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Cells Apr 2024In mammals, hearing loss is irreversible due to the lack of the regenerative capacity of the auditory epithelium. However, stem/progenitor cells in mammalian cochleae...
In mammals, hearing loss is irreversible due to the lack of the regenerative capacity of the auditory epithelium. However, stem/progenitor cells in mammalian cochleae may be a therapeutic target for hearing regeneration. The ubiquitin proteasome system plays an important role in cochlear development and maintenance. In this study, we investigated the role of ubiquitin C-terminal hydrolase L1 (UCHL1) in the process of the transdifferentiation of auditory supporting cells (SCs) into hair cells (HCs). The expression of UCHL1 gradually decreased as HCs developed and was restricted to inner pillar cells and third-row Deiters' cells between P2 and P7, suggesting that UCHL1-expressing cells are similar to the cells with Lgr5-positive progenitors. UCHL1 expression was decreased even under conditions in which supernumerary HCs were generated with a γ-secretase inhibitor and Wnt agonist. Moreover, the inhibition of UCHL1 by LDN-57444 led to an increase in HC numbers. Mechanistically, LDN-57444 increased mTOR complex 1 activity and allowed SCs to transdifferentiate into HCs. The suppression of UCHL1 induces the transdifferentiation of auditory SCs and progenitors into HCs by regulating the mTOR pathway.
Topics: Ubiquitin Thiolesterase; Cell Transdifferentiation; TOR Serine-Threonine Kinases; Animals; Hair Cells, Auditory; Mice; Signal Transduction; Labyrinth Supporting Cells; Indoles; Oximes
PubMed: 38727276
DOI: 10.3390/cells13090737 -
Acta Crystallographica. Section E,... Apr 2024In the structure of the title co-crystal, CHNO·CHN, the components are linked by a set of directional O-H⋯N, N-H⋯O, N-H⋯N and C-H⋯O hydrogen bonds to yield a...
In the structure of the title co-crystal, CHNO·CHN, the components are linked by a set of directional O-H⋯N, N-H⋯O, N-H⋯N and C-H⋯O hydrogen bonds to yield a two-dimensional mono-periodic arrangement. The structure propagates in the third dimension by extensive π-π stacking inter-actions of nearly parallel mol-ecules of the two components, following an alternating sequence. The primary structure-defining inter-action is very strong oxime-OH donor to pyrazole-N acceptor hydrogen bond [O⋯N = 2.587 (2) Å], while the significance of weaker hydrogen bonds and π-π stacking inter-actions is comparable. The distinct structural roles of different kinds of inter-actions agree with the results of a Hirshfeld surface analysis and calculated inter-action energies. The title compound provides insights into co-crystals of active agrochemical mol-ecules and features the rational integration in one structure of a fungicide, CHNO, and a second active component, CHN, known for alleviation the toxic effects of fungicides on plants. The material appears to be well suited for practical uses, being non-volatile, air-stable, water-soluble, but neither hygroscopic nor efflorescent.
PubMed: 38721422
DOI: 10.1107/S2056989024002809 -
Upsala Journal of Medical Sciences 2024Metastatic neuroendocrine carcinoma (NEC) is associated with short survival. Other than platinum-based chemotherapy, there is no clear standard regimen. Current...
BACKGROUND
Metastatic neuroendocrine carcinoma (NEC) is associated with short survival. Other than platinum-based chemotherapy, there is no clear standard regimen. Current guidelines suggest that combination treatment with BRAF-inhibitors should be considered for patients with V600E-mutated NEC. However, since only eight such patients have been reported in the literature, our object was to confirm the validity of this recommendation.
METHODS
This was a single-center retrospective cohort study conducted at Uppsala University Hospital. The included patients 1) had a histopathologically confirmed diagnosis of NEC, 2) were diagnosed between January 1, 2018 and December 31, 2023, 3) had tumor tissue genetically screened by a broad next-generation sequencing (NGS) panel, and 4) showed a tumor mutation for which there is a currently available targeted therapy.
RESULTS
We screened 48 patients diagnosed with NEC between January 1, 2018 and December 31, 2023. Twelve had been analyzed with a broad NGS-panel, and two had a targetable mutation. Both these patients harbored a V600E-mutated colon-NEC and were treated with BRAF- and MEK-inhibitors dabrafenib and trametinib in second-line. At first radiological evaluation (RECIST 1.1), both patients had a reduction of tumor size, which decreased by 31 and 40%. Both had short response periods, and their overall survival was 12 and 9 months.
CONCLUSIONS
-mutated NEC is sensitive to treatment with BRAF- and MEK-inhibitor combination. These results further support that DNA sequencing should be considered as standard of care in NECs to screen for potential treatment targets.
Topics: Adult; Aged; Female; Humans; Male; Middle Aged; Carcinoma, Neuroendocrine; High-Throughput Nucleotide Sequencing; Imidazoles; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retrospective Studies; Treatment Outcome
PubMed: 38716076
DOI: 10.48101/ujms.v129.10660 -
Toxicology Letters Jun 2024Animal research continues to serve a critical role in the testing and development of medical countermeasures. The Göttingen minipig, developed for laboratory research,...
Animal research continues to serve a critical role in the testing and development of medical countermeasures. The Göttingen minipig, developed for laboratory research, may provide many benefits for addressing research questions within chemical defense. Targeted development of the Göttingen minipig model could reduce reliance upon non-human primates, and improve study design, statistical power, and throughput to advance medical countermeasures for regulatory approval and fielding. In this vein, we completed foundational pharmacokinetics and physiological safety studies of intramuscularly administered atropine sulfate, pralidoxime chloride (2-PAM), and diazepam across a broad range of doses (1-6 autoinjector equivalent) using adult male Göttingen minipigs (n=11; n=4-8/study) surgically implanted with vascular access ports and telemetric devices to monitor cardiovascular, respiratory, arterial pressure, and temperature signals. Pharmacokinetic data were orderly and the concentration maximum mirrored available human data at comparably scaled doses clearly for atropine, moderately for 2-PAM, and poorly for diazepam. Time to peak concentration approximated 2, 7, and 20 min for atropine, 2-PAM, and diazepam, respectively, and the elimination half-life of these drugs approximated 2 hr (atropine), 3 hr (2-PAM), and 8 hr (diazepam). Atropine sulfate dose-dependently increased the magnitude and duration of tachycardia and decreased the PR and ST intervals (consistent with findings obtained from other species). Mild hypothermia was observed at the highest diazepam dose. Göttingen minipigs appear to provide a ready and appropriate large animal alternative to non-human primates, and further development and evaluation of novel nerve agent medical countermeasures and treatment strategies in this model are justified.
Topics: Animals; Swine, Miniature; Swine; Male; Diazepam; Atropine; Nerve Agents; Dose-Response Relationship, Drug; Injections, Intramuscular; Half-Life; Heart Rate; Telemetry; Models, Animal; Pralidoxime Compounds
PubMed: 38703967
DOI: 10.1016/j.toxlet.2024.04.014 -
Comprehensive Psychiatry Aug 2024To examine the long-term safety and tolerability of off-label high-dose serotonin reuptake inhibitors (OLHD-SRIs) in the treatment of obsessive-compulsive disorder (OCD).
OBJECTIVE
To examine the long-term safety and tolerability of off-label high-dose serotonin reuptake inhibitors (OLHD-SRIs) in the treatment of obsessive-compulsive disorder (OCD).
METHODS
A retrospective longitudinal study was performed on 105 randomly selected outpatients diagnosed with OCD and were treated with OLHD-SRIs for at least 6 months. Patients received sertraline >200 mg/day, escitalopram >20 mg/day, fluvoxamine >300 mg/day, and fluoxetine >60 mg/day, combined with exposure and response prevention therapy. Patients were divided into three dosing groups: sertraline equivalent dose (SED) ≤ 200 mg/day (n = 26, 24.7%), 201-400 mg/day (n = 51, 48.5%) and 401-650 mg/day (n = 28, 26.6%). Safety and tolerability were assessed with an electrocardiogram, blood biochemistry, complete blood count, and side-effects monitoring.
RESULTS
SED ranged from 100 to 650 mg/day and the mean duration of OLHD-SRI treatment was 20.8 months. The most common side-effects reported were sexual dysfunction (n = 36, 34%), weight gain (n = 28, 27%), sedation (n = 27, 26%), hyperhidrosis (n = 20, 19%), and tremor (n = 11, 10%). Abnormal ECG was documented in one patient, and another patient experienced a first-time seizure, whereas elevated liver enzymes were seen in 4.8% of the sample (n = 5). None of the patients had serotonin syndrome or drug-induced liver injury. Side-effects did not differ among the three dosing groups.
CONCLUSION
OLHD-SRIs appear to be safe and well tolerated in OCD patients in SED ≤ 650 mg/day doses and the side-effects did not differ between the three dosing groups.
Topics: Humans; Obsessive-Compulsive Disorder; Selective Serotonin Reuptake Inhibitors; Female; Adult; Male; Retrospective Studies; Off-Label Use; Fluvoxamine; Sertraline; Middle Aged; Longitudinal Studies; Fluoxetine; Escitalopram; Young Adult; Treatment Outcome; Dose-Response Relationship, Drug
PubMed: 38703743
DOI: 10.1016/j.comppsych.2024.152486 -
Molecules (Basel, Switzerland) Apr 2024The structural features and optical properties of supramolecular cyanoiron salts containing bis-pyridinium-4-oxime Toxogonin (TOXO) as an electron acceptor are...
The structural features and optical properties of supramolecular cyanoiron salts containing bis-pyridinium-4-oxime Toxogonin (TOXO) as an electron acceptor are presented. The properties of the new TOXO-based cyanoiron materials were probed by employing two cyanoiron platforms: hexacyanoferrate(II), [Fe(CN)] (HCF); and nitroprusside, [Fe(CN)(NO)] (NP). Two water-insoluble inter-ionic donor-acceptor phases were characterized: the as-prepared microcrystalline reddish-brown (TOXO)[Fe(CN)]·8HO () with a medium-responsive, hydrochromic character; and the dark violet crystalline (TOXO)[Fe(CN)]·3.5HO (). Complex , upon external stimulation, transforms to the violet anhydrous phase (TOXO)[Fe(CN)] (), which upon water uptake transforms back to . Using the NP platform resulted in the water-insoluble crystalline salt TOXO[Fe(CN)(NO)]·2HO (). The structures of and , solved by single-crystal X-ray diffraction, along with a comparative spectroscopic (UV-vis-NIR diffuse reflectance, IR, solid-state MAS-NMR, Mössbauer), thermal, powder X-ray diffraction, and microscopic analysis (SEM, TEM) of the isolated materials, provided insight for the supramolecular binding, electron-accepting, and H-bonding capabilities of TOXO in the self-assembly of these functionalized materials.
PubMed: 38675518
DOI: 10.3390/molecules29081698 -
Pharmaceutics Mar 2024Polysaccharides are gaining increasing attention for their relevance in the production of sustainable materials. In the domain of biomaterials, polysaccharides play an... (Review)
Review
Polysaccharides are gaining increasing attention for their relevance in the production of sustainable materials. In the domain of biomaterials, polysaccharides play an important role as hydrophilic components in the design of amphiphilic block copolymers for the development of drug delivery systems, in particular nanocarriers due to their outstanding biocompatibility, biodegradability, and structural versatility. The presence of a reducing end in polysaccharide chains allows for the synthesis of polysaccharide-based block copolymers. Compared with polysaccharide-based graft copolymers, the structure of block copolymers can be more precisely controlled. In this review, the synthesis methods of polysaccharide-based amphiphilic block copolymers are discussed in detail, taking into consideration the structural characteristics of polysaccharides. Various synthetic approaches, including reductive amination, oxime ligation, and other chain-end modification reactions, are explored. This review also focuses on the advantages of polysaccharides as hydrophilic blocks in polymeric nanocarriers. The structure and unique properties of different polysaccharides such as cellulose, hyaluronic acid, chitosan, alginate, and dextran are described along with examples of their applications as hydrophilic segments in the synthesis of amphiphilic copolymers to construct nanocarriers for sustained drug delivery.
PubMed: 38675130
DOI: 10.3390/pharmaceutics16040467 -
International Journal of Molecular... Apr 2024Directed structural modifications of natural products offer excellent opportunities to develop selectively acting drug candidates. Natural product hybrids represent a...
Directed structural modifications of natural products offer excellent opportunities to develop selectively acting drug candidates. Natural product hybrids represent a particular compound group. The components of hybrids constructed from different molecular entities may result in synergic action with diminished side effects. Steroidal homo- or heterodimers deserve special attention owing to their potentially high anticancer effect. Inspired by our recently described antiproliferative core-modified estrone derivatives, here, we combined them into heterodimers via Cu(I)-catalyzed azide-alkyne cycloaddition reactions. The two -16-azido-3-(-benzyl)-17-hydroxy-13α-estrone derivatives were reacted with 3--propargyl-D-secoestrone alcohol or oxime. The antiproliferative activities of the four newly synthesized dimers were evaluated against a panel of human adherent gynecological cancer cell lines (cervical: Hela, SiHa, C33A; breast: MCF-7, T47D, MDA-MB-231, MDA-MB-361; ovarian: A2780). One heterodimer () exerted substantial antiproliferative activity against all investigated cell lines in the submicromolar or low micromolar range. A pronounced proapoptotic effect was observed by fluorescent double staining and flow cytometry on three cervical cell lines. Additionally, cell cycle blockade in the G2/M phase was detected, which might be a consequence of the effect of the dimer on tubulin polymerization. Computational calculations on the taxoid binding site of tubulin revealed potential binding of both steroidal building blocks, mainly with hydrophobic interactions and water bridges.
Topics: Humans; Estrone; Cell Proliferation; Antineoplastic Agents; Cell Line, Tumor; Apoptosis; Dimerization; Molecular Docking Simulation; Female; Drug Screening Assays, Antitumor; HeLa Cells; Tubulin; MCF-7 Cells
PubMed: 38673860
DOI: 10.3390/ijms25084274 -
Scientific Reports Apr 2024We investigated the usefulness of quantitative Tc-white blood cell (WBC) single photon emission computed tomography (SPECT)/computed tomography (CT) for predicting lower...
We investigated the usefulness of quantitative Tc-white blood cell (WBC) single photon emission computed tomography (SPECT)/computed tomography (CT) for predicting lower extremity amputation in diabetic foot infection (DFI). A total of 93 feet of 83 consecutive patients with DFI who underwent WBC SPECT/CT for treatment planning were retrospectively analysed. The clinical and SPECT/CT parameters were collected along with the measurements of the maximum standardized uptake value (SUVmax) at DFI. Statistical logistic regression analysis was performed to explore the predictors of LEA and receiver operating characteristic (ROC) curve was analysed to assess the predictive value of SPECT/CT. The independent predictors of amputation were previous amputation (OR 11.9), numbers of SPECT/CT lesions (OR 2.1), and SUVmax of DFI; either continuous SUVmax (1-increase) (OR 1.3) or categorical SUVmax > 1.1 (OR 21.6). However, the conventional SPECT/CT interpretation failed to predict amputation. In ROC analysis, the SUVmax yielded a fair predictor (area under the curve (AUC) 0.782) of amputation. The model developed from these independent predictors yielded an excellent performance for predicting amputation (AUC 0.873). Quantitative WBC SPECT/CT can provide new information useful for predicting the outcomes and guiding treatment for patients with DFI.
Topics: Humans; Diabetic Foot; Male; Female; Amputation, Surgical; Aged; Middle Aged; Single Photon Emission Computed Tomography Computed Tomography; Leukocytes; Lower Extremity; Retrospective Studies; Technetium Tc 99m Exametazime; ROC Curve; Aged, 80 and over
PubMed: 38649465
DOI: 10.1038/s41598-024-59764-3 -
ACS Omega Apr 2024Pharmacologically active salicylanilides (2-hydroxy--phenylbenzamides) have been a promising area of interest in medicinal chemistry-related research for quite some...
Pharmacologically active salicylanilides (2-hydroxy--phenylbenzamides) have been a promising area of interest in medicinal chemistry-related research for quite some time. This group of compounds has shown a wide spectrum of biological activities, including but not limited to anticancer effects. In this study, substituted salicylanilides were chosen to evaluate the activity on U87 human glioblastoma (GBM) cells. The parent salicylanilide, salicylanilide 5-chloropyrazinoates, a 4-aminosalicylic acid derivative, and the new salicylanilide 4-formylbenzoates were chemically and characterized. To enhance the internalization of the compounds, they were conjugated to delivery peptides with the formation of oxime bonds. Oligotuftsins ([TKPKG], = 1-4), the ligands of neuropilin receptors, were used as GBM-targeting carrier peptides. The cellular uptake, intracellular localization, and penetration ability on tissue-mimicking models of the fluorescent peptide derivatives were determined. The compounds and their peptide conjugates significantly decreased the viability of U87 glioma cells. Salicylanilide compound-induced GBM cell death was associated with activation of autophagy, as characterized by immunodetection of autophagy-related processing of light chain 3 protein.
PubMed: 38645331
DOI: 10.1021/acsomega.3c05727