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American Journal of Hematology Feb 2022Anemia is the predominant cytopenia in myelodysplastic syndromes (MDS) and treatment options are limited. Roxadustat is a hypoxia-inducible factor prolyl hydroxylase... (Randomized Controlled Trial)
Randomized Controlled Trial
Anemia is the predominant cytopenia in myelodysplastic syndromes (MDS) and treatment options are limited. Roxadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor approved for the treatment of anemia of chronic kidney disease in the UK, EU, China, Japan, South Korea, and Chile. MATTERHORN is a phase 3, randomized, double-blind, placebo-controlled study to assess the efficacy and safety of roxadustat in anemia of lower risk-MDS. Eligible patients had baseline serum erythropoietin ≤ 400 mIU/mL, and a low packed RBC transfusion burden. In this open-label (OL), dose-selection, lead-in phase, enrolled patients were assigned to 1 of 3 roxadustat starting doses (n = 8 each): 1.5, 2.0, and 2.5 mg/kg. The primary efficacy endpoint of the OL phase was the proportion of patients with transfusion independence (TI) for ≥ 8 consecutive weeks in the first 28 treatment weeks. A secondary efficacy endpoint was the proportion of patients with a ≥ 50% reduction in RBC transfusions over an 8-week period compared with baseline. Adverse events were monitored. Patients were followed for 52 weeks. Of the 24 treated patients, TI was achieved in 9 patients (37.5%) at 28 and 52 weeks; 7 of these patients were receiving 2.5 mg/kg dose when TI was achieved. A ≥ 50% reduction in RBC transfusions was achieved in 54.2% and 58.3% of patients at 28 and 52 weeks, respectively. Oral roxadustat dosed thrice weekly was well tolerated. There were no fatalities or progression to acute myeloid leukemia. Based on these outcomes, 2.5 mg/kg was the chosen starting roxadustat dose for the ongoing double-blind study phase.
Topics: Aged; Anemia; Double-Blind Method; Female; Glycine; Humans; Isoquinolines; Male; Middle Aged; Myelodysplastic Syndromes; Placebo Effect; Treatment Outcome
PubMed: 34724251
DOI: 10.1002/ajh.26397 -
Cell Reports Jan 2021Axonal degeneration is responsible for disease progression and accumulation of disability in many neurodegenerative conditions. The axonal degenerative process can...
Axonal degeneration is responsible for disease progression and accumulation of disability in many neurodegenerative conditions. The axonal degenerative process can generate a metastable pool of damaged axons that remain structurally and functionally viable but fated to degenerate in the absence of external intervention. SARM1, an NADase that depletes axonal energy stores upon activation, is the central driver of an evolutionarily conserved program of axonal degeneration. We identify a potent and selective small molecule isoquinoline inhibitor of SARM1 NADase that recapitulates the SARM1 phenotype and protects axons from degeneration induced by axotomy or mitochondrial dysfunction. SARM1 inhibition post-mitochondrial injury with rotenone allows recovery and rescues axons that already entered the metastable state. We conclude that SARM1 inhibition with small molecules has the potential to treat axonopathies of the central and peripheral nervous systems by preventing axonal degeneration and by allowing functional recovery of a metastable pool of damaged, but viable, axons.
Topics: Animals; Armadillo Domain Proteins; Axons; Biomarkers; Cell Line; Cytoskeletal Proteins; HEK293 Cells; Humans; Isoquinolines; Mice; Mice, Inbred C57BL; Mice, Knockout; NAD+ Nucleosidase; Nerve Degeneration; Neurodegenerative Diseases; Phenotype; Recovery of Function
PubMed: 33406435
DOI: 10.1016/j.celrep.2020.108588 -
Cardiovascular Therapeutics 2008Sanguinarine is an alkaloid found in many medicinal plants. It has diverse biological activities, including modulation of nuclear factor-kappaB and of several enzymes.... (Review)
Review
Sanguinarine is an alkaloid found in many medicinal plants. It has diverse biological activities, including modulation of nuclear factor-kappaB and of several enzymes. It is also known to induce apoptosis, perturb microtubules, and to have antimicrobial effects. This article reviews its cardiovascular properties, including hypotensive, antiplatelet, and positive inotropic effects. Its pharmacokinetics, and toxicology, including its carcinogenic potential, are also discussed. Further pharmacological and toxicological studies with sanguinarine are needed before its therapeutic use can be considered.
Topics: Antihypertensive Agents; Benzophenanthridines; Carcinogens; Cardiotonic Agents; Humans; Isoquinolines; Mutagens
PubMed: 18466423
DOI: 10.1111/j.1527-3466.2007.00037.x -
Medicinal Research Reviews Nov 2020Isoquinoline alkaloids, an important class of N-based heterocyclic compounds, have attracted considerable attention from researchers worldwide since the early 19th... (Review)
Review
Isoquinoline alkaloids, an important class of N-based heterocyclic compounds, have attracted considerable attention from researchers worldwide since the early 19th century. Over the past 200 years, many compounds from this class were isolated, and most of them and their analogs possess various bioactivities. In this review, we survey the updated literature on bioactive alkaloids and highlight research achievements of this alkaloid class during the period of 2014-2018. We reviewed over 400 molecules with a broad range of bioactivities, including antitumor, antidiabetic and its complications, antibacterial, antifungal, antiviral, antiparasitic, insecticidal, anti-inflammatory, antioxidant, neuroprotective, and other activities. This review should provide new indications or directions for the discovery of new and better drugs from the original naturally occurring isoquinoline alkaloids.
Topics: Alkaloids; Anti-Infective Agents; Anti-Inflammatory Agents; Antioxidants; Humans; Isoquinolines
PubMed: 32729169
DOI: 10.1002/med.21703 -
Anesthesiology Apr 2005
Topics: Anesthesia; Animals; Clinical Trials as Topic; Hemodynamics; Humans; Isoquinolines; Muscle Relaxants, Central; Rats
PubMed: 15791119
DOI: 10.1097/00000542-200504000-00024 -
Marine Drugs Feb 2015In 1985 the first lamellarins were isolated from a small oceanic sea snail. Today, more than 50 lamellarins have been inventoried and numerous derivatives synthesized... (Review)
Review
In 1985 the first lamellarins were isolated from a small oceanic sea snail. Today, more than 50 lamellarins have been inventoried and numerous derivatives synthesized and tested as antiviral or anticancer agents. The lead compound in the family is lamellarin D, characterized as a potent inhibitor of both nuclear and mitochondrial topoisomerase I but also capable of directly interfering with mitochondria to trigger cancer cell death. The pharmacology and chemistry of lamellarins are discussed here and the mechanistic portrait of lamellarin D is detailed. Lamellarins frequently serve as a starting point in the design of anticancer compounds. Extensive efforts have been devoted to create novel structures as well as to improve synthetic methods, leading to lamellarins and related pyrrole-derived marine alkaloids.
Topics: Animals; Antineoplastic Agents; Cell Death; Coumarins; Drug Design; Heterocyclic Compounds, 4 or More Rings; Humans; Isoquinolines; Mitochondria; Mollusca; Neoplasms; Structure-Activity Relationship
PubMed: 25706633
DOI: 10.3390/md13031105 -
Molecules (Basel, Switzerland) Mar 2015Curine is a bisbenzylisoquinoline alkaloid isolated from Chondrodendron platyphyllum (Menispermaceae). Recent findings have shed light on the actions of curine in... (Review)
Review
Curine is a bisbenzylisoquinoline alkaloid isolated from Chondrodendron platyphyllum (Menispermaceae). Recent findings have shed light on the actions of curine in different models of allergy and inflammation. Here we review the properties and mechanisms of action of curine focusing on its anti-allergic effects. Curine pre-treatment significantly inhibited the scratching behavior, paw edema and systemic anaphylaxis induced by either ovalbumin (OVA) in sensitized animals or compound 48/80, through mechanisms of mast cell stabilization and inhibition of mast cell activation to generate lipid mediators. In addition, oral administration of curine significantly inhibited eosinophil recruitment and activation, as well as, OVA-induced airway hyper-responsiveness in a mouse model of asthma, through inhibition of the production of IL-13 and eotaxin, and of Ca2+ influx. In conclusion, curine exhibit anti-allergic effects in models of lung, skin and systemic allergy in the absence of significant toxicity, and as such has the potential for anti-allergic drug development.
Topics: Animals; Anti-Allergic Agents; Benzylisoquinolines; Humans; Hypersensitivity; Inflammation; Isoquinolines; Lung; Mast Cells; Mice; Skin
PubMed: 25781071
DOI: 10.3390/molecules20034695 -
Plant Biotechnology Journal Jun 2016Several plant isoquinoline alkaloids (PIAs) possess powerful pharmaceutical and biotechnological properties. Thus, PIA metabolism and its fascinating molecules,... (Review)
Review
Several plant isoquinoline alkaloids (PIAs) possess powerful pharmaceutical and biotechnological properties. Thus, PIA metabolism and its fascinating molecules, including morphine, colchicine and galanthamine, have attracted the attention of both the industry and researchers involved in plant science, biochemistry, chemical bioengineering and medicine. Currently, access and availability of high-value PIAs [commercialized (e.g. galanthamine) or not (e.g. narciclasine)] is limited by low concentration in nature, lack of cultivation or geographic access, seasonal production and risk of overharvesting wild plant species. Nevertheless, most commercial PIAs are still extracted from plant sources. Efforts to improve the production of PIA have largely been impaired by the lack of knowledge on PIA metabolism. With the development and integration of next-generation sequencing technologies, high-throughput proteomics and metabolomics analyses and bioinformatics, systems biology was used to unravel metabolic pathways allowing the use of metabolic engineering and synthetic biology approaches to increase production of valuable PIAs. Metabolic engineering provides opportunity to overcome issues related to restricted availability, diversification and productivity of plant alkaloids. Engineered plant, plant cells and microbial cell cultures can act as biofactories by offering their metabolic machinery for the purpose of optimizing the conditions and increasing the productivity of a specific alkaloid. In this article, is presented an update on the production of PIA in engineered plant, plant cell cultures and heterologous micro-organisms.
Topics: Alkaloids; Biotechnology; Isoquinolines; Metabolic Engineering; Metabolic Networks and Pathways; Plants, Genetically Modified
PubMed: 26503307
DOI: 10.1111/pbi.12494 -
Molecules (Basel, Switzerland) Jun 2023Neuronal injury and apoptosis are important causes of the occurrence and development of many neurodegenerative diseases, such as cerebral ischemia, Alzheimer's disease,... (Review)
Review
Neuronal injury and apoptosis are important causes of the occurrence and development of many neurodegenerative diseases, such as cerebral ischemia, Alzheimer's disease, and Parkinson's disease. Although the detailed mechanism of some diseases is unknown, the loss of neurons in the brain is still the main pathological feature. By exerting the neuroprotective effects of drugs, it is of great significance to alleviate the symptoms and improve the prognosis of these diseases. Isoquinoline alkaloids are important active ingredients in many traditional Chinese medicines. These substances have a wide range of pharmacological effects and significant activity. Although some studies have suggested that isoquinoline alkaloids may have pharmacological activities for treating neurodegenerative diseases, there is currently a lack of a comprehensive summary regarding their mechanisms and characteristics in neuroprotection. This paper provides a comprehensive review of the active components found in isoquinoline alkaloids that have neuroprotective effects. It thoroughly explains the various mechanisms behind the neuroprotective effects of isoquinoline alkaloids and summarizes their common characteristics. This information can serve as a reference for further research on the neuroprotective effects of isoquinoline alkaloids.
Topics: Humans; Neuroprotective Agents; Alkaloids; Neurodegenerative Diseases; Parkinson Disease; Isoquinolines
PubMed: 37375352
DOI: 10.3390/molecules28124797 -
Biomedicine & Pharmacotherapy =... Dec 2023Acute lung injury (ALI) is a major pathological problem characterized by severe inflammatory reactions and is a critical disease with high clinical morbidity and...
Acute lung injury (ALI) is a major pathological problem characterized by severe inflammatory reactions and is a critical disease with high clinical morbidity and mortality. Liensinine, a major isoquinoline alkaloid, is extracted from the green embryos of mature Nelumbonaceae seeds. It has been reported to have an inhibitory effect on tumors. However, the effects of liensinine on ALI have not been reported to-date. The aim of this study was to explore the inhibitory effects of liensinine on lipopolysaccharide (LPS)-induced ALI and its possible mechanism. We found that liensinine significantly reduced LPS-induced ALI and reduced the production of inflammatory factors IL-6, IL-8, and TNF-α. In addition, liensinine blocked autophagic flux and increased the number of autophagosomes by upregulating LC3-II/I and p62 protein levels. More importantly, pretreatment with the early stages autophagy inhibitor 3-Methyladenine (3-MA) can reverse the inhibitory effects of liensinine on the secretion of inflammatory factors in ALI. The PI3K/AKT/mTOR pathway is involved in LPS-induced autophagy regulated by liensinine in ALI. In summary, this study suggests that liensinine inhibits the production of inflammatory factors in LPS-induced ALI by regulating autophagy via the PI3K/AKT/mTOR pathway, which may provide a new therapeutic strategy to alleviate ALI.
Topics: Humans; Lipopolysaccharides; Proto-Oncogene Proteins c-akt; Phosphatidylinositol 3-Kinases; Signal Transduction; TOR Serine-Threonine Kinases; Acute Lung Injury; Isoquinolines; Autophagy; Lung
PubMed: 37922654
DOI: 10.1016/j.biopha.2023.115813