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Biomedica : Revista Del Instituto... Aug 2023Sporotrichosis is an implantation mycosis caused by Sporothrix spp. It is distributed worldwide and can be found in vegetation and soil. The most frequent route of...
INTRODUCTION
Sporotrichosis is an implantation mycosis caused by Sporothrix spp. It is distributed worldwide and can be found in vegetation and soil. The most frequent route of infection is by trauma with elements contaminated with fungal propagules. Since domestic cats are the most affected animals and can transmit this infection to humans, sporotrichosis is considered a zoonosis. Clinical presentations include nodular lymphangitis, fixed cutaneous, pulmonary (rare), and disseminated (exceptional).
OBJECTIVES
To analyze the epidemiology of sporotrichosis in Argentina during 2010 and 2022. To describe the clinical presentation, diagnostic methods, and treatment of cases diagnosed during this period. To know the circulating genotypes and to observe possible associations with the geographic location where the infection was acquired.
MATERIALS AND METHODS
Analytical, retrospective, and observational study. We analyzed the medical records of patients with sporotrichosis from 12 health institutions in Argentina, between 2010 and 2022.
RESULTS
We present 54 cases in which the most frequent clinical form was nodular lymphangitis, and the treatment of choice was itraconazole. Conventional diagnosis was made in all cases. Culture of clinical samples was more sensitive than direct examination because it allowed the isolation of Sporothrix spp. in all 54 cases. Molecular identification was performed in 22 cases, with Sporothrix schenkii sensu stricto being the most frequently isolated species.
CONCLUSIONS
This study allowed to know the epidemiology of this mycosis in Argentina, as well as the availability of diagnostic methods and the treatment of choice.
Topics: Animals; Argentina; Itraconazole; Tolnaftate; Zoonoses
PubMed: 37721908
DOI: 10.7705/biomedica.6886 -
Brain : a Journal of Neurology Feb 2024The unfolded protein response (UPR) is rapidly gaining momentum as a therapeutic target for protein misfolding neurodegenerative diseases, in which its overactivation...
The unfolded protein response (UPR) is rapidly gaining momentum as a therapeutic target for protein misfolding neurodegenerative diseases, in which its overactivation results in sustained translational repression leading to synapse loss and neurodegeneration. In mouse models of these disorders, from Alzheimer's to prion disease, modulation of the pathway-including by the licensed drug, trazodone-restores global protein synthesis rates with profound neuroprotective effects. However, the precise nature of the translational impairment, in particular the specific proteins affected in disease, and their response to therapeutic UPR modulation are poorly understood. We used non-canonical amino acid tagging (NCAT) to measure de novo protein synthesis in the brains of prion-diseased mice with and without trazodone treatment, in both whole hippocampus and cell-specifically. During disease the predominant nascent proteome changes occur in synaptic, cytoskeletal and mitochondrial proteins in both hippocampal neurons and astrocytes. Remarkably, trazodone treatment for just 2 weeks largely restored the whole disease nascent proteome in the hippocampus to that of healthy, uninfected mice, predominantly with recovery of proteins involved in synaptic and mitochondrial function. In parallel, trazodone treatment restored the disease-associated decline in synapses and mitochondria and their function to wild-type levels. In conclusion, this study increases our understanding of how translational repression contributes to neurodegeneration through synaptic and mitochondrial toxicity via depletion of key proteins essential for their function. Further, it provides new insights into the neuroprotective mechanisms of trazodone through reversal of this toxicity, relevant for the treatment of neurodegenerative diseases via translational modulation.
Topics: Mice; Animals; Prions; Proteome; Trazodone; Prion Diseases; Neurodegenerative Diseases; Synapses; Alzheimer Disease
PubMed: 37703312
DOI: 10.1093/brain/awad313 -
International Journal of Molecular... Mar 2024Recently, we identified a novel mechanism of enzyme inhibition in N-myristoyltransferases (NMTs), which we have named 'inhibitor trapping'. Inhibitor trapping occurs...
Recently, we identified a novel mechanism of enzyme inhibition in N-myristoyltransferases (NMTs), which we have named 'inhibitor trapping'. Inhibitor trapping occurs when the protein captures the small molecule within its structural confines, thereby preventing its free dissociation and resulting in a dramatic increase in inhibitor affinity and potency. Here, we demonstrate that inhibitor trapping also occurs in the kinases. Remarkably, the drug imatinib, which has revolutionized targeted cancer therapy, is entrapped in the structure of the Abl kinase. This effect is also observed in p38α kinase, where inhibitor trapping was found to depend on a 'magic' methyl group, which stabilizes the protein conformation and increases the affinity of the compound dramatically. Altogether, these results suggest that inhibitor trapping is not exclusive to N-myristoyltransferases, as it also occurs in the kinase family. Inhibitor trapping could enhance the binding affinity of an inhibitor by thousands of times and is as a key mechanism that plays a critical role in determining drug affinity and potency.
Topics: Pyrimidines; Piperazines; Benzamides; Imatinib Mesylate; Fusion Proteins, bcr-abl; src-Family Kinases; Protein Kinase Inhibitors
PubMed: 38542228
DOI: 10.3390/ijms25063249 -
Journal of Natural Products Sep 2023This review provides a critical analysis of shielding effects induced by an aromatic (indole) ring of small molecules mainly including three members of naturally... (Review)
Review
This review provides a critical analysis of shielding effects induced by an aromatic (indole) ring of small molecules mainly including three members of naturally occurring secondary metabolites asterric acid analogs, diketopiperazines (DKPs) possessing an aromatic or an indole ring, and rubrolides. Empirical rules about the shielding effects induced by an aromatic (indole) ring are classified, based on which some H NMR chemical shift values in the A-ring and structures of asterric acid analogs are revised, and the relative configurations of some DKPs possessing an indole ring are also assigned or revised. The empirical rules could provide an efficient and convenient method for NMR data analysis and configuration determination for the three members of small molecules mentioned above.
Topics: Phenyl Ethers; Data Analysis; Diketopiperazines; Indoles
PubMed: 37646572
DOI: 10.1021/acs.jnatprod.3c00434 -
Journal of Medicinal Chemistry Dec 2023The ongoing transmission of SARS-CoV-2 necessitates the development of additional potent antiviral agents capable of combating the current highly infectious variants and...
Design, Synthesis, and Biological Evaluation of Trisubstituted Piperazine Derivatives as Noncovalent Severe Acute Respiratory Syndrome Coronavirus 2 Main Protease Inhibitors with Improved Antiviral Activity and Favorable Druggability.
The ongoing transmission of SARS-CoV-2 necessitates the development of additional potent antiviral agents capable of combating the current highly infectious variants and future coronaviruses. Here, we present the discovery of potent nonpeptide main protease (M) inhibitors with prominent antiviral activity and improved pharmacokinetic properties. Three series of 1,2,4-trisubstituted piperazine derivatives were designed and synthesized, and the optimal demonstrated high enzyme-inhibitory potency (IC = 0.19 μM) and exhibited excellent antiviral activity (EC = 0.40 μM), reaching the same level as Nirmatrelvir (EC = 0.38 μM). Additionally, displayed potent antiviral activities against various SARS-CoV-2 variants as well as HCoV-OC43 and HCoV-229E, indicating its potential broad-spectrum anticoronaviral activity. Notably, the pharmacokinetic properties of were somewhat enhanced compared to those of the lead compound. Furthermore, the cocrystal and molecular docking elucidated the mechanism of action. In conclusion, we discovered a novel nonpeptidic M inhibitor with promising antiviral activity and a favorable pharmacokinetic profile.
Topics: Humans; SARS-CoV-2; COVID-19; Molecular Docking Simulation; Protease Inhibitors; Antiviral Agents; Piperazines
PubMed: 37992202
DOI: 10.1021/acs.jmedchem.3c01876 -
Molecular Pharmaceutics Oct 2023Multidrug salts represent more than one drug in a crystal lattice and thus could be used to deliver multiple drugs in a single dose. It showcases unique physicochemical...
Multidrug salts represent more than one drug in a crystal lattice and thus could be used to deliver multiple drugs in a single dose. It showcases unique physicochemical properties in comparison to individual components, which could lead to improved efficacy and therapeutic synergism. This study presents the preparation and scale-up of sulfamethoxazole-piperazine salt, which has been thoroughly characterized by X-ray diffraction and thermal and spectroscopic analyses. A detailed mechanistic study investigates the impact of piperazine on the microenvironmental pH of the salt and its effect on the speciation profile, solubility, dissolution, and diffusion profile. Also, the improvement in the physicochemical properties of sulfamethoxazole due to the formation of salt was explored with lattice energy contributions. A greater ionization of sulfamethoxazole (due to pH changes contributed by piperazine) and lesser lattice energy of sulfamethoxazole-piperazine contributed to improved solubility, dissolution, and permeability. Moreover, the prepared salt addresses the stability issues of piperazine and exhibits good stability behavior under accelerated stability conditions. Due to the improvement of physicochemical properties, the sulfamethoxazole-piperazine salt demonstrates better pharmacokinetic parameters in comparison to sulfamethoxazole and provides a strong suggestion for the reduction of dose. The following study suggests that multidrug salts can concurrently enhance the physicochemical properties of drugs and present themselves as improved fixed-dose combinations.
Topics: Piperazine; Salts; X-Ray Diffraction; Solubility
PubMed: 37677085
DOI: 10.1021/acs.molpharmaceut.3c00646 -
Molecules (Basel, Switzerland) Dec 2023The piperazine moiety is often found in drugs or in bioactive molecules. This widespread presence is due to different possible roles depending on the position in the... (Review)
Review
The piperazine moiety is often found in drugs or in bioactive molecules. This widespread presence is due to different possible roles depending on the position in the molecule and on the therapeutic class, but it also depends on the chemical reactivity of piperazine-based synthons, which facilitate its insertion into the molecule. In this paper, we take into consideration the piperazine-containing drugs approved by the Food and Drug Administration between January 2011 and June 2023, and the synthetic methodologies used to prepare the compounds in the discovery and process chemistry are reviewed.
Topics: United States; Piperazine; United States Food and Drug Administration
PubMed: 38202651
DOI: 10.3390/molecules29010068 -
The American Journal of the Medical... Mar 2024The vast majority of antianginal drugs decrease heart rate and or blood pressure levels or the inotropic status of the left ventricle to decrease myocardial oxygen... (Review)
Review
The vast majority of antianginal drugs decrease heart rate and or blood pressure levels or the inotropic status of the left ventricle to decrease myocardial oxygen consumption (MVO2) and thus anginal symptoms. Ranolazine presents a completely different mechanism of action, which reduces the sodium-dependent calcium overload inhibiting the late sodium current. Current European Society of Cardiology (ESC) guidelines for the management of angina in patients with chronic coronary symptoms recommend the use of several drugs such as ranolazine, b-blockers, calcium channel blockers, long-acting nitrates, ivabradine, nicorandil and trimetazidine for angina relief. However, ranolazine, in addition to symptom relief properties, is an antianginal drug showing favorable effects in decreasing the arrhythmic burden and in ameliorating the glycemic profile of these patients. In this review, we summarize the available data regarding the antianginal and pleiotropic effects of this drug.
Topics: Humans; Ranolazine; Cardiovascular Agents; Angina Pectoris; Ivabradine; Sodium
PubMed: 38072070
DOI: 10.1016/j.amjms.2023.12.001 -
Cell Death and Differentiation Apr 2024Poly ADP-ribose polymerase inhibitors (PARPis) exhibit promising efficacy in patients with BRCA mutations or homologous repair deficiency (HRD) in ovarian cancer (OC)....
Poly ADP-ribose polymerase inhibitors (PARPis) exhibit promising efficacy in patients with BRCA mutations or homologous repair deficiency (HRD) in ovarian cancer (OC). However, less than 40% of patients have HRD, it is vital to expand the indications for PARPis in BRCA-proficient patients. Ferroptosis suppressor protein 1 (FSP1) is a key protein in a newly identified ferroptosis-protective mechanism that occurs in parallel with the GPX4-mediated pathway and is associated with chemoresistance in several cancers. Herein, FSP1 is reported to be negatively correlated with the prognosis in OC patients. Combination therapy comprising olaparib and iFSP1 (a FSP1 inhibitor) strongly inhibited tumour proliferation in BRCA-proficient OC cell lines, patient-derived organoids (PDOs) and xenograft mouse models. Surprisingly, the synergistic killing effect could not be reversed by ferroptosis inhibitors, indicating that mechanisms other than ferroptosis were responsible for the synergistic lethality. In addition, cotreatment was shown to induce increased γH2A.X foci and to impair nonhomologous end joining (NHEJ) activity to a greater extent than did any single drug. Mass spectrometry and immunoprecipitation analyses revealed that FSP1 interacted with Ku70, a classical component recruited to and occupying the end of double-strand breaks (DSBs) in the NHEJ process. FSP1 inhibition decreased Ku70 PARylation, impaired subsequent DNA-PKcs recruitment to the Ku complex at DSB sites and was rescued by restoring PARylation. These findings unprecedentedly reveal a novel role of FSP1 in DNA damage repair and provide new insights into how to sensitize OC patients to PARPi treatment.
Topics: Humans; Ovarian Neoplasms; Female; Phthalazines; Piperazines; Animals; Mice; Ferroptosis; Cell Line, Tumor; BRCA1 Protein; Poly(ADP-ribose) Polymerase Inhibitors; Cell Proliferation; S100 Calcium-Binding Protein A4
PubMed: 38374229
DOI: 10.1038/s41418-024-01263-z -
Journal of Natural Products Jul 2023Bioassay-guided fractionation of the essential oil of led to the identification of α-santalol () and β-santalol () as new chemotypes of cannabinoid receptor type II...
Bioassay-guided fractionation of the essential oil of led to the identification of α-santalol () and β-santalol () as new chemotypes of cannabinoid receptor type II (CB) ligands with values of 10.49 and 8.19 μM, respectively. Nine structurally new α-santalol derivatives (- and ) were synthesized to identify more selective and potent CB ligands. Compound with a piperazine structural moiety demonstrated a value of 0.99 μM against CB receptor and did not show binding activity against cannabinoid receptor type I (CB) at 10 μM. Compounds , , and increased intracellular calcium influx in SH-SY5Y human neuroblastoma cells that were attenuated by CB antagonism or inverse agonism, supporting the results that these compounds are CB agonists. Molecular docking showed that and had similar binding poses, exhibiting a unique interaction with Thr114 within the CB receptor, and that the piperazine structural moiety is required for the binding affinity of . A 200 ns molecular dynamics simulation of CB complexed with confirmed the stability of the complex. This structural insight lays a foundation to further design and synthesize more potent and selective α-santalol-based CB ligands for drug discovery.
Topics: Humans; Molecular Docking Simulation; Ligands; Drug Inverse Agonism; Neuroblastoma; Receptors, Cannabinoid; Piperazines; Receptor, Cannabinoid, CB2; Receptor, Cannabinoid, CB1; Molecular Structure; Structure-Activity Relationship
PubMed: 37450763
DOI: 10.1021/acs.jnatprod.3c00282