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1.
Fungal Naphthalenones; Promising Metabolites for Drug Discovery: Structures, Biosynthesis, Sources, and Pharmacological Potential.
Ibrahim, SRM, Fadil, SA, Fadil, HA, Eshmawi, BA, Mohamed, SGA, Mohamed, GA
Toxins. 2022;(2)
Abstract
Fungi are well-known for their abundant supply of metabolites with unrivaled structure and promising bioactivities. Naphthalenones are among these fungal metabolites, that are biosynthesized through the 1,8-dihydroxy-naphthalene polyketide pathway. They revealed a wide spectrum of bioactivities, including phytotoxic, neuro-protective, cytotoxic, antiviral, nematocidal, antimycobacterial, antimalarial, antimicrobial, and anti-inflammatory. The current review emphasizes the reported naphthalenone derivatives produced by various fungal species, including their sources, structures, biosynthesis, and bioactivities in the period from 1972 to 2021. Overall, more than 167 references with 159 metabolites are listed.
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2.
Evocalcet with vitamin D receptor activator treatment for secondary hyperparathyroidism.
Shigematsu, T, Asada, S, Endo, Y, Kawata, T, Fukagawa, M, Akizawa, T
PloS one. 2022;(2):e0262829
Abstract
This ad hoc analysis of a previously conducted phase 3 head-to-head comparison study of evocalcet and cinacalcet in secondary hyperparathyroidism patients undergoing maintenance hemodialysis evaluated the efficacy and safety of combined once-daily oral evocalcet and intravenous vitamin D receptor activator treatment stratified by weekly vitamin D receptor activator dose (117, 45, and 91 patients in no, low [< 1.5 μg], and high [≥ 1.5 μg] dose groups, respectively). Effects of vitamin D receptor activator were assessed on the basis of intact parathyroid hormone, corrected calcium, phosphorus, and fibroblast growth factor-23 levels; percent changes from baseline; proportions of patients who achieved target intact parathyroid hormone, corrected calcium, and phosphorus at Weeks 28-30; and adverse drug reactions. Intact parathyroid hormone, corrected calcium, phosphorus, and fibroblast growth factor-23 levels decreased in all groups; phosphorus and fibroblast growth factor-23 levels remained high in the high dose group. In the low and high dose groups, greater proportions of patients achieved the corrected calcium target compared with the no dose group (p = 0.043). Ratios of intact-to-C-terminal fibroblast growth factor-23 decreased in all groups. In low and high dose groups, hypocalcemia was less common than in the no dose group (p = 0.014). Evocalcet with concomitant vitamin D receptor activator demonstrated benefits such that more patients achieved the corrected calcium target and exhibited decreased fibroblast growth factor-23 synthesis; the incidence of hypocalcemia also decreased. Clinical trial registration: ClinicalTrials.gov (NCT02549391) and JAPIC (JapicCTI-153013).
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3.
Sirtuin 1 and 2 inhibitors enhance the inhibitory effect of sorafenib in hepatocellular carcinoma cells.
Ceballos, MP, Angel, A, Delprato, CB, Livore, VI, Ferretti, AC, Lucci, A, Comanzo, CG, Alvarez, ML, Quiroga, AD, Mottino, AD, et al
European journal of pharmacology. 2021;:173736
Abstract
Multidrug resistance (MDR) counteracts the efficiency of sorafenib, an important first-line therapy for hepatocellular carcinoma (HCC). Sirtuins (SIRTs) 1 and 2 are associated with tumor progression and MDR. We treated 2D and 3D cultures (which mimic the features of in vivo tumors) from HCC cells with sorafenib alone or in the presence of SIRTs 1 and 2 inhibitors (cambinol or EX-527; combined treatments). Cultures subjected to combined treatments showed a greater fall in cellular viability, proliferation (PCNA, cyclin D1 and Ki-67 expression and cell cycle analysis), migration and invasion when compared with cultures treated only with sorafenib. Similarly, combined treatments produced more apoptosis (annexin V/PI, caspase-3/7 activity) than sorafenib alone. Since cell cycle dysregulation and apoptotic blockage are reported mechanisms of MDR, the modulation found in PCNA, cyclin D1, Ki-67 and caspase-3/7 proteins by cambinol and EX-527 are probably playing a role in enhancing the sensitivity of HCC cell lines to sorafenib. EX-527 reduced MRP3 and BCRP expression in sorafenib-treated HCC cells. Since ABC transporters contribute to MDR, MRP3 and BCRP could be also influencing in the response of HCC cells to sorafenib. Overall, 2D and 3D cultures behave similarly except that 3D cultures were less sensitive to treatments, reinforcing the clinical relevance of the current study. Findings presented in this manuscript support a potential application for SIRTs 1 and 2 inhibitors since we demonstrated that these compounds enhance the inhibitory effect of sorafenib upon treatment of hepatocellular carcinoma cells lines.
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4.
Evocalcet: A New Oral Calcimimetic for Dialysis Patients With Secondary Hyperparathyroidism.
Akizawa, T, Ikejiri, K, Kondo, Y, Endo, Y, Fukagawa, M
Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy. 2020;(3):248-257
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Abstract
Patients with chronic kidney disease often develop secondary hyperparathyroidism (SHPT), marked by high levels of circulating parathyroid hormone (PTH) and increased risk of morbidity and mortality. Patients with SHPT are treated with a therapeutic combination that commonly includes calcimimetics, which have recently become popular in clinical settings, and other agents such as vitamin D preparations. Calcimimetics are a drug class that reduces PTH levels by targeting the calcium-sensing receptor. Cinacalcet, a representative calcimimetic, is widely used; however, a high incidence of upper gastrointestinal (GI) tract-related adverse events (AEs) can result in insufficient dosage and poor long-term compliance. The newly approved evocalcet has equivalent efficacy to cinacalcet at a lower clinical dose, with improved bioavailability, fewer upper GI tract-related AEs, and fewer safety concerns. This review gives an overview of calcimimetic agents, with a special focus on evocalcet, and describes the clinical advantages of evocalcet in the treatment of dialysis patients with SHPT.
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5.
Effect of energy deprivation on metabolite release by anaerobic marine naphthalene-degrading sulfate-reducing bacteria.
Chen, G, Widdel, F, Musat, F
Environmental microbiology. 2020;(9):4057-4066
Abstract
The aromatic hydrocarbon naphthalene, which occurs in coal and oil, can be degraded by aerobic or anaerobic microorganisms. A wide-spread electron acceptor for the latter is sulfate. Evidence for in situ naphthalene degradation stems in particular from the detection of 2-naphthoate and [5,6,7,8]-tetrahydro-2-naphthoate in oil field samples. Because such intermediates are usually not detected in laboratory cultures with high sulfate concentrations, one may suppose that conditions in reservoirs, such as sulfate limitation, trigger metabolite release. Indeed, if naphthalene-grown cells of marine sulfate-reducing Deltaproteobacteria (strains NaphS2, NaphS3 and NaphS6) were transferred to sulfate-free medium, they released 2-naphthoate and [5,6,7,8]-tetrahydro-2-naphthoate while still consuming naphthalene. With 2-naphthoate as initial substrate, cells produced [5,6,7,8]-tetrahydro-2-naphthoate and the hydrocarbon, naphthalene, indicating reversibility of the initial naphthalene-metabolizing reaction. The reactions in the absence of sulfate were not coupled to observable growth. Excretion of naphthalene-derived metabolites was also achieved in sulfate-rich medium upon addition of the protonophore carbonyl cyanide4-(trifluoromethoxy)phenylhydrazone or the ATPase inhibitor N,N'-dicyclohexylcarbodiimide. In conclusion, obstruction of electron flow and energy gain by sulfate limitation offers an explanation for the occurrence of naphthalene-derived metabolites in oil reservoirs, and provides a simple experimental tool for gaining insights into the anaerobic naphthalene oxidation pathway from an energetic perspective.
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[Pharmacological and clinical profiles of a novel calcimimetic, evocalcet (ORKEDIA®)].
Tokunaga, S, Endo, Y, Kawata, T
Nihon yakurigaku zasshi. Folia pharmacologica Japonica. 2019;(1):35-43
Abstract
Calcimimetics allosterically activate the calcium receptor (CaR) and inhibit the secretion of parathyroid hormone (PTH). Cinacalcet hydrochloride (cinacalcet) has been approved as the first calcimimetic drug for the treatment of secondary hyperparathyroidism (SHPT) in patients with hemodialysis. Cinacalcet improved the achievement of target serum PTH and Ca levels and helped drastically reduce the number of parathyroidectomies. However, cinacalcet has side effects involving the gastrointestinal tract, such as nausea and vomiting, which makes it difficult to increase the dose and may result in reduced compliance. Evocalcet has been developed to improve defects of cinacalcet for management of SHPT. Evocalcet acts as an allosteric modulator of CaR, just like cinacalcet. However, its metabolic pathway is different from that of cinacalcet. The metabolism of evocalcet by cytochrome P450 is very low, so evocalcet has higher bioavailability. As a result, its pharmacologically effective dose for the inhibition of PTH secretion is lower than that of cinacalcet. Evocalcet had less of an effect on the gastrointestinal tract than cinacalcet because of the reduced dose required. In a clinical trial with a randomized, double-blind, head-to-head comparison study, it was also confirmed that the incidence of gastrointestinal-related adverse events was lower in the evocalcet group than in the cinacalcet group. Evocalcet may thus be a potent option for the management of SHPT.
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Tinea Capitis by Microsporum audouinii: Case Reports and Review of Published Global Literature 2000-2016.
Brito-Santos, F, Figueiredo-Carvalho, MHG, Coelho, RA, Sales, A, Almeida-Paes, R
Mycopathologia. 2017;(11-12):1053-1060
Abstract
Tinea capitis caused by Microsporum audouinii is reported herein from two Brazilian schoolchildren, which are brothers. Arthroconidia were evidenced on direct examination of scalp hair, and a fungus of the genus Microsporum was isolated from cultures of each patient. The isolated fungi were classified as M. audouinii by visualization of species-specific structures, including: pectinate hyphae, chlamydospores, and fusiform macroconidia, sterile growth with characteristic brown pigment in rice grains, and through DNA sequencing of the internal transcriber spacer region. Patients were refractory to ketoconazole, but the two cases had a satisfactory response to oral terbinafine. All M. audouinii infections described in this century were reviewed, and to our knowledge, this is the first literature description of this species from South America. Misidentification of M. audouinii with Microsporum canis can occur in this area, leading to erroneous data about the occurrence of this species.
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Translation of a Tissue-Selective Rexinoid, UAB30, to the Clinic for Breast Cancer Prevention.
Muccio, DD, Atigadda, VR, Brouillette, WJ, Bland, KI, Krontiras, H, Grubbs, CJ
Current topics in medicinal chemistry. 2017;(6):676-695
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Abstract
This review focuses on our efforts to translate a low-toxicity retinoid X receptor-selective agonist, UAB30, to the clinic for the prevention of breast cancers. The review is divided into several sections. First, the current status of breast cancer prevention is discussed. Next, preclinical studies are presented that support translation of rexinoids to the clinic for cancer prevention. While current FDAapproved retinoids and rexinoids demonstrate profound effects in treating cancers, they lack sufficient safety for long term use in the high risk population that is otherwise disease free. The review stresses the need to identify cancer preventive drugs that are effective and safe in order to gain wide use in the clinic. Due to the heterogeneity of the disease, UAB30 is evaluated for the prevention of ER-positive and ER-negative mammary cancers. Since selective estrogen receptor modulators and aromatase inhibitors are used clinically to prevent and treat ER-positive breast cancers, preclinical studies also must demonstrate efficacy of UAB30 in combination with existing drugs under use in the clinic. To support an Investigational New Drug Application to the FDA, data on pharmacology and toxicity as well as mutagenicity is gathered prior to human trials. The review concludes with a discussion of the outcomes of human Phase 0/1 clinical trials that determine the safety and pharmacology of UAB30. These studies are essential before this agent is evaluated for efficacy in phase 2 trials. Success in phase 2 evaluation is critical before long-term and costly phase 3 trials are undertaken. The lack of surrogate biomarkers as endpoints for phase 2 evaluation of rexinoid preventive agents is discussed.
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Naphthalene biodegradation under oxygen-limiting conditions: community dynamics and the relevance of biofilm-forming capacity.
Martirani-Von Abercron, SM, Marín, P, Solsona-Ferraz, M, Castañeda-Cataña, MA, Marqués, S
Microbial biotechnology. 2017;(6):1781-1796
Abstract
Toxic polycyclic aromatic hydrocarbons (PAHs) are frequently released into the environment from anthropogenic sources. PAH remediation strategies focus on biological processes mediated by bacteria. The availability of oxygen in polluted environments is often limited or absent, and only bacteria able to thrive in these conditions can be considered for bioremediation strategies. To identify bacterial strains able to degrade PAHs under oxygen-limiting conditions, we set up enrichment cultures from samples of an oil-polluted aquifer, using either anoxic or microaerophilic condition and with PAHs as the sole carbon source. Despite the presence of a significant community of nitrate-reducing bacteria, the initial community, which was dominated by Betaproteobacteria, was incapable of PAH degradation under strict anoxic conditions, although a clear shift in the structure of the community towards an increase in the Alphaproteobacteria (Sphingomonadaceae), Actinobacteria and an uncultured group of Acidobacteria was observed in the enrichments. In contrast, growth under microaerophilic conditions with naphthalene as the carbon source evidenced the development of a biofilm structure around the naphthalene crystal. The enrichment process selected two co-dominant groups which finally reached 97% of the bacterial communities: Variovorax spp. (54%, Betaproteobacteria) and Starkeya spp. (43%, Xanthobacteraceae). The two dominant populations were able to grow with naphthalene, although only Starkeya was able to reproduce the biofilm structure around the naphthalene crystal. The pathway for naphthalene degradation was identified, which included as essential steps dioxygenases with high affinity for oxygen, showing 99% identity with Xanthobacter polyaromaticivorans dbd cluster for PAH degradation. Our results suggest that the biofilm formation capacity of Starkeya provided a structure to allocate its cells at an appropriate distance from the toxic carbon source.
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Effects of Grapefruit and Pomegranate Juices on the Pharmacokinetic Properties of Dapoxetine and Midazolam in Healthy Subjects.
Abdlekawy, KS, Donia, AM, Elbarbry, F
European journal of drug metabolism and pharmacokinetics. 2017;(3):397-405
Abstract
BACKGROUND The package leaflet for dapoxetine, an effective treatment for premature ejaculation, includes a strict warning against coadministration with drugs or herbal remedies that strongly induce or inhibit the activity of Cytochrome P450 (CYP) 3A4 enzyme. OBJECTIVE To assess the effects of multiple daily consumption of grapefruit juice (GFJ) and pomegranate juice (PJ) on the pharmacokinetics of dapoxetine, we conducted an open-label, three-way crossover study in 12 healthy subjects using midazolam as a probe substrate for CYP3A4. METHODS Participants received a single oral dose of dapoxetine (60 mg) and midazolam (7.5 mg) after pretreatment with 250 ml of either water, undiluted GFJ, or PJ for three consecutive days. All subjects were monitored for adverse effects during the study period. RESULTS Compared to pretreatment with water, GFJ increased the area under the plasma concentration-time curve from time zero to infinity (AUC0-∞) and peak plasma concentration (C max) of dapoxetine by 60 and 80 %, respectively, and prolonged its elimination half-life (t 1/2) by 43 %. Similar effects of GFJ on the pharmacokinetics of midazolam were observed with a significant increase in AUC0-∞ (75 %), C max (40 %), and t 1/2 (92 %). Slight but not statistically significant changes were observed in the pharmacokinetics of dapoxetine and midazolam after pretreatment with PJ. Time to reach C max (T max) did not differ among the three phases. CONCLUSION These results suggest that GFJ increases the extent of absorption and reduces clearance of dapoxetine possibly by inhibition of both intestinal and hepatic CYP3A4, whereas PJ has little effect on dapoxetine pharmacokinetics. Although the impact of GFJ on the pharmacokinetics of dapoxetine was mild, a great caution should be considered when they are concomitantly administered.