Discovery of Novel Ortho-Aminophenol Derivatives Targeting Lipid Peroxidation with Potent Antiferroptotic Activities.

The concept of ferroptosis inhibition has gained growing recognition as a promising therapeutic strategy for addressing a wide range of diseases. Here, we present the discovery of four series of ortho-aminophenol derivatives as potential ferroptosis inhibitors beginning with the endogenous substance 3-hydroxyanthranilic acid (3-HA) by employing quantum chemistry techniques, in vitro and in vivo assays. Our findings reveal that these ortho-aminophenol derivatives exhibit unique intra-H bond interactions, compelling ortho-amines to achieve enhanced alignment with the aromatic π-system, thereby expanding their activity. Notably, compounds from all four series display remarkable activity against RSL3-induced ferroptosis, showcasing an activity 100 times more than that of 3-HA. Furthermore, these compounds also demonstrate robust in vivo efficacy in protecting mice from kidney ischemia-reperfusion injury and acetaminophen-induced hepatotoxicity. In summary, we provide four distinct series of active scaffolds that significantly expand the chemical space of ferroptosis inhibitors, serving as valuable insights for future structural modifications.

New indolizidine- and pyrrolidine-type alkaloids with anti-angiogenic activities from Anisodus tanguticus.

Eleven alkaloids, including five previously undescribed indolizidine alkaloids (1, 2a, 2b, 3a, and 3b) and four new pyrrolidine alkaloids (5-8), were isolated from the roots of Anisodus tanguticus. Of these, two new pairs of enantiomeric alkaloids (2a/2b and 3a/3b) are the first examples of alkaloids containing both indolizidine and pyrrolidine structural fragments. The one-carbon bridge connections with two pyrrolidine rings (6) or with a pyrrolidine ring and a pyridine ring (8) are the first reported from nature. Extensive spectroscopic techniques were used to elucidate their structures, and NMR and ECD calculations were used to determine the absolute configurations. The viability of human umbilical vein endothelial cells (HUVECs) was inhibited by compounds 2a, 2b, 3a, 4b, and 5, and compound 2b exhibited a potential anti-angiogenic effect by inhibiting the proliferation, migration, and tube formation of HUVECs. A chorioallantoic membrane assay also demonstrated the anti-angiogenic activity of 2b. In addition, compounds 2a, 2b, 3a, and 4b exhibited moderate cytotoxicity against A2780 cells.

Inhibitory Effect of Astragalus Polysaccharide on Premetastatic Niche of Lung Cancer through the S1PR1-STAT3 Signaling Pathway.

As a common malignant tumor, the morbidity and mortality of lung cancer have been rising in recent years. The concept of "premetastatic niche" may lead to a revolutionary change in antitumor metastasis therapeutic strategies. Traditional Chinese medicine with multitargets and lower poisonous agents may be a potentially effective means to intervene in the "premetastatic niche (PMN)" to prevent and treat tumor metastasis. Astragalus polysaccharide (APS) is a substance with strong immune activity in Astragalus membranaceus that has excellent biological activities such as immunomodulation, anti-inflammatory, and antitumor. In this study, we constructed a tumor lung metastasis animal model to explore the intervention mechanism of APS on the premetastatic niche. We found that APS inhibited the formation of the lung premetastatic niche and inhibited the recruitment of myeloid-derived suppressor cells (MDSCs) in the lung. Mechanistically, we showed that the proteins and gene expression of S1PR1, STAT3, and p-STAT3 in the S1PR1/STAT3 signaling pathway were suppressed by APS. In line with the above findings, our results confirmed that APS may inhibit the accumulation of MDSCs in the premetastatic niche through the intervention of the S1PR1-STAT3 signaling pathway to achieve the antitumor effect.

[Correlation of sperm HDS with sperm DFI and morphology and its influence on in vitro fertilization in infertile males].

OBJECTIVE: To invest the correlation of sperm high DNA stainability (HDS) with sperm DNA fragmentation index (DFI) and sperm abnormalities and its influence on in vitro fertilization (IVF) in male infertility patients, and assess the clinical value of HDS. METHODS: Using flow cytometry-assisted sperm chromatin structure assay (SCSA), we examined sperm HDS and sperm DFI in 322 male infertility patients undergoing IVF due to female fallopian tube factors only. Based on sperm HDS, we divided the patients into five groups and compared the semen routine parameters, percentage of morphologically abnormal sperm (MAS), sperm DFI, rates of fertilization, cleavage and high-quality embryos, and pregnancy outcomes among different HDS groups. RESULTS: Among the 322 male infertility patients, 119 (36.96%) were found with a sperm HDS of 0 － <5%, 117 (36.34%) of 5% － <10%, 50 (15.53%) of 10% － <15%, 23 (7.14%) of 15% － <20%, and 13 (4.03%) of ≥20%. Sperm concentration, motility and progressive motility were decreased with the increase of sperm HDS, but with no statistically significant difference (P > 0.05), so were the rates of fertilization, high-quality embryos and pregnancy (P > 0.05). Sperm DFI and sperm abnormality were correlated positively with sperm HDS (r = 0.236, r = 0.203). The rate of early abortion was remarkably increased in those with sperm HDS greater than 10%. CONCLUSION: Sperm HDS may be a risk indicator of sperm DFI and sperm abnormality, and can be used as a predictive indicator of early abortion in IVF.

[A preliminary pharmacophylogenetic study of Solanaceae medicinal plants containing tropane alkaloids].

The Solanaceae plants distributed in China belong to 105 species and 35 varietas of 24 genera. Some medicinal plants of Solanaceae are rich in tropane alkaloids(TAs), which have significant pharmacological activities. In this paper, the geographical distribution, chemical components, traditional therapeutic effect, pharmacological activities, and biosynthetic pathways of TAs in Solanaceous plants were summarized. Besides, the phylogeny of medicinal plants belonging to Solanaceae was visualized by network diagram. Fourteen genera of Solanaceae plants in China contain TAs and have medical records. TAs mainly exist in Datura, Anisodus, Atropa, Physochlaina, and Hyoscyamus. The TAs-containing species were mainly concentrated in Southwest China, and the content of TAs was closely related to plant distribution area and altitude. The Solanaceae plants containing TAs mainly have antispasmodic, analgesic, antiasthmatic, and antitussive effects. Modern pharmacological studies have proved the central sedative, pupil dilating, glandular secretion-inhibiting, and anti-asthma activities of TAs. These pharmacological activities provide a reasonable explanation for the traditional therapeutic efficacy of tropane drugs. In this paper, the geographical distribution, chemical components, traditional therapeutic effect, and modern pharmacological activities of TAs-containing species in Solanaceae were analyzed for the first time. Based on these data, the genetic relationship of TAs-containing Solanaceae species was preliminarily discussed, which provided a scientific basis for the basic research on TAs-containing solanaceous species and was of great significance for the development of natural medicinal plant resources containing TAs.

Comparative analysis of the dust retention capacity and leaf microstructure of 11 Sophora japonica clones.

We used fresh leaves of Sophora japonica L. variety 'Qingyun 1' (A0) and 10 superior clones of the same species (A1-A10) to explore leaf morphological characteristics and total particle retention per unit leaf area under natural and artificial simulated dust deposition treatments. Our objectives were to explore the relationship between the two methods and to assess particle size distribution, X-ray fluorescence (XRF) heavy metal content, and scanning electron and atomic force microscopy (SEM and AFM) characteristics of leaf surface microstructure. Using the membership function method, we evaluated the dust retention capacity of each clone based on the mean degree of membership of its dust retention index. Using correlation analysis, we selected leaf morphological and SEM and AFM indices related significantly to dust retention capacity. Sophora japonica showed excellent overall dust retention capacity, although this capacity differed among clones. A5 had the strongest overall retention capacity, A2 had the strongest retention capacity for PM2.5, A9 had the strongest retention capacity for PM2.5-10, A0 had the strongest retention capacity for PM>10, and A2 had the strongest specific surface area (SSA) and heavy metal adsorption capacity. Overall, A1 had the strongest comprehensive dust retention ability, A5 was intermediate, and A7 had the weakest capacity. Certain leaf morphological and SEM and AFM characteristic indices correlated significantly with the dust retention capacity.

Reverse contralateral proximal tibial plating and cannulated screws fixation for Hoffa fracture: A case report.

Hoffa fracture is a rare type of distal femoral fracture occurs in the coronal plane of either femoral epicondyle. To date, screws in combination with lateral plate fixation is widely accepted to achieve stable fixation and good results. However, up to now there has not been a specially designed anatomical plate for lateral fixation of Hoffa fracture. In this report, we demonstrate a case of Hoffa fracture fixed with reverse application of "L" shaped contralateral proximal tibia plate and cannulated screws, resulting in good one-year results.

Patient expectations predict outcomes following distal radius fracture: a prospective cohort study using the TEFTOM questionnaire.

INTRODUCTION: The relationship between patient expectations and clinical outcomes has recently been of increasing interest in the field of orthopaedics. The objective of this study was to evaluate the relationships between (1) patient pre-treatment expectations and post-treatment clinical outcomes, and (2) fulfillment of expectations and patient satisfaction, following distal radius fracture. METHODS: This was a prospective multicenter cohort study conducted across three hospitals. A total of 133 patients admitted to hospital between 2016 and 2018 with a distal radius fracture were recruited. Patients were administered the Trauma Expectation Factor (TEF) at baseline to measure expectations of pain and functioning at one-year post-injury. Patients were followed up at 6 and 12 months post-injury and outcomes were measured using the Trauma Outcome Measure (TOM), Shortened Disabilities of the Arm, Shoulder and Hand (QuickDASH) questionnaire, and Short-Form 12-item (SF-12) health survey. Fulfillment of expectations was measured as TEF score minus TOM score at each time point. Patient satisfaction was also measured using the Patient Satisfaction Questionnaire Short Form (PSQ-18). Multivariate regression models were created to evaluate the effect of expectations on outcomes. RESULTS: Patient expectations correlated moderately with outcomes at 6 and 12 months post-injury. In the multivariate analysis, patient expectations were predictive of better outcomes at 6 and 12 months. Injury severity, age, mechanism of injury, and whether the injury occurred on duty also contributed significantly to one or more regression models. Patient satisfaction correlated weakly with fulfillment of expectations at 6 months, but moderately with all outcome scores. At 12 months, satisfaction did not correlate significantly with expectations fulfillment but correlated moderately to highly with all outcome scores. CONCLUSION: Patient expectations independently predicted outcomes at 6 and 12 months post-injury. Standardized assessment and management of patient expectations may be relevant to future clinical practice and research to best quantify and optimize patient outcomes.

Theoretical insight into the multiple interactions of quinazoline inhibitors with breast cancer resistance protein (BCRP/ABCG2).

Communicated by Ramaswamy H. Sarma.

Leonurus japonicus (Chinese motherwort), an excellent traditional medicine for obstetrical and gynecological diseases: A comprehensive overview.

Leonurus japonicus Houtt. is a traditional medicinal herb with significant effects; dating back more than 1800 years, it is widely used in Asia. In traditional Chinese medicine, it is essential in the treatment of menstrual and delivery disorders caused by blood stasis, such as dysmenorrhea, amenorrhea, and postpartum hemorrhage. In the last three decades, many phytochemists, pharmacologists, and doctors have focused on the chemical components, pharmacological activities, and clinical applications of L. japonicus. More than 280 chemical compounds have been isolated from this plant. The effects of most of the terpenoids and alkaloids isolated from the plant have been found to be closely related to the traditional functions of L. japonicus. Owing to its excellent therapeutic effects for obstetrical and gynecological diseases, L. japonicus has been widely used in both ancient and modern times. Nowadays, it has also been developed into a series of Chinese patent medicines in clinics in China. This review summarizes the phytochemistry, pharmacology, and clinical applications of L. japonicus.

Reactions of the Lipid Hydroperoxides With Aminic Antioxidants: The Influence of Stereoelectronic and Resonance Effects on Hydrogen Atom Transfer.

Aminic radical-trapping antioxidants (RTAs), as one of the most important antioxidants, have not received sufficient attention yet. But, an increasing number of aminic RTAs have been identified as ferroptosis inhibitors in recent years, which can potentially mediate many pathological states including inflammation, cancer, neurodegenerative disease, as well as ocular and kidney degeneration. This highlights the importance of aminic RTAs in the field of medicine. Herein, we systematically explored the radical scavenging mechanism of aminic RTAs with a quantum chemical method, particularly emphasizing the role of stereoelectronic factors and resonance factors on the transfer of H-atom and the stability to one-electron oxidation. These theoretical results elucidate the diversity of free radical scavenging mechanisms for aminic RTAs, and has significant implications for the rational design of new aminic RTAs.

Alkaloids and flavonoid glycosides from the aerial parts of Leonurus japonicus and their opposite effects on uterine smooth muscle.

The crude extract and some Chinese patented medicines of Leonurus japonicus Houtt. have been proven to affect the uterine smooth muscle. L. japonicus injection is widely used in obstetric departments in China for treating postpartum hemorrhage caused by uterine inertia. Bioassay-guided isolation of the 95% EtOH extract of L. japonicus yielded four cyclopeptides, nine alkaloids, and three flavonoid glycosides, including two previously undescribed cyclopeptides, namely, cycloleonuripeptide G and cycloleonuripeptide H. The structures of the cyclopeptides were elucidated to be cyclo-(L-Phe-L-Phe-Gly-L-Pro-Gly-L-Pro) and cyclo-(L-Phe-L-Ala-L-Pro-L-Ile-L-His-Gly-L-Ala-L-Pro), respectively, via spectroscopic and chemical methods. Cyclopeptides (cycloleonuripeptides C and D) and alkaloids (imperialine-3ß-D-glucoside and leonurine) promoted contraction of uterine smooth muscle strips isolated from normal rats. However, it was observed that flavonoid glycosides (spinosin, linarin, and apigenin-7-O-ß-D-glucopyranoside) significantly inhibited contraction of the uterine smooth muscle strips.

Leonuketal, a Spiroketal Diterpenoid from Leonurus japonicus.

An architecturally complex spiroketal diterpenoid, leonuketal (1), was isolated from the aerial parts of the plant Leonurus japonicus. This compound possessed an unprecedented tetracyclic skeleton that comprised a bridged spiroketal moiety fused with a ketal-γ-lactone unit. The structure and absolute configuration were determined by spectroscopic analyses, a modified Mosher's method, and ECD (electronic circular dichroism) calculations. Leonuketal (1) showed significant vasorelaxant activity against KCl-induced contraction of rat aorta, with the EC50 value of 2.32 µM.

Bis-spirolabdane diterpenoids from Leonurus japonicus and their anti-platelet aggregative activity.

Six bis-spirolabdane diterpenoids along with four known analogues were isolated from the aerial parts of Leonurus japonicus. Their structures and absolute configurations were elucidated by spectroscopic analyses, single-crystal X-ray diffraction, and a modified Mosher's method. The inhibitory activity of the compounds against the abnormal increase in platelet aggregation induced by adenosine diphosphate was investigated. Only the (13R)-bis-spirolabdane diterpenoids exhibited a significant effect.

Expression of ENaC, SGK1 and Nedd4 isoforms in the cochlea of guinea pig.

It has been demonstrated that the epithelial sodium channel (ENaC) may play critical roles in (re)absorbing Na+ from apical plasma membrane in various tissues and cells. Moreover, the serum glucocorticoid-inducible kinase 1 (SGK1) and the ubiquitin-protein ligase neural precursor cell-expressed, developmentally downregulated isoforms Nedd4 are involved in ENaC regulation in response to hormones such as aldosterone, vasopressin and insulin. The aim of the study was to investigate the cellular localizations of ENaC subunits, SGK1, and Nedd4 isoforms in the cochlea of guinea pig. Ten adult guinea pigs were sacrificed and their cochleas were collected. The expression patterns of ENaC subunits, SGK1 and Nedd4-2 isoforms in the guinea pig cochlea were studied by immunohistochemistry with the specific polyclonal rabbit antibodies against rat α-, ß- and γ-ENaC, SGK1, Nedd4-1/2 and Nedd4-2. The results showed that all these proteins were extensively expressed in various regions of the cochlea. They were found in the spiral ligament, organ of Corti, spiral limbus, spiral ganglion and Reissner's membrane with different staining patterns. The results indicated that a Na+ transport system may exist in the cochlea of guinea pig consisting of ENaC, SGK1 and Nedd4, which may work in concert to transport Na+ and to maintain homeostasis in inner ear as it does in other epithelia.

[Coumarins from Leonurus japonicus and their anti-platelet aggregative activity].

Chemical constituents of Leonurus japonicus were isolated and purified by a combination of various chromatographic techniques including column chromatography over silica gel, Sephadex LH-20, MCI, and Rp C18. Structures of the isolates were determined by spectroscopic analysis as 10 coumarins: bergapten (1), xanthotoxin (2), isopimpinellin (3), isogosferal (4), imperatorin (5), meransin hydrate(6), isomeranzin(7), murrayone(8) , auraptenol(9), and osthol(10). In addition to compound 9, the others were isolated from the genus Leonurus for the first time. In the in vitro assay, compounds 4 and 8 significantly inhibited the abnormal increase of platelet aggregation induced by ADP.

Coevolutionary particle swarm optimization using AIS and its application in multiparameter estimation of PMSM.

In this paper, a coevolutionary particle-swarmoptimization (PSO) algorithm associating with the artificial immune principle is proposed. In the proposed algorithm, the wholepopulation is divided into two kinds of subpopulations consisting of one elite subpopulation and several normal subpopulations. The best individual of each normal subpopulation will be memorized into the elite subpopulation during the evolution process. A hybrid method, which creates new individuals by using three different operators, is presented to ensure the diversity of all the subpopulations. Furthermore, a simple adaptive wavelet learning operator is utilized for accelerating the convergence speed of the pbest particles. The improved immune-clonal-selection operator is employed for optimizing the elite subpopulation, while the migration scheme is employed for the information exchange between elite subpopulation and normal subpopulations. The performance of the proposed algorithm is verified by testing on a suite of standard benchmark functions, which shows faster convergence and global search ability. Its performance is further evaluated by its application to multiparameter estimation of permanentmagnet synchronous machines, which shows that its performance significantly outperforms existing PSOs. The proposed algorithm can estimate the machine dq-axis inductances, stator winding resistance, and rotor flux linkage simultaneously.

Sesquiterpenoids from the herb of Leonurus japonicus.

Two new sesquiterpenoids, (-)-(1S*,2S*,3R*)-3-ethoxycupar-5-ene-1,2-diol (1) and (-)-(1S*,4S*,9S*)-1,9-epoxybisabola-2,10-diene-4-ol (2), along with six known compounds 3-8, were isolated from the EtOH extract of the herb of Leonurus japonicus. Their structures were elucidated by physical and spectroscopic analysis. In the in vitro assays, compounds 7 and 8 showed obvious antibacterial activity against several bacteria strains, while compound 3 significantly inhibited abnormal increase of platelet aggregation induced by ADP.

Different regulatory processes control pollen hydration and germination in Arabidopsis.

To elucidate the functional differences in how Arabidopsis stigmas regulate pollen hydration and germination, we analyzed receptivity of stigmas, epidermal surfaces (leaves, stems of inflorescence bolts, and floral organs), and an abiotic surface (cover glass) for pollen hydration and germination. Using 65% relative humidity (RH), we found that mature pollen grains were able to hydrate and germinate on stigmas at flower developmental stages 9-13, but not on the distal end of pistils at stage 8, epidermal surfaces, or glass. Furthermore, under 100% RH, pollen grains could hydrate on all tested surfaces, but pollen germination was observed only on the young floral organs (stages 9-12) and the stigmas at stages 9-13. The distal ends of pistils at stage 8, the epidermal surfaces, and the cover glass did not support pollen germination even under 100% RH. Our results indicate that pistil factors regulating pollen hydration and germination are synthesized at stage 9 when stigmatic papillar cells begin to develop. Although pistil factors involved in pollen hydration may only be present on the stigma, the factors involved in pollen germination may localize on both the stigma and surfaces of unopened floral organs.