scholarly journals Tauroursodeoxycholate—Bile Acid with Chaperoning Activity: Molecular and Cellular Effects and Therapeutic Perspectives

Cells ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 1471 ◽  
Author(s):  
Magdalena Kusaczuk
Keyword(s):  
Bile Acid ◽  
Primary Biliary Cholangitis ◽  
In Vivo Models ◽  
Chemical Chaperone ◽  
Cytoprotective Activity ◽  
Cellular Effects ◽  
Positive Effects ◽  
Therapeutic Benefits

Tauroursodeoxycholic acid (TUDCA) is a naturally occurring hydrophilic bile acid that has been used for centuries in Chinese medicine. Chemically, TUDCA is a taurine conjugate of ursodeoxycholic acid (UDCA), which in contemporary pharmacology is approved by Food and Drug Administration (FDA) for treatment of primary biliary cholangitis. Interestingly, numerous recent studies demonstrate that mechanisms of TUDCA functioning extend beyond hepatobiliary disorders. Thus, TUDCA has been demonstrated to display potential therapeutic benefits in various models of many diseases such as diabetes, obesity, and neurodegenerative diseases, mostly due to its cytoprotective effect. The mechanisms underlying this cytoprotective activity have been mainly attributed to alleviation of endoplasmic reticulum (ER) stress and stabilization of the unfolded protein response (UPR), which contributed to naming TUDCA as a chemical chaperone. Apart from that, TUDCA has also been found to reduce oxidative stress, suppress apoptosis, and decrease inflammation in many in-vitro and in-vivo models of various diseases. The latest research suggests that TUDCA can also play a role as an epigenetic modulator and act as therapeutic agent in certain types of cancer. Nevertheless, despite the massive amount of evidence demonstrating positive effects of TUDCA in pre-clinical studies, there are certain limitations restraining its wide use in patients. Here, molecular and cellular modes of action of TUDCA are described and therapeutic opportunities and limitations of this bile acid are discussed.

Carbon monoxide-releasing molecules (CO-RMs): vasodilatory, anti-ischaemic and anti-inflammatory activities

2007 ◽  
Vol 35 (5) ◽  
pp. 1142-1146 ◽  
Author(s):  
R. Motterlini
Keyword(s):  
Carbon Monoxide ◽  
Scientific Evidence ◽  
Cellular Systems ◽  
Controlled Delivery ◽  
In Vivo Models ◽  
Therapeutic Benefits ◽  
Haem Oxygenase ◽  
Anti Inflammatory

The well-known adverse effects of CO (carbon monoxide) intoxication are counterbalanced by its positive actions when small amounts are produced intracellularly by the cytoprotective enzyme HO-1 (haem oxygenase-1). As compelling scientific evidence accumulated to sustain that HO-1 plays a fundamental role in counteracting vascular and inflammatory disorders, we began to appreciate that a controlled delivery of CO to mammals may provide therapeutic benefits in a number of pathological states. This is the rationale for the recent development of CO-RMs (CO-releasing molecules), a group of compounds capable of carrying and liberating controlled quantities of CO in cellular systems, which offer a plausible tool for studying the pharmacological effects of this gas and identifying its mechanism(s) of action. The present review will highlight the encouraging results obtained so far on the vasodilatory, anti-ischaemic and anti-inflammatory effects elicited by CO-RMs in in vitro and in vivo models with an emphasis on the prospect of converting chemical CO carriers into CO-based pharmaceuticals.

scholarly journals Lipid Formulations and Bioconjugation Strategies for Indomethacin Therapeutic Advances

Molecules ◽  
2021 ◽  
Vol 26 (6) ◽  
pp. 1576
Author(s):  
Anna Gliszczyńska ◽  
Marta Nowaczyk
Keyword(s):  
Adverse Effects ◽  
Renal Toxicity ◽  
In Vivo Models ◽  
Practical Applications ◽  
Therapeutic Benefits ◽  
Central Nervous System Disorders ◽  
Lipid Formulations ◽  
Gastrointestinal Ulceration

Indomethacin (IND) is a drug which after successful clinical trials became available for general prescription in 1965 and from that time is one of the most widely used anti-inflammatory drug with the highest potencies in the in vitro and in vivo models. However, despite its high therapeutic efficacy in relieving the symptoms of certain arthritis and in treating gout or collagen diseases, administration of IND causes a number of adverse effects, such as gastrointestinal ulceration, frequent central nervous system disorders and renal toxicity. These obstacles significantly limit the practical applications of IND and make that 10–20% of patients discontinue its use. Therefore, during the last three decades many attempts have been made to design novel formulations of IND aimed to increase its therapeutic benefits minimizing its adverse effects. In this review we summarize pharmacological information about IND and analyze its new lipid formulations and lipid bioconjugates as well as discuss their efficacy and potential application.

scholarly journals Hypolipidemic Roles of Casein-Derived Peptides by Regulation of Trans-Intestinal Cholesterol Excretion and Bile Acid Synthesis

Nutrients ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 3058
Author(s):  
Sungmin Lee ◽  
BuHyun Youn
Keyword(s):  
Bile Acid ◽  
Bioactive Peptides ◽  
Oral Treatment ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
In Vivo Models ◽  
Intestinal Excretion ◽  
Cholesterol Excretion

Hyperlipidemia, a syndrome characterized by an abnormal elevation of blood lipids, causes chronic lethal metabolic disorders. Although statins are regularly prescribed to patients, an alternative to treat the burden of excessive lipids is required for cholesterol control. In this study, it was found that the treatment of casein hydrolyzed by pepsin and trypsin induced trans-intestinal cholesterol excretion (TICE) through ATP-binding cassette subfamily G members 5 (ABCG5) expression. Next, we analyzed sequences of the peptides responsible for TICE induction, synthesized artificial peptides based on the sequences, and the hypolipidemic effects of the peptide treatments were assessed in both in vitro and in vivo models. We determined that two bioactive peptides contained in casein hydrolysates (SQSKVLPVPQK and HPHPHLSF) induced TICE through the expression of ABCG5 in enterocytes and suppressed hepatic mRNA expression of cytochrome P450 family 7 subfamily A member 1 (CYP7A1) and CYP8B1by ileal FGF19 expression both in an liver X receptor α (LXRα)-mediated manner. In the hyperlipidemic mouse models, the oral administration of peptides reduced serum cholesterol levels through elevation of the ABCG5 expression in proximal intestine and fecal cholesterol secretion. Besides this, peptides induced ileal expression of fibroblast growth factor 15/19 (FGF15/19) and inhibited hepatic bile acid synthesis. We found that the oral treatment of casein-derived bioactive peptides could improve hyperlipidemia by regulating intestinal excretion and hepatic synthesis of cholesterols.

scholarly journals A Small Molecule, 4-Phenylbutyric Acid, Suppresses HCV Replication via Epigenetically Induced Hepatic Hepcidin

2020 ◽  
Vol 21 (15) ◽  
pp. 5516 ◽  
Author(s):  
Kiyoon Kim ◽  
Young-seok Lee ◽  
Suyun Jeong ◽  
Daehong Kim ◽  
Suk Chon ◽  
...  
Keyword(s):  
Epigenetic Modification ◽  
Membrane Vesicles ◽  
Interferon Α ◽  
Dependent Manner ◽  
In Vivo Models ◽  
Chemical Chaperone ◽  
Hepcidin Expression ◽  
Phenylbutyric Acid

Hepatic hepcidin is a well-known major iron regulator and has been reported to be closely related to hepatitis C virus (HCV) replication. However, pharmacological targeting of the hepcidin in HCV replication has not been reported. A short-chain fatty acid, 4-Phenyl butyrate (4-PBA), is an acid chemical chaperone that acts as a histone deacetylase inhibitor (HDACi) to promote chromosomal histone acetylation. Here, we investigated the therapeutic effect of 4-PBA on hepcidin expression and HCV replication. We used HCV genotype 1b Huh 7.5-Con1 replicon cells and engraftment of NOD/SCID mice as in vitro and in vivo models to test the effect of 4-PBA. It was found that 4-PBA inhibited HCV replication in Huh7.5-Con1 replicon cells in a concentration- and time-dependent manner through the induction of hepcidin expression by epigenetic modification and subsequent upregulation of interferon-α signaling. HCV formed a membranous web composed of double-membrane vesicles and was utilized for RNA replication. Moreover, 4-PBA also disrupted the integrity of the membranous web and interfered with the molecular interactions critical for the assembly of the HCV replication complex. These findings suggest that 4-PBA is a key epigenetic inducer of anti-HCV hepatic hepcidin and might at least in part play a role in targeting host factors related to HCV infection as an attractive complement to current HCV therapies.

scholarly journals PARA UMA DOENÇA TÃO ANTIGA, O VISLUMBRE DE NOVOS TRATAMENTOS PROMISSORES NA DOENÇA DE CHAGAS

2021 ◽  
Vol 58 (1) ◽  
pp. eUJ4087
Author(s):  
Sabrina Sehn Hilgert ◽  
◽  
Sofia Comássio de Paula Lima ◽  
Sofia Ferreira Salviano ◽  
Cristiane Tefé-Silva ◽  
...  
Keyword(s):  
Treatment Time ◽  
Parasite Load ◽  
New Drugs ◽  
In Vivo Models ◽  
Beneficial Effects ◽  
Positive Effects ◽  
Production And Distribution ◽  
Synthase Inhibitor

It has been more than 100 years since the discovery of Chagas Disease (CD). However, the repertoire indicated for its treatment is still limited. Thus, this article aims to present a review of the new pharmacological strategies being studied for CD. This literature review, consisting of 68 articles, from 1957 to 2021, was carried out on several scientific platforms. Positive effects from benznidazole have been described in the acute and chronic phases, in addition to its association with itraconazole in the acute phase. Among the cruzain inhibitors, the compound K777 presented trypanocidal effects, although demonstrating major adverse effects, while its analogue WRR-483 demonstrated great beneficial effects in vivo and in vitro. As for the nitroheterocyclics, fexinidazole showed high rates of cure in animal model, in addition to low toxicity. Nifurtimox, in early chronic stages, was able to delay the progression of tissue damage and reduce the parasite load. The compound WC-9, a squalene synthase inhibitor, showed potential inhibition of T. cruzi replication. Regarding aromatic diamidines, many compounds were able to stop the trypanosome, both in vitro and in vivo models. It was concluded that there are favorable findings to improve the treatment of CD. However, the development of effective new drugs does not only depend on their effective action, but also on numerous variables that must be circumvented, such as the reduction of side effects, treatment time and adherence to the current medication of choice, as well as the investment in production and distribution to the population.

Melatonin modifies tumor hypoxia and metabolism by inhibiting HIF-1α and energy metabolic pathway in the in vitro and in vivo models of breast cancer

2019 ◽  
Vol 2 (4) ◽  
pp. 83-98 ◽  
Author(s):  
André De Lima Mota ◽  
Bruna Vitorasso Jardim-Perassi ◽  
Tialfi Bergamin De Castro ◽  
Jucimara Colombo ◽  
Nathália Martins Sonehara ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Glucose Metabolism ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Carbonic Anhydrases ◽  
In Vivo Models ◽  
Ca Ix ◽  
Gene And Protein Expression

Breast cancer is the most common cancer among women and has a high mortality rate. Adverse conditions in the tumor microenvironment, such as hypoxia and acidosis, may exert selective pressure on the tumor, selecting subpopulations of tumor cells with advantages for survival in this environment. In this context, therapeutic agents that can modify these conditions, and consequently the intratumoral heterogeneity need to be explored. Melatonin, in addition to its physiological effects, exhibits important anti-tumor actions which may associate with modification of hypoxia and Warburg effect. In this study, we have evaluated the action of melatonin on tumor growth and tumor metabolism by different markers of hypoxia and glucose metabolism (HIF-1α, glucose transporters GLUT1 and GLUT3 and carbonic anhydrases CA-IX and CA-XII) in triple negative breast cancer model. In an in vitro study, gene and protein expressions of these markers were evaluated by quantitative real-time PCR and immunocytochemistry, respectively. The effects of melatonin were also tested in a MDA-MB-231 xenograft animal model. Results showed that melatonin treatment reduced the viability of MDA-MB-231 cells and tumor growth in Balb/c nude mice (p <0.05). The treatment significantly decreased HIF-1α gene and protein expression concomitantly with the expression of GLUT1, GLUT3, CA-IX and CA-XII (p <0.05). These results strongly suggest that melatonin down-regulates HIF-1α expression and regulates glucose metabolism in breast tumor cells, therefore, controlling hypoxia and tumor progression. 

Metabolomics of Healthy Berry Fruits

2019 ◽  
Vol 25 (37) ◽  
pp. 4888-4902 ◽  
Author(s):  
Gilda D'Urso ◽  
Sonia Piacente ◽  
Cosimo Pizza ◽  
Paola Montoro
Keyword(s):  
Biological Activities ◽  
Biologically Active ◽  
In Vivo Studies ◽  
Bioactive Metabolites ◽  
Active Metabolites ◽  
Positive Effects ◽  
Cell Functions ◽  
Berry Fruits

The consumption of berry-type fruits has become very popular in recent years because of their positive effects on human health. Berries are in fact widely known for their health-promoting benefits, including prevention of chronic disease, cardiovascular disease and cancer. Berries are a rich source of bioactive metabolites, such as vitamins, minerals, and phenolic compounds, mainly anthocyanins. Numerous in vitro and in vivo studies recognized the health effects of berries and their function as bioactive modulators of various cell functions associated with oxidative stress. Plants have one of the largest metabolome databases, with over 1200 papers on plant metabolomics published only in the last decade. Mass spectrometry (MS) and NMR (Nuclear Magnetic Resonance) are the most important analytical technologies on which the emerging ''omics'' approaches are based. They may provide detection and quantization of thousands of biologically active metabolites from a tissue, working in a ''global'' or ''targeted'' manner, down to ultra-trace levels. In the present review, we highlighted the use of MS and NMR-based strategies and Multivariate Data Analysis for the valorization of berries known for their biological activities, important as food and often used in the preparation of nutraceutical formulations.

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