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Biomedicine & Pharmacotherapy =... Jun 2022Ligusticum chuanxiong Hort (known as Chuanxiong in China, CX) is one of the most widely used and long-standing medicinal herbs in China. Tetramethylpyrazine (TMP) is an... (Review)
Review
Ligusticum chuanxiong Hort (known as Chuanxiong in China, CX) is one of the most widely used and long-standing medicinal herbs in China. Tetramethylpyrazine (TMP) is an alkaloid and one of the active components of CX. Over the past few decades, TMP has been proven to possess several pharmacological properties. It has been used to treat a variety of diseases with excellent therapeutic effects. Here, the pharmacological characteristics and molecular mechanism of TMP in recent years are reviewed, with an emphasis on the signal-regulation mechanism of TMP. This review shows that TMP has many physiological functions, including anti-oxidant, anti-inflammatory, and anti-apoptosis properties; autophagy regulation; vasodilation; angiogenesis regulation; mitochondrial damage suppression; endothelial protection; reduction of proliferation and migration of vascular smooth muscle cells; and neuroprotection. At present, TMP is used in treating cardiovascular, nervous, and digestive system conditions, cancer, and other conditions and has achieved good curative effects. The therapeutic mechanism of TMP involves multiple targets, multiple pathways, and bidirectional regulation. TMP is, thus, a promising drug with great research potential.
Topics: Antineoplastic Agents; Autophagy; Ligusticum; Pyrazines
PubMed: 35483189
DOI: 10.1016/j.biopha.2022.113005 -
International Journal of Molecular... Jan 2021Bortezomib, a first-generation proteasome inhibitor widely used in chemotherapy for hematologic malignancy, has effective anti-cancer activity but often causes severe... (Review)
Review
Bortezomib, a first-generation proteasome inhibitor widely used in chemotherapy for hematologic malignancy, has effective anti-cancer activity but often causes severe peripheral neuropathy. Although bortezomib-induced peripheral neuropathy (BIPN) is a dose-limiting toxicity, there are no recommended therapeutics for its prevention or treatment. One of the most critical problems is a lack of knowledge about pathological mechanisms of BIPN. Here, we summarize the known mechanisms of BIPN based on preclinical evidence, including morphological abnormalities, involvement of non-neuronal cells, oxidative stress, and alterations of transcriptional programs in both the peripheral and central nervous systems. Moreover, we describe the necessity of advancing studies that identify the potential efficacy of approved drugs on the basis of pathological mechanisms, as this is a convincing strategy for rapid translation to patients with cancer and BIPN.
Topics: Antineoplastic Agents; Boronic Acids; Bortezomib; Humans; Peripheral Nervous System Diseases; Proteasome Inhibitors; Pyrazines
PubMed: 33477371
DOI: 10.3390/ijms22020888 -
British Journal of Pharmacology May 2018The mechanosensitive Piezo1 channel has important roles in vascular physiology and disease. Yoda1 is a small-molecule agonist, but the pharmacology of these channels is...
BACKGROUND AND PURPOSE
The mechanosensitive Piezo1 channel has important roles in vascular physiology and disease. Yoda1 is a small-molecule agonist, but the pharmacology of these channels is otherwise limited.
EXPERIMENTAL APPROACH
Yoda1 analogues were generated by synthetic chemistry. Intracellular Ca and Tl measurements were made in HEK 293 or CHO cell lines overexpressing channel subunits and in HUVECs, which natively express Piezo1. Isometric tension recordings were made from rings of mouse thoracic aorta.
KEY RESULTS
Modification of the pyrazine ring of Yoda1 yielded an analogue, which lacked agonist activity but reversibly antagonized Yoda1. The analogue is referred to as Dooku1. Dooku1 inhibited 2 μM Yoda1-induced Ca -entry with IC s of 1.3 μM (HEK 293 cells) and 1.5 μM (HUVECs) yet failed to inhibit constitutive Piezo1 channel activity. It had no effect on endogenous ATP-evoked Ca elevation or store-operated Ca entry in HEK 293 cells or Ca entry through TRPV4 or TRPC4 channels overexpressed in CHO and HEK 293 cells. Yoda1 caused dose-dependent relaxation of aortic rings, which was mediated by an endothelium- and NO-dependent mechanism and which was antagonized by Dooku1 and analogues of Dooku1.
CONCLUSION AND IMPLICATIONS
Chemical antagonism of Yoda1-evoked Piezo1 channel activity is possible, and the existence of a specific chemical interaction site is suggested with distinct binding and efficacy domains.
Topics: Animals; Aorta, Thoracic; CHO Cells; Cells, Cultured; Cricetulus; HEK293 Cells; Humans; Ion Channels; Mice; Pyrazines; Structure-Activity Relationship
PubMed: 29498036
DOI: 10.1111/bph.14188 -
Molecules (Basel, Switzerland) Jul 2022Pyrazines and pyridazines fused to 1,2,3-triazoles comprise a set of heterocycles obtained through a variety of synthetic routes. Two typical modes of constructing these... (Review)
Review
Pyrazines and pyridazines fused to 1,2,3-triazoles comprise a set of heterocycles obtained through a variety of synthetic routes. Two typical modes of constructing these heterocyclic ring systems are cyclizing a heterocyclic diamine with a nitrite or reacting hydrazine hydrate with dicarbonyl 1,2,3-triazoles. Several unique methods are known, particularly for the synthesis of 1,2,3-triazolo[1,5-]pyrazines and their benzo-fused quinoxaline and quinoxalinone-containing analogs. Recent applications detail the use of these heterocycles in medicinal chemistry (c-Met inhibition or GABA modulating activity) as fluorescent probes and as structural units of polymers.
Topics: Pyrazines; Pyridazines; Quinoxalines; Triazoles
PubMed: 35897857
DOI: 10.3390/molecules27154681 -
Advances in Therapy Jan 2022In the event-driven GRIPHON randomised-controlled trial, the oral prostacyclin receptor agonist selexipag significantly reduced the risk of disease progression... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
In the event-driven GRIPHON randomised-controlled trial, the oral prostacyclin receptor agonist selexipag significantly reduced the risk of disease progression (composite primary endpoint of morbidity/mortality), compared with placebo, in patients with pulmonary arterial hypertension (PAH). The ongoing open-label extension study (GRIPHON OL) collects further data on long-term safety, tolerability, and survival of PAH patients treated with selexipag.
METHODS
Patients randomised to selexipag or placebo in GRIPHON could enter GRIPHON OL either after experiencing a morbidity event during double-blind treatment or at the end of the study. Patients were followed for adverse events (AE) and survival from selexipag initiation up to 3 days and 30 days after end of treatment, respectively. Data are presented up to a cut-off date of 1 September 2019.
RESULTS
Overall, 953 patients in GRIPHON and GRIPHON OL were treated with selexipag. At the time of selexipag initiation, 81.2% of patients were receiving background PAH therapy. Median (min, max) exposure to selexipag was 31.7 months (0, 106), corresponding to a total of 3054.4 patient-years. The most frequently reported AEs were related to known prostacyclin-related effects or underlying disease. There were 305 (32.0%) patients who experienced an AE leading to treatment discontinuation. Survival during GRIPHON and GRIPHON OL was assessed for the 574 patients randomised to selexipag in GRIPHON. Kaplan-Meier survival estimates (95%CI) at 1, 3, 5 and 7 years were 92.0% (89.4, 94.0), 79.3% (75.4, 82.6), 71.2% (66.5, 75.3) and 63.0% (57.4, 68.1), respectively.
CONCLUSIONS
These results provide the longest follow-up period published to date for a PAH therapy. The safety profile of selexipag over this extended treatment period was consistent with that observed in GRIPHON. A large proportion of the population was receiving background therapy at selexipag initiation, providing further insight into the long-term safety of selexipag as part of a combination therapy regimen.
TRIAL REGISTRATION
ClinicalTrials.gov Identifiers: NCT01106014 and NCT01112306.
Topics: Acetamides; Antihypertensive Agents; Humans; Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Pyrazines
PubMed: 34727317
DOI: 10.1007/s12325-021-01898-1 -
Biochemistry. Biokhimiia Jun 2015Bioluminescence is a widespread natural phenomenon. Luminous organisms are found among bacteria, fungi, protozoa, coelenterates, worms, molluscs, insects, and fish.... (Review)
Review
Bioluminescence is a widespread natural phenomenon. Luminous organisms are found among bacteria, fungi, protozoa, coelenterates, worms, molluscs, insects, and fish. Studies on bioluminescent systems of various organisms have revealed an interesting feature - the mechanisms underlying visible light emission are considerably different in representatives of different taxa despite the same final result of this biochemical process. Among the several substrates of bioluminescent reactions identified in marine luminous organisms, the most commonly used are imidazopyrazinone derivatives such as coelenterazine and Cypridina luciferin. Although the substrate used is the same, bioluminescent proteins that catalyze light emitting reactions in taxonomically remote luminous organisms do not show similarity either in amino acid sequences or in spatial structures. In this review, we consider luciferases of various luminous organisms that use coelenterazine or Cypridina luciferin as a substrate, as well as modifications of these proteins that improve their physicochemical and bioluminescent properties and therefore their applicability in bioluminescence imaging in vivo.
Topics: Animals; Imidazoles; Luciferases; Luminescent Proteins; Pyrazines
PubMed: 26531017
DOI: 10.1134/S0006297915060073 -
The Netherlands Journal of Medicine Apr 2013Peripheral neuropathy is a frequent side effect of bortezomib chemotherapy. Relatively little is known about the clinical characteristics of this neuropathy, especially...
BACKGROUND
Peripheral neuropathy is a frequent side effect of bortezomib chemotherapy. Relatively little is known about the clinical characteristics of this neuropathy, especially with respect to pain. Our aim was to describe the clinical characteristics and course of bortezomib-induced polyneuropathy.
METHODS
This is a retrospective cohort study of 39 patients diagnosed with bortezomib-induced polyneuropathy.
RESULTS
Pain is the most prominent symptom and 14 of 39 patients suffered from severe pain. More than 50% of our patients used analgesics due to moderate or severe pain. We found no correlation between severity of symptoms of bortezomib-induced polyneuropathy and cumulative dose or dose intensity of bortezomib. Nerve conduction studies did not correlate well with symptom severity. Dose reduction or discontinuation of treatment reduced severity in most cases.
CONCLUSION
Painful polyneuropathy is a frequent, dose-limiting side effect of bortezomib with a relatively good prognosis. Careful neurological monitoring of symptoms and timely dose adjustment is important.
Topics: Antineoplastic Agents; Boronic Acids; Bortezomib; Cohort Studies; Humans; Multiple Myeloma; Polyneuropathies; Pyrazines; Retrospective Studies
PubMed: 23712808
DOI: No ID Found -
Journal of Enzyme Inhibition and... Dec 2022Acipimox, a nicotinic acid derivative in clinical use for the treatment of hyperlipidaemia, incorporates a free carboxylic acid and an N-oxide moiety, functionalities...
Acipimox, a nicotinic acid derivative in clinical use for the treatment of hyperlipidaemia, incorporates a free carboxylic acid and an N-oxide moiety, functionalities known to interact with the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) and inhibit its activity. Herein we report that acipimox acts as a low micromolar CA inhibitor (CAI) against most human (h) isoforms possessing catalytic activity, hCA I - XIV. By using computational techniques (docking and molecular dynamics simulations), we propose that acipimox coordinates through its carboxylate group to the zinc ion from the enzyme active site cavity, whereas the N-oxide group is hydrogen-bonded to the proton shuttle His residue in some isoforms (hCA I) or to active site Thr or Gln residues in other isoforms (hCA II, III, IV, VII, etc). As some CA isoforms are involved in lipogenesis, these data may be useful for the design of more effective CAIs with antiobesity activity.
Topics: Carbonic Anhydrase Inhibitors; Carbonic Anhydrases; Dose-Response Relationship, Drug; Humans; Isoenzymes; Models, Molecular; Molecular Structure; Pyrazines; Structure-Activity Relationship
PubMed: 35139721
DOI: 10.1080/14756366.2022.2037579 -
European Journal of Medicinal Chemistry Dec 2022A set of fifteen triterpenoid pyrazines and pyridines was prepared from parent triterpenoid 3-oxoderivatives (betulonic acid, dihydrobetulonic acid, oleanonic acid,...
A set of fifteen triterpenoid pyrazines and pyridines was prepared from parent triterpenoid 3-oxoderivatives (betulonic acid, dihydrobetulonic acid, oleanonic acid, moronic acid, ursonic acid, heterobetulonic acid, and allobetulone). Cytotoxicity of all compounds was tested in eight cancer and two non-cancer cell lines. Evaluation of the structure-activity relationships revealed that the triterpenoid core determined whether the final molecule is active or not, while the heterocycle is able to increase the activity and modulate the specificity. Five compounds (1b, 1c, 2b, 2c, and 8) were found to be preferentially and highly cytotoxic (IC ≈ 1 μM) against leukemic cancer cell lines (CCRF-CEM, K562, CEM-DNR, or K562-TAX). Surprisingly, compounds 1c, 2b, and 2c are 10-fold more active in multidrug-resistant leukemia cells (CEM-DNR and K562-TAX) than in their non-resistant analogs (CCRF-CEM and K562). Pharmacological parameters were measured for the most promising candidates and two types of prodrugs were synthesized: 1) Sugar-containing conjugates, most of which had improved cell penetration and retained high cytotoxicity in the CCRF-CEM cell line, unfortunately, they lost the selectivity against resistant cells. 2) Medoxomil derivatives, among which compounds 26-28 gained activities of IC 0.026-0.043 μM against K562 cells. Compounds 1b, 8, 21, 22, 23, and 24 were selected for the evaluation of the mechanism of action based on their highest cytotoxicity against CCRF-CEM cell line. Several experiments showed that the majority of them cause apoptosis via the mitochondrial pathway. Compounds 1b, 8, and 21 inhibit growth and disintegrate spheroid cultures of HCT116 and HeLa cells, which would be important for the treatment of solid tumors. In summary, compounds 1b, 1c, 2b, 2c, 24, and 26-28 are highly and selectively cytotoxic against cancer cell lines and were selected for future in vivo tests and further development of anticancer drugs.
Topics: Humans; Prodrugs; Pyrazines; Membrane Potential, Mitochondrial; Antineoplastic Agents, Phytogenic; HeLa Cells; Drug Resistance, Neoplasm; Cell Line, Tumor; Triterpenes; Antineoplastic Agents; Pyridines
PubMed: 36174412
DOI: 10.1016/j.ejmech.2022.114777 -
Chemical & Pharmaceutical Bulletin 2022Knoevenagel condensation, an olefin-forming reaction from active methyl/methylene-containing compounds and aldehydes, is a fundamental and useful synthetic method....
Knoevenagel condensation, an olefin-forming reaction from active methyl/methylene-containing compounds and aldehydes, is a fundamental and useful synthetic method. Benzothiazoles are, however, out of the scope of Knoevenagel condensation. Here, we report that Knoevenagel condensation between aldehydes and 2-methyl-thiazolo[4,5-b]pyrazines (MeTPy), a fused ring structure comprising pyrazine and thiazole, proceeded smoothly, despite minor structural differences from benzothiazoles. This finding will be useful for short synthesis of MeTPy-containing functional molecules, such as a tau probe analog 1.
Topics: Aldehydes; Alkenes; Molecular Structure; Pyrazines
PubMed: 34980738
DOI: 10.1248/cpb.c21-00780