of CA inhibitors, AN11-740 and AN6-277 and the reference compound acetazolamide (ACTZ) were investigated in two models of brain ischaemia in rat hippocampal acute slices exposed to severe oxygen, glucose deprivation (OGD) and in an in vivo model of focal cerebral ischaemia induced by permanent occlusion of the middle cerebral artery (pMCAo) in the rat. In vitro, the application of selective CAIs significantly delayed the appearance of anoxic depolarisation induced by OGD. In vivo, sub-chronic systemic treatment with AN11-740 and ACTZ significantly reduced the neurological deficit and decreased the infarct volume after pMCAo. CAIs counteracted neuronal loss, reduced microglia activation and partially counteracted astrocytes degeneration inducing protection from functional and tissue damage.
Toxicity data are unavailable for many thousands of chemicals in commerce and the environment. Therefore, risk assessors need to rapidly screen these chemicals for potential risk to public health. High-throughput screening (HTS) for
bioactivity, when used with high-throughput toxicokinetic (HTTK) data and models, allows characterization of these thousands of chemicals.
This review covers generic physiologically based toxicokinetic (PBTK) models and high-throughput PBTK modeling for
extrapolation (IVIVE) of HTS data. We focus on 'httk', a public, open-source set of computational modeling tools and
toxicokinetic (TK) data.
HTTK benefits chemical risk assessors with its ability to support rapid chemical screening/prioritization, perform IVIVE, and provide provisional TK modeling for large numbers of chemicals using only limited chemical-specific data. Although generic TK model design can increase prediction uncertainty, these models provide offsetting benefits by increasing model implementation acical prioritization and rapid dose estimation to facilitate rapid hazard assessments.
Gestational diabetes mellitus (GDM) is one of the most common metabolic dysfunction in pregnancy and as overweight and obesity are of the major risk factors. The aim of this study was to determine the effect of Information-Motivation and Behavioral skills (IMB) model-based counseling on preventing GDM in overweight and obese pregnant women.
This randomized controlled trial study was conducted on 137 pregnant women in two groups; education and counseling IMB model-based for four sessions (
= 70), and antenatal usual care (AUC) (
= 67). This study was conducted on overweight and obese pregnant women, at the 12 to 16 weeks' gestation and recruited from the Prenatal Clinic of Rohani Hospital in north of Iran. Blood glucose was measured before and 8 weeks after the intervention. Descriptive and inferential statistics including mean, frequency, t-test, chi-square and ANCOVA were used.
The prevalence of GDM was lower in the intervention group than the control group (10% and 29.9%, respectively, RR = 0.33, CI 95% (0.15- 0.74)
= .004) as well as mean fasting blood glucose (Cohen's
= 0.28,
= .07), and glucose tolerance test at the first and second hour (
= 0.41 and Cohen's
= 0.73, respectively,
< .01).
A lifestyle intervention in early pregnancy by IMB counseling in overweight and obese pregnant women can be effective in decrease GDM.
A lifestyle intervention in early pregnancy by IMB counseling in overweight and obese pregnant women can be effective in decrease GDM.
This study aims at emphasizing the significant impact of the incentives to promote the United States (US) pharmaceutical innovation.
We carried out a retrospective single-case study. We analyzed the innovation process of Epogen basic research, applied research, regulatory, and marketing.
Incentives and policies of pharmaceutical innovation significantly facilitates the entire life cycle of Epogen. The transfer of patent presented by the Bayh-Dole Act allowed Amgen to purchase the research results of Epogen. Relying on the intellectual property mechanisms and financing incentives, Amgen raised the funds needed for Epogen in applied research. Special review shortened the regulatory of Epogen. Epogen obtained orphan drug designation twice and 8 years of market exclusivity. Tax deduction and research funding provided direct economic compensation. The patent system enabled Epogen to obtain 32 years of patent protection (1983-2015). Monopoly pricing was a significant determinant to increase the sales of Epogen through pricing strategies.
We pointed out that Amgen has developed the successful innovation of Epogen taking advantages of the incentives. Effective and flexible incentives and policies are essential to support the entire life cycle of new drugs, ultimately forming a sustainable driver for the long-run pharmaceutical innovation.
We pointed out that Amgen has developed the successful innovation of Epogen taking advantages of the incentives. Effective and flexible incentives and policies are essential to support the entire life cycle of new drugs, ultimately forming a sustainable driver for the long-run pharmaceutical innovation.
