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IUCrData Feb 2024In the title complex, [Ru(CHN)(CHNO)(HO)](CFSO), the central Ru atom is sixfold coordinated by two bidentate 2,2'-bi-pyridine, an isonic-otinamide ligand, and a water...
In the title complex, [Ru(CHN)(CHNO)(HO)](CFSO), the central Ru atom is sixfold coordinated by two bidentate 2,2'-bi-pyridine, an isonic-otinamide ligand, and a water mol-ecule in a distorted octa-hedral environment with tri-fluoro-methane-sulfonate ions completing the outer coordination sphere of the complex. Hydrogen bonding involving the water mol-ecule and weak π-π stacking inter-actions between the pyridyl rings in adjacent mol-ecules contribute to the alignment of the complexes in columns parallel to the axis.
PubMed: 38455113
DOI: 10.1107/S2414314624001147 -
Biomedicine & Pharmacotherapy =... Sep 2023Male infertility is a global concern, with a noticeable increase in the decline of spermatogenesis and sperm quality. However, there are limited clinically effective...
Male infertility is a global concern, with a noticeable increase in the decline of spermatogenesis and sperm quality. However, there are limited clinically effective treatments available. This study aimed to investigate the potential effectiveness of puerarin in treating male infertility, which leads to gonadal changes. The results obtained from various analyses such as CASA, immunofluorescence, DIFF-Quick, hematoxylin and eosin (H&E), and periodic acid-Schiff (PAS) staining demonstrated that puerarin supplementation significantly alleviated the busulfan-induced reduction in spermatogenesis and sperm quality in both young and adult mice. Furthermore, puerarin exhibited a marked improvement in the damage caused by busulfan to the architecture of seminiferous tubules, causal epididymis, blood-testicular barrier (BTB), as well as spermatogonia and Sertoli cells. Similarly, puerarin significantly reduced the levels of total antioxidant capacity (T-AOC), malondialdehyde (MDA), and caspase-3 in the testes of busulfan-induced mice, as determined by microplate reader analysis. Additionally, RNA-seq data, RT-qPCR, and western blotting revealed that puerarin restored the abnormal gene expressions induced by busulfan to nearly healthy levels. Notably, puerarin significantly reversed the impact of busulfan on the expression of marker genes involved in spermatogenesis and oxidative stress. Moreover, puerarin suppressed the phosphorylation of p38, ERK1/2, and JNK in the testes, as observed through testicular analysis. Consequently, this study concludes that puerarin may serve as a potential alternative for treating busulfan-induced damage to male fertility by inactivating the testicular MAPK pathways. These findings may pave the way for the use of puerarin in addressing chemotherapy- or other factors-induced male infertility in humans.
Topics: Humans; Male; Animals; Mice; Busulfan; Semen; Spermatogenesis; Testis; Infertility, Male
PubMed: 37516022
DOI: 10.1016/j.biopha.2023.115231 -
Acta Crystallographica. Section E,... Apr 2024Two 2,4,6-tri-methyl-aniline-based trifuloro-methane-sulfonate (tri-fluoro-methane-sulfonate) salts were synthesized and characterized by single-crystal X-ray...
Synthesis and crystal structures of ,2,4,6-tetra-methyl-anilinium tri-fluoro-methane-sulfonate and -iso-propyl-idene-,2,4,6-tetra-methyl-anilinium tri-fluoro-methane-sulfonate.
Two 2,4,6-tri-methyl-aniline-based trifuloro-methane-sulfonate (tri-fluoro-methane-sulfonate) salts were synthesized and characterized by single-crystal X-ray diffraction. ,2,4,6-Tetra-methyl-anilinium tri-fluoro-methane-sulfonate, [CHNH ][CFOS] (), was synthesized methyl-ation of 2,4,6-tri-methyl-aniline. -Iso-propyl-idene-,2,4,6-tetra-methyl-anilinium tri-fluoro-meth-ane-sulfonate, [CHN][CFOS] (), was synthesized in a two-step reaction where the imine, -iso-propyl-idene-2,4,6-tri-methyl-aniline, was first prepared a dehydration reaction to form the Schiff base, followed by methyl-ation using methyl tri-fluoro-methane-sulfonate to form the iminium ion. In compound , both hydrogen bonding and π-π inter-actions form the main inter-molecular inter-actions. The primary inter-action is a strong N-H⋯O hydrogen bond with the oxygen atoms of the tri-fluoro-methane-sulfonate anions bonded to the hydrogen atoms of the ammonium nitro-gen atom to generate a one-dimensional chain. The [CHNH ] cations form dimers where the benzene rings form a π-π inter-action with a parallel-displaced geometry. The separation distance between the calculated centroids of the benzene rings is 3.9129 (8) Å, and the inter-planar spacing and ring slippage between the dimers are 3.5156 (5) and 1.718 Å, respectively. For , the [CHN] cations also form dimers as in , but with the benzene rings highly slipped. The distance between the calculated centroids of the benzene rings is 4.8937 (8) Å, and inter-planar spacing and ring slippage are 3.3646 (5) and 3.553 Å, respectively. The major inter-molecular inter-actions in are instead a series of weaker C-H⋯O hydrogen bonds [C⋯O distances of 3.1723 (17), 3.3789 (18), and 3.3789 (18) Å], an inter-action virtually absent in the structure of . Fluorine atoms are not involved in strong directional inter-actions in either structure.
PubMed: 38721416
DOI: 10.1107/S2056989024003438 -
Journal of Pharmacological Sciences Sep 2023Premature ovarian insufficiency (POI) is a clinical syndrome that declines ovarian function in women. Berberine (BBR) is a compound with anti-inflammatory, antioxidant,...
Premature ovarian insufficiency (POI) is a clinical syndrome that declines ovarian function in women. Berberine (BBR) is a compound with anti-inflammatory, antioxidant, and anti-apoptotic activities. However, the role of BBR on POI is still unknown. In this study, we investigated the role of BBR on ovarian function decline by establishing a POI mouse model using cyclophosphamide (CTX) and busulfan (BU). Our results showed that POI was attenuated by BBR, which was evidenced by enhanced body weight and ovarian weight, improved morphology of ovary, increased the number of healthy follicles, decreased the production of atretic follicles and restored serum hormone levels, including estradiol, anti-Müllerian hormone and follicle-stimulating hormone. In addition, we showed that germ cell function markers, mouse vasa homologue (MVH) and octamer-binding transcription factor 4 (OCT4) were enhanced by BBR, at both protein and mRNA levels. Furthermore, our results revealed that BBR inhibited inflammation and oxidative stress by reducing nuclear factor kappa B (NF-κB) and enhancing nuclear factor erythroid 2-related factor 2 (Nrf2) pathways. Taken together, we demonstrate that BBR can effectively improve ovarian function in POI mice, which is mainly mediated by reducing oxidative stress and inflammatory response. Our study also provides new strategy for POI treatment.
Topics: Mice; Female; Humans; Animals; Busulfan; Berberine; Primary Ovarian Insufficiency; Cyclophosphamide; Estradiol
PubMed: 37524454
DOI: 10.1016/j.jphs.2023.07.004 -
Theranostics 2024In recent years, nicotinamide adenine dinucleotide (NAD) precursors (Npre) have been widely employed to ameliorate female reproductive problems in both humans and...
In recent years, nicotinamide adenine dinucleotide (NAD) precursors (Npre) have been widely employed to ameliorate female reproductive problems in both humans and animal models. However, whether and how Npre plays a role in the male reproductive disorder has not been fully clarified. In the present study, a busulfan-induced non-obstructive azoospermic mouse model was used, and Npre was administered for five weeks following the drug injection, with the objective of reinstating spermatogenesis and fertility. Initially, we assessed the NAD level, germ cell types, semen parameters and sperm fertilization capability. Subsequently, testis tissues were examined through RNA sequencing analysis, ELISA, H&E, immunofluorescence, quantitative real-time PCR, and Western blotting techniques. The results indicated that Npre restored normal level of NAD in blood and significantly alleviated the deleterious effects of busulfan (BU) on spermatogenesis, thereby partially reestablishing fertilization capacity. Transcriptome analysis, along with recovery of testicular Fe, GSH, NADPH, and MDA levels, impaired by BU, and the fact that Fer-1, an inhibitor of ferroptosis, restored spermatogenesis and semen parameters close to CTRL values, supported such possibility. Interestingly, the reduction in SIRT2 protein level by the specific inhibitor AGK2 attenuated the beneficial effects of Npre on spermatogenesis and ferroptosis by affecting PGC-1α and ACLY protein levels, thus suggesting how these compounds might confer spermatogenesis protection. Collectively, these findings indicate that NAD protects spermatogenesis against ferroptosis, probably through SIRT2 dependent mechanisms. This underscores the considerable potential of Npre supplementation as a feasible strategy for preserving or restoring spermatogenesis in specific conditions of male infertility and as adjuvant therapy to preserve male fertility in cancer patients receiving sterilizing treatments.
Topics: Animals; Busulfan; Male; Spermatogenesis; Mice; NAD; Ferroptosis; Sirtuin 2; Disease Models, Animal; Testis; Azoospermia
PubMed: 38646657
DOI: 10.7150/thno.92416 -
Blood Advances Jan 2024Allogeneic hematopoietic stem cell transplantation (HSCT) is highly effective for treating pediatric high-risk or relapsed acute lymphoblastic leukemia (ALL). For young...
Allogeneic hematopoietic stem cell transplantation (HSCT) is highly effective for treating pediatric high-risk or relapsed acute lymphoblastic leukemia (ALL). For young children, total body irradiation (TBI) is associated with severe late sequelae. In the FORUM study (NCT01949129), we assessed safety, event-free survival (EFS), and overall survival (OS) of 2 TBI-free conditioning regimens in children aged <4 years with ALL. Patients received fludarabine (Flu), thiotepa (Thio), and either busulfan (Bu) or treosulfan (Treo) before HSCT. From 2013 to 2021, 191 children received transplantation and were observed for ≥6 months (median follow-up: 3 years). The 3-year OS was 0.63 (95% confidence interval [95% CI], 0.52-0.72) and 0.76 (95% CI, 0.64-0.84) for Flu/Thio/Bu and Flu/Thio/Treo (P = .075), respectively. Three-year EFS was 0.52 (95% CI, 0.41-0.61) and 0.51 (95% CI, 0.39-0.62), respectively (P = .794). Cumulative incidence of nonrelapse mortality (NRM) and relapse at 3 years were 0.06 (95% CI, 0.02-0.12) vs 0.03 (95% CI: <0.01-0.09) (P = .406) and 0.42 (95% CI, 0.31-0.52) vs 0.45 (95% CI, 0.34-0.56) (P = .920), respectively. Grade >1 acute graft-versus-host disease (GVHD) occurred in 29% of patients receiving Flu/Thio/Bu and 17% of those receiving Flu/Thio/Treo (P = .049), whereas grade 3/4 occurred in 10% and 9%, respectively (P = .813). The 3-year incidence of chronic GVHD was 0.07 (95% CI, 0.03-0.13) vs 0.05 (95% CI, 0.02-0.11), respectively (P = .518). In conclusion, both chemotherapeutic conditioning regimens were well tolerated and NRM was low. However, relapse was the major cause of treatment failure. This trial was registered at www.clinicaltrials.gov as #NCT01949129.
Topics: Child; Child, Preschool; Humans; Busulfan; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Thiotepa; Transplantation Conditioning
PubMed: 37738088
DOI: 10.1182/bloodadvances.2023010591 -
Acta Crystallographica. Section E,... Jul 2023The novel bench-stable -quaternized ketene ,-acetal, CHNO·CFOS, was synthesized and its structure determined. The title compound is a rare example of a pyridinium...
Synthesis and crystal structure of a bench-stable pyridinium ketene hemiaminal: 1-(1-eth-oxy-ethen-yl)-2-[meth-yl(phen-yl)amino]-pyridin-1-ium tri-fluoro-methane-sulfonate.
The novel bench-stable -quaternized ketene ,-acetal, CHNO·CFOS, was synthesized and its structure determined. The title compound is a rare example of a pyridinium ketene hemiaminal for which a crystal structure has been determined, joining the 2-chloro-1-(1-ethyoxyethen-yl)pyridin-1-ium tri-fluoro-methane-sulfonate salt from which it was synthesized. The cationic species of the title compound can be defined by three individually planar fragments assembling into a non-coplanar cation. The phenyl substituent extending from the amino nitro-gen atom and the ethyoxyvinyl substituent extending from the pyridine N atom are oriented on the same side of the mol-ecule and maintain the closest coplanar relationship of the three fragments. Supra-molecular inter-actions are dominated by C-H⋯O inter-actions from the cation to the SO side of the tri-fluoro-methane-sulfonate anion, forming a two-dimensional substructure.
PubMed: 37601406
DOI: 10.1107/S2056989023005741 -
ELife Jun 2023The replication checkpoint is essential for accurate DNA replication and repair, and maintenance of genomic integrity when a cell is challenged with genotoxic stress....
The replication checkpoint is essential for accurate DNA replication and repair, and maintenance of genomic integrity when a cell is challenged with genotoxic stress. Several studies have defined the complement of proteins that change subcellular location in the budding yeast following chemically induced DNA replication stress using methyl methanesulfonate (MMS) or hydroxyurea (HU). How these protein movements are regulated remains largely unexplored. We find that the essential checkpoint kinases Mec1 and Rad53 are responsible for regulating the subcellular localization of 159 proteins during MMS-induced replication stress. Unexpectedly, Rad53 regulation of the localization of 52 proteins is independent of its known kinase activator Mec1, and in some scenarios independent of Tel1 or the mediator proteins Rad9 and Mrc1. We demonstrate that Rad53 is phosphorylated and active following MMS exposure in cells lacking Mec1 and Tel1. This noncanonical mode of Rad53 activation depends partly on the retrograde signaling transcription factor Rtg3, which also facilitates proper DNA replication dynamics. We conclude that there are biologically important modes of Rad53 protein kinase activation that respond to replication stress and operate in parallel to Mec1 and Tel1.
Topics: Protein Serine-Threonine Kinases; Cell Cycle Proteins; Saccharomyces cerevisiae Proteins; Intracellular Signaling Peptides and Proteins; Checkpoint Kinase 2; Saccharomyces cerevisiae; Phosphorylation; DNA Damage; Methyl Methanesulfonate; DNA Replication
PubMed: 37278514
DOI: 10.7554/eLife.82483 -
Haematologica Jul 2023Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only curative treatment for myelofibrosis. However, the optimal conditioning regimen either with...
Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only curative treatment for myelofibrosis. However, the optimal conditioning regimen either with reduced-intensity conditioning (RIC) or myeloablative conditioning (MAC) is not well known. Using the Center for International Blood and Marrow Transplant Research database, we identified adults aged ≥18 years with myelofibrosis undergoing allo-HCT between 2008-2019 and analyzed the outcomes separately in the RIC and MAC cohorts based on the conditioning regimens used. Among 872 eligible patients, 493 underwent allo-HCT using RIC (fludarabine/ busulfan n=166, fludarabine/melphalan n=327) and 379 using MAC (fludarabine/busulfan n=247, busulfan/cyclophosphamide n=132). In multivariable analysis with RIC, fludarabine/melphalan was associated with inferior overall survival (hazard ratio [HR]=1.80; 95% confidenec interval [CI]: 1.15-2.81; P=0.009), higher early non-relapse mortality (HR=1.81; 95% CI: 1.12-2.91; P=0.01) and higher acute graft-versus-host disease (GvHD) (grade 2-4 HR=1.45; 95% CI: 1.03-2.03; P=0.03; grade 3-4 HR=2.21; 95%CI: 1.28-3.83; P=0.004) compared to fludarabine/busulfan. In the MAC setting, busulfan/cyclophosphamide was associated with a higher acute GvHD (grade 2-4 HR=2.33; 95% CI: 1.67-3.25; P<0.001; grade 3-4 HR=2.31; 95% CI: 1.52-3.52; P<0.001) and inferior GvHD-free relapse-free survival (GRFS) (HR=1.94; 95% CI: 1.49-2.53; P<0.001) as compared to fludarabine/busulfan. Hence, our study suggests that fludarabine/busulfan is associated with better outcomes in RIC (better overall survival, lower early non-relapse mortality, lower acute GvHD) and MAC (lower acute GvHD and better GRFS) in myelofibrosis.
Topics: Adult; Humans; Adolescent; Primary Myelofibrosis; Busulfan; Melphalan; Retrospective Studies; Hematopoietic Stem Cell Transplantation; Cyclophosphamide; Graft vs Host Disease; Transplantation Conditioning; Vidarabine
PubMed: 36779595
DOI: 10.3324/haematol.2022.281958 -
Blood Advances Sep 2023Busulfan is an alkylating drug routinely used in conditioning regimens for allogeneic hematopoietic cell transplantation (allo-HCT). A myeloablative conditioning...
Busulfan is an alkylating drug routinely used in conditioning regimens for allogeneic hematopoietic cell transplantation (allo-HCT). A myeloablative conditioning regimen, including busulfan, is commonly used in patients undergoing T-cell depletion (TCD) and allo-HCT, but data on optimal busulfan pharmacokinetic (PK) exposure in this setting are limited. Between 2012 and 2019, busulfan PK was performed to target an area under the curve exposure between 55 and 66 mg × h/L over 3 days using a noncompartmental analysis model. We retrospectively re-estimated busulfan exposure following the published population PK (popPK) model (2021) and correlated it with outcomes. To define optimal exposure, univariable models were performed with P splines, wherein hazard ratio (HR) plots were drawn, and thresholds were found graphically as the points at which the confidence interval crossed 1. Cox proportional hazard and competing risk models were used for analyses. 176 patients were included, with a median age of 59 years (range, 2-71). Using the popPK model, the median cumulative busulfan exposure was 63.4 mg × h/L (range, 46.3-90.7). The optimal threshold was at the upper limit of the lowest quartile (59.5 mg × h/L). 5-year overall survival (OS) with busulfan exposure ≥59.5 vs <59.5 mg × h/L was 67% (95% CI, 59-76) vs 40% (95% CI, 53-68), respectively (P = .02), and this association remained in a multivariate analyses (HR, 0.5; 95% CI, 0.29; 0.88; P = .02). In patients undergoing TCD allo-HCT, busulfan exposure is significantly associated with OS. The use of a published popPK model to optimize exposure may significantly improve the OS.
Topics: Humans; Child, Preschool; Child; Adolescent; Young Adult; Adult; Middle Aged; Aged; Busulfan; Retrospective Studies; Transplantation, Homologous; Transplantation Conditioning; Hematopoietic Stem Cell Transplantation
PubMed: 37379285
DOI: 10.1182/bloodadvances.2023009708