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1.
Dual Enkephalinase Inhibitors and Their Role in Chronic Pain Management.
Southerland, WA, Gillis, J, Kuppalli, S, Fonseca, A, Mendelson, A, Horine, SV, Bansal, N, Gulati, A
Current pain and headache reports. 2021;(5):29
Abstract
PURPOSE OF REVIEW Dual enkephalinase inhibitors (DENKIs) are pain medications that indirectly activate opioid receptors and can be used as an alternative to traditional opioids. Understanding the physiology of enkephalins and their inhibitors and the pharmacology of these drugs will allow for proper clinical application for chronic pain patients in the future. RECENT FINDINGS DENKIs can be used as an alternative mode of analgesia for patients suffering from chronic pain by preventing the degradation of endogenous opioid ligands. By inhibiting the two major enkephalin-degrading enzymes (neprilysin and aminopeptidase N), DENKIs can provide analgesia with less adverse effects than nonendogenous opioids. The purpose of this paper is to review the current literature investigating DENKIs and explore their contribution to chronic pain management.
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2.
Updates in adrenal steroidogenesis inhibitors for Cushing's syndrome - A practical guide.
Varlamov, EV, Han, AJ, Fleseriu, M
Best practice & research. Clinical endocrinology & metabolism. 2021;(1):101490
Abstract
Medical therapy is essential in the management of patients with Cushing's syndrome (CS) when curative surgery has failed, surgery is not feasible, when awaiting radiation effect, and in recurrent cases of CS. Steroidogenesis inhibitors have a rapid onset of action and are effective in reducing hypercortisolism, however, adverse effects, including adrenal insufficiency require very close patient monitoring. Osilodrostat is the only steroidogenesis inhibitor to have been assessed in prospective randomized controlled trials and approved for Cushing's disease (CD) by the US Food and Drug Administration and for CS by the European Medical Agency (EMA). Osilodrostat has been shown to be highly effective at maintaining normal urinary free cortisol in patients with CD. Drugs such as metyrapone, ketoconazole (both EMA approved), and etomidate lack prospective evaluation(s). There is, however, considerable clinical experience and retrospective data that show a very wide efficacy range in treating patients with CS. In the absence of head-to-head comparative clinical trials, therapy choice is determined by the specific clinical setting, risk of adverse events, cost, availability, and other factors. In this review practical points to help clinicians who are managing patients with CS being treated with steroidogenesis inhibitors are presented.
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3.
The Anticancer Effect of Natural Plant Alkaloid Isoquinolines.
Yun, D, Yoon, SY, Park, SJ, Park, YJ
International journal of molecular sciences. 2021;(4)
Abstract
Isoquinoline alkaloids-enriched herbal plants have been used as traditional folk medicine for their anti-inflammatory, antimicrobial, and analgesic effects. They induce cell cycle arrest, apoptosis, and autophagy, leading to cell death. While the molecular mechanisms of these effects are not fully understood, it has been suggested that binding to nucleic acids or proteins, enzyme inhibition, and epigenetic modulation by isoquinoline alkaloids may play a role in the effects. This review discusses recent evidence on the molecular mechanisms by which the isoquinoline alkaloids can be a therapeutic target of cancer treatment.
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4.
Managing Anemia across the Stages of Kidney Disease in Those Hyporesponsive to Erythropoiesis-Stimulating Agents.
Weir, MR
American journal of nephrology. 2021;(6):450-466
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Abstract
BACKGROUND Patients with CKD frequently have anemia that results from iron-restricted erythropoiesis and inflammation. Anemia of CKD is currently managed with iron supplements and erythropoiesis-stimulating agents (ESAs) to promote erythropoiesis and with RBC transfusion in severe cases. Hyporesponse to ESAs, or the need for larger than usual doses to attain a given hemoglobin (Hb) level, is associated with increased morbidity and mortality and presents a pressing clinical challenge, particularly for patients on dialysis. This paper reviews ESA hyporesponse and potential new therapeutic options in the management of anemia of CKD. SUMMARY The most common causes of ESA hyporesponse include iron deficiency and inflammation, and to a lesser degree, secondary hyperparathyroidism, inadequate dialysis, malnutrition, and concomitant medications. Management of ESA hyporesponse is multipronged and involves treating low level infections, ensuring adequate nutrition, and optimizing iron status and dialysis modality, although some patients can remain refractory. Inflammation directly increases production and secretion of hepcidin, contributes to an impaired response to hypoxia, and suppresses proliferation of erythroid progenitors. Coordination of renal and hepatic erythropoietin (EPO) production and iron metabolism is under the control of hypoxia-inducible factors (HIF), which are in turn regulated by HIF-prolyl hydroxylases (HIF-PHs). HIF-PHs and hepcidin are therefore attractive potential drug targets particularly in patients with ESA hyporesponse. Several oral HIF-PH inhibitors have been evaluated in patients with anemia of CKD and have been shown to increase Hb and reduce hepcidin regardless of inflammation, iron status, or dialysis modality. These sustained effects are achieved through more modest increases in endogenous EPO compared with ESAs. Key Messages: Treatments that address ESA hyporesponse remain a significant unmet clinical need in patients with anemia of CKD. New therapies such as HIF-PH inhibitors have the potential to address fundamental aspects of ESA hyporesponse and provide a new therapeutic option in these patients.
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5.
Nicotinamide N-methyl transferase (NNMT): An emerging therapeutic target.
Gao, Y, Martin, NI, van Haren, MJ
Drug discovery today. 2021;(11):2699-2706
Abstract
Nicotinamide N-methyltransferase (NNMT) methylates nicotinamide (NA) to generate 1-methyl nicotinamide. Since its discovery 70 years ago, the appreciation of the role of NNMT in human health has evolved from serving only metabolic functions to also being a driving force in diseases, including a variety of cancers. Despite the increasing evidence indicating NNMT as a viable therapeutic target, the development of cell-active inhibitors against this enzyme is lacking. In this review, we provide an overview of the current status of NNMT inhibitor development, relevant in vitro and in vivo studies, and a discussion of the challenges faced in the development of NNMT inhibitors.
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6.
Chemical probes for protein arginine methyltransferases.
Li, ASM, Li, F, Eram, MS, Bolotokova, A, Dela Seña, CC, Vedadi, M
Methods (San Diego, Calif.). 2020;:30-43
Abstract
Protein arginine methyltransferases (PRMTs) catalyze the transfer of methyl groups to specific arginine residues of their substrates using S-adenosylmethionine as a methyl donor, contributing to regulation of many biological processes including transcription, and DNA damage repair. Dysregulation of PRMT expression is often associated with various diseases including cancers. Different methods have been used to characterize the activities of PRMTs and determine their kinetic parameters including mass spectrometry, radiometric, and antibody-based assays. Here, we present kinetic characterization of PRMTs using a radioactivity-based assay for better comparison along with previously reported values. We also report on full characterization of PRMT9 activity with SAP145 peptide as substrate. We further review the potent, selective and cell-active PRMT inhibitors discovered in recent years to provide a better understanding of available tools to investigate the roles these proteins play in health and disease.
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Inhibitors of lipogenic enzymes as a potential therapy against cancer.
Montesdeoca, N, López, M, Ariza, X, Herrero, L, Makowski, K
FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2020;(9):11355-11381
Abstract
Cancer cells rely on several metabolic pathways such as lipid metabolism to meet the increase in energy demand, cell division, and growth and successfully adapt to challenging environments. Fatty acid synthesis is therefore commonly enhanced in many cancer cell lines. Thus, relevant efforts are being made by the scientific community to inhibit the enzymes involved in lipid metabolism to disrupt cancer cell proliferation. We review the rapidly expanding body of inhibitors that target lipid metabolism, their side effects, and current status in clinical trials as potential therapeutic approaches against cancer. We focus on their molecular, biochemical and structural properties, selectivity and effectiveness and discuss their potential role as antitumor drugs.
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8.
Targeting obesity with plant-derived pancreatic lipase inhibitors: A comprehensive review.
Rajan, L, Palaniswamy, D, Mohankumar, SK
Pharmacological research. 2020;:104681
Abstract
The prevalence of obesity is alarmingly increasing in the last few decades and leading to many serious public health concerns worldwide. The dysregulated lipid homeostasis due to various genetic, environmental and lifestyle factors is considered one of the critical putative pathways mediating obesity. Nonetheless, the scientific advancements unleashing the molecular dynamics of lipid metabolism have provided deeper insights on the emerging roles of lipid hydrolysing enzymes, including pancreatic lipase. It is hypothesized that inhibiting pancreatic lipase would prevent the breakdown of triglyceride and delays the absorption of fatty acids into the systemic circulation and adipocytes. Whilst, orlistat is the only conventional pancreatic lipase enzyme inhibitor available in clinics, identifying the safe clinical alternatives from plants to inhibit pancreatic lipase has been considered a significant advancement. Consequently, plants which have shown significant potential to combat obesity are now revisited for its abilities to inhibit pancreatic lipase. In this regard, our review surveyed the potential of medicinal plants and its phytoconstituents to inhibit pancreatic lipase and to elicit anti-obesity effects. Thus, the review collate and critically appraise the potential of medicinal plants and phyto-molecules inhibiting pancreatic lipase enzyme and consequently modulating triglyceride absorption in gut, and discuss its implications in the development of novel therapeutic strategies to combat obesity.
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9.
Naturally Occurring PCSK9 Inhibitors.
Adorni, MP, Zimetti, F, Lupo, MG, Ruscica, M, Ferri, N
Nutrients. 2020;(5)
Abstract
Genetic, epidemiological and pharmacological data have led to the conclusion that antagonizing or inhibiting Proprotein convertase subtilisin/kexin type 9 (PCSK9) reduces cardiovascular events. This clinical outcome is mainly related to the pivotal role of PCSK9 in controlling low-density lipoprotein (LDL) cholesterol levels. The absence of oral and affordable anti-PCSK9 medications has limited the beneficial effects of this new therapeutic option. A possible breakthrough in this field may come from the discovery of new naturally occurring PCSK9 inhibitors as a starting point for the development of oral, small molecules, to be used in combination with statins in order to increase the percentage of patients reaching their LDL-cholesterol target levels. In the present review, we have summarized the current knowledge on natural compounds or extracts that have shown an inhibitory effect on PCSK9, either in experimental or clinical settings. When available, the pharmacodynamic and pharmacokinetic profiles of the listed compounds are described.
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10.
Unique structural and mechanistic properties of mycobacterial F-ATP synthases: Implications for drug design.
Kamariah, N, Ragunathan, P, Shin, J, Saw, WG, Wong, CF, Dick, T, Grüber, G
Progress in biophysics and molecular biology. 2020;:64-73
Abstract
The causative agent of Tuberculosis (TB) Mycobacterium tuberculosis (Mtb) encounters unfavourable environmental conditions in the lungs, including nutrient limitation, low oxygen tensions and/or low/high pH values. These harsh conditions in the host triggers Mtb to enter a dormant state in which the pathogen does not replicate and uses host-derived fatty acids instead of carbohydrates as an energy source. Independent to the energy source, the bacterium's energy currency ATP is generated by oxidative phosphorylation, in which the F1FO-ATP synthase uses the proton motive force generated by the electron transport chain. This catalyst is essential in Mtb and inhibition by the diarylquinoline class of drugs like Bedaquilline, TBAJ-587, TBAJ-876 or squaramides demonstrated that this engine is an attractive target in TB drug discovery. A special feature of the mycobacterial F-ATP synthase is its inability to establish a significant proton gradient during ATP hydrolysis, and its latent ATPase activity, to prevent energy waste and to control the membrane potential. Recently, unique epitopes of mycobacterial F1FO-ATP synthase subunits absent in their prokaryotic or mitochondrial counterparts have been identified to contribute to the regulation of the low ATPase activity. Most recent structural insights into individual subunits, the F1 domain or the entire mycobacterial enzyme added to the understanding of mechanisms, regulation and differences of the mycobacterial F1FO-ATP synthase compared to other bacterial and eukaryotic engines. These novel insights provide the basis for the design of new compounds targeting this engine and even novel regimens for multidrug resistant TB.