Bletilla striata Polysaccharide-/Chitosan-Based Self-Healing Hydrogel with Enhanced Photothermal Effect for Rapid Healing of Diabetic Infected Wounds via the Regulation of Microenvironment.

The management of diabetic ulcers poses a significant challenge worldwide, and persistent hyperglycemia makes patients susceptible to bacterial infections. Unfortunately, the overuse of antibiotics may lead to drug resistance and prolonged infections, contributing to chronic inflammation and hindering the healing process. To address these issues, a photothermal therapy technique was incorporated in the preparation of wound dressings. This innovative solution involved the formulation of a self-healing and injectable hydrogel matrix based on the Schiff base structure formed between the oxidized Bletilla striata polysaccharide (BSP) and hydroxypropyltrimethylammonium chloride chitosan. Furthermore, the introduction of CuO nanoparticles encapsulated in polydopamine imparted excellent photothermal properties to the hydrogel, which promoted the release of berberine (BER) loaded on the nanoparticles and boosted the antibacterial performance. In addition to providing a reliable physical protection to the wound, the developed hydrogel, which integrated the herbal components of BSP and BER, effectively accelerated wound closure via microenvironment regulation, including alleviated inflammatory reaction, stimulated re-epithelialization, and reduced oxidative stress based on the promising results from cell and animal experiments. These impressive outcomes highlighted their clinical potential in safeguarding the wound against bacterial intrusion and managing diabetic ulcers.

Robustness of response-adaptive randomization.

Doubly adaptive biased coin design (DBCD), a response-adaptive randomization scheme, aims to skew subject assignment probabilities based on accrued responses for ethical considerations. Recent years have seen substantial advances in understanding DBCD's theoretical properties, assuming correct model specification for the responses. However, concerns have been raised about the impact of model misspecification on its design and analysis. In this paper, we assess the robustness to both design model misspecification and analysis model misspecification under DBCD. On one hand, we confirm that the consistency and asymptotic normality of the allocation proportions can be preserved, even when the responses follow a distribution other than the one imposed by the design model during the implementation of DBCD. On the other hand, we extensively investigate three commonly used linear regression models for estimating and inferring the treatment effect, namely difference-in-means, analysis of covariance (ANCOVA) I, and ANCOVA II. By allowing these regression models to be arbitrarily misspecified, thereby not reflecting the true data generating process, we derive the consistency and asymptotic normality of the treatment effect estimators evaluated from the three models. The asymptotic properties show that the ANCOVA II model, which takes covariate-by-treatment interaction terms into account, yields the most efficient estimator. These results can provide theoretical support for using DBCD in scenarios involving model misspecification, thereby promoting the widespread application of this randomization procedure.

Are the facet joint parameters risk factors for cage subsidence after TLIF in patients with lumbar degenerative spondylolisthesis?

PURPOSE: To assess whether preoperative facet joint parameters in patients with degenerative lumbar spondylolisthesis (DS) are risk factors for cage subsidence (CS) following transforaminal lumbar interbody fusion (TLIF). METHODS: We enrolled 112 patients with L4-5 DS who underwent TLIF and were followed up for > 1 year. Preoperative demographic characteristics, functional areas of paraspinal muscles and psoas major muscles (PS), total functional area relative to vertebral body area, functional cross-sectional area (FCSA) of PS and lumbar spine extensor muscles, normalized FCSA of PS to the vertebral body area (FCSA/VBA), lumbar indentation value, facet joint orientation, facet joint tropism (FT), cross-sectional area of the superior articular process (SAPA), intervertebral height index, vertebral Hounsfield unit (HU) value, lordosis distribution index, t-scores, sagittal plane parameters, visual analog scale (VAS) for low back pain, VAS for leg pain, Oswestry disability index, global alignment and proportion score and European quality of life-5 dimensions (EQ-5D) were assessed. RESULTS: Postoperative CS showed significant correlations with preoperative FO(L3-4), FT (L3 and L5), SAPA(L3-5), L5-HU, FCSA/VBA(L3-4), Pre- T-score, post-6-month VAS for back pain and EQ-5D scores among other factors. According to ROC curve analysis, the optimal decision points for FO(L3-4), L3-SAPA, FCSA/VBA(L3-4), L5-HU, and Pre- T-score were 35.88°, 43.76°,114.93, 1.73, 1.55, 136, and - 2.49. CONCLUSIONS: This study identified preoperative FO, SAPA, preoperative CT, Pre- T-score and the FCSA/VBA as independent risk factors for CS after TLIF for DS. These risk factors should enable spinal surgeons to closely monitor and prevent the occurrence of CS.

Triclosan induces earlier puberty onset in female mice via interfering with L-type calcium channels and activating Pik3cd.

Triclosan (TCS) is a broad-spectrum antibacterial chemical widely presents in people's daily lives. Epidemiological studies have revealed that TCS exposure may affect female puberty development. However, the developmental toxicity after low-dose TCS continuous exposure remains to be confirmed. In our study, 8-week-old ICR female mice were continuously exposed to TCS (30, 300, 3000 µg/kg/day) or vehicle (corn oil) from 2 weeks before mating to postnatal day 21 (PND 21) of F1 female mice, while F1 female mice were treated with TCS intragastric administration from PND 22 until PND 56. Vaginal opening (VO) observation, hypothalamic-pituitary-ovarian (HPO) axis related hormones and genes detection, and ovarian transcriptome analysis were carried out to investigate the effects of TCS exposure on puberty onset. Meanwhile, human granulosa-like tumor cell lines (KGN cells) were exposed to TCS to further explore the biological mechanism of the ovary in vitro. The results showed that long-term exposure to low-dose TCS led to approximately a 3-day earlier puberty onset in F1 female mice. Moreover, TCS up-regulated the secretion of estradiol (E2) and the expression of ovarian steroidogenesis genes. Notably, ovarian transcriptomes analysis as well as bidirectional validation in KGN cells suggested that L-type calcium channels and Pik3cd were involved in TCS-induced up-regulation of ovarian-related hormones and genes. In conclusion, our study demonstrated that TCS interfered with L-type calcium channels and activated Pik3cd to up-regulate the expression of ovarian steroidogenesis and related genes, thereby inducing the earlier puberty onset in F1 female mice.

Association between exposure to persistent organic pollutants and pubertal timing in boys and girls: A systematic review and meta-analysis.

In recent years, the phenomenon of abnormal pubertal timing in children has become increasingly common worldwide. Persistent organic pollutants (POPs) may be one of the risk factors contributing to this phenomenon, but the relationship between them is unclear based on current evidence. The purpose of this study was to determine the association of POPs exposure with pubertal timing in girls and boys by conducting a systematic review and meta-analysis. We searched PubMed and Embase databases for studies before June 1, 2023. Meta-analysis was performed by pooling relative risk (RR) or odds ratio (OR) or prevalence ratio (PR) or hazard ratio (HR) estimates with 95 % confidence intervals (CIs). Subgroup analysis, publication bias assessment and sensitivity analysis were also carried out. A total of 21 studies were included, involving 2479 boys and 8718 girls. The results of meta-analysis showed that exposure to POPs was significantly associated with delayed pubertal timing in girls (RR: 0.85; 95 % CI: 0.79-0.91; p < 0.001). There was no statistically significant association between exposure to POPs and pubertal timing in boys (RR: 1.18; 95 % CI: 0.99-1.40; p = 0.070). Subgroup analysis showed that there may be gender differences in the effects of exposure to POPs on pubertal timing. Our results suggested that exposure to POPs could delay pubertal timing in girls. However, based on current evidence, no significant association was found between POPs exposure and pubertal timing in boys.

Toxicity, formation, contamination, determination and mitigation of acrylamide in thermally processed plant-based foods and herbal medicines: A review.

Thermal processing is one of the important techniques for most of the plant-based food and herb medicines before consumption and application in order to meet the specific requirement. The plant and herbs are rich in amino acids and reducing sugars, and thermal processing may lead to Maillard reaction, resulting as a high risk of acrylamide pollution. Acrylamide, an organic pollutant that can be absorbed by the body through the respiratory tract, digestive tract, skin and mucous membranes, has potential carcinogenicity, neurological, genetic, reproductive and developmental toxicity. Therefore, it is significant to conduct pollution determination and risk assessment for quality assurance and security of medication. This review demonstrates state-of-the-art research of acrylamide focusing on the toxicity, formation, contamination, determination, and mitigation in taking food and herb medicine, to provide reference for scientific processing and ensure the security of consumers.

A Berberine-Loaded Bletilla striata Polysaccharide Hydrogel as a New Medical Dressing for Diabetic Wound Healing.

The healing process of a diabetic wound (DW) is often impeded by a series of interrelated factors, including severe infection, persistent inflammation, and excessive oxidative stress. Therefore, it is particularly crucial to develop a medical dressing that can address these issues simultaneously. To this end, different ratios of Bletilla striata polysaccharide (BSP) and berberine (BER) were physically blended with Carbomer 940 (CBM940) to develop a composite hydrogel as a medical dressing. The BSP/BER hydrogel was characterized using SEM, FTIR, rheological testing and other techniques. The anti-inflammatory, antioxidant, and antibacterial properties of the hydrogel were evaluated using cell and bacterial models in vitro. A DW model of ICR mice was established to evaluate the effect of the hydrogel on DW healing in vivo. The hydrogel exhibited excellent biocompatibility and remarkable antibacterial, anti-inflammatory, and antioxidant properties. In addition, animal experiments showed that the BSP/BER hydrogel significantly accelerated wound healing in DW mice. Among the different formulations, the LBSP/BER hydrogel (2% BSP, mBER:mBSP = 1:40) demonstrated the most remarkable efficacy. In conclusion, the BSP/BER hydrogel developed exhibited immense properties and great potential as a medical dressing for the repair of DW, addressing a crucial need in clinical practice.

Amygdalin attenuates PM2.5-induced human umbilical vein endothelial cell injury via the TLR4/NF-κB and Bcl-2/Bax signaling pathways.

Mounting evidence supports that long-term exposure to fine particle pollutants (PM2.5) is closely implicated in cardiovascular diseases, especially atherosclerosis. Amygdalin is reported to attenuate external stimuli-induced cardiovascular diseases. However, the underlying mechanisms are still not understood. In this study, we aim to explore the protective effects of amygdalin on PM2.5-induced human umbilical vein endothelial cell (HUVEC) injury and unravel the specific mechanisms by MTT, DCFH-DA, biochemical, immunofluorescence, ELISA, RT-qPCR, flow cytometry, TUNEL and western blot analysis. The results reveal that amygdalin reverses PM2.5-induced cytotoxicity and attenuates intracellular ROS production. Moreover, amygdalin increases the levels of SOD and GSH and alleviates the MDA content. Additionally, amygdalin causes a decline of IL-6, IL-1ß, TNF-α and COX-2 levels. Moreover, amygdalin inhibits NF-κB p50 and TLR4 protein expressions and NF-κB p65 nuclear translocation. Concomitantly, a decline of phospho-NF-κB p65/NF-κB p65 and phospho-IκB-α/IκB-α is detected. Meanwhile, amygdalin pretreatment reduces HUVEC apoptosis. In addition, amygdalin triggers an upregulation of Bcl-2 and a downregulation of Bax after stimulation with PM2.5. Collectively, these results suggest that amygdalin suppresses PM2.5-induced HUVEC injury by regulating the TLR4/NF-κB and Bcl-2/Bax signaling pathways, indicating that amygdalin may be a novel target for atherosclerosis treatments.

Antifouling BaTiO3/PVDF piezoelectric membrane for ultrafiltration of oily bilge water.

Barium titanate/polyvinylidene fluoride (BaTiO3/PVDF) piezoelectric membrane was successfully prepared and generated in-situ vibrations to reduce membrane fouling by applying alternating current (AC) signal for oily bilge water ultrafiltration. The effect of in-situ vibration on membrane fouling was investigated through changing in the excitation alternating voltage and its frequency, pH, crossflow rate. The results indicated that the piezoelectric membrane by applying AC signal remarkably alleviated the membrane fouling for bilge water ultrafiltration. The membrane fouling decreased with increasing the AC signal voltage. The final steady-state permeate flux from the piezoelectric membrane for bilge water ultrafiltration increased with the AC signal voltage, raising it by up to 63.4% at AC signal voltage of 20 V compared to that of the membrane without applying AC voltage. The high permeate flux was obtained at the resonant frequency of 220 kHz. During the 50-h ultrafiltration of bilge water with the piezoelectric membrane excited at 220 kHz and 15 V, the permeate flux from the membrane was stable. The oil concentration in outflow from the piezoelectric membrane was below 14 ppm, which met the discharged level required by IMO convention. The total organic carbon removal rate in bilge water was over 94%.

Association study of a genetic variant in the long intergenic noncoding RNA (linc01080) with schizophrenia in Han Chinese.

BACKGROUND: Schizophrenia is currently considered to be a polygene-related disease with unknown etiology. This research will verify whether the single nucleotide polymorphism (SNP) of the long intergenic noncoding RNA01080 (linc01080) contributes to the susceptibility and phenotypic heterogeneity of schizophrenia, with a view to providing data support for the prevention and individualized treatment of this disease. METHOD: The SNP rs7990916 in linc01080 were genotyped in 1139 schizophrenic and 1039 controls in a Southern Chinese Han population by the improved multiplex ligation detection reaction (imLDR) technique. Meanwhile, we assessed and analyzed the association between this SNP and schizophrenics' clinical symptoms, and the cognitive function. RESULT: There was no significant difference in genotype distribution, allele frequency distribution, gender stratification analysis between the two groups. However, the SNP of rs7990916 was significantly associated with the age of onset in patients with schizophrenia (P = 8.22E-07), patients with T allele had earlier onset age compared with CC genotype carriers. In terms of cognitive function, patients with T allele scored lower than CC genotype carriers in the Tower of London score and symbol coding score in the Brief assessment of Cognition (BACS), and the difference was statistically significant (P = 0.014, P = 0.022, respectively). CONCLUSION: Our data show for the first time that linc01080 polymorphism may affect the age of onset and neurocognitive function in patients with schizophrenia.

Selective termination of the fetus in multiple pregnancies using ultrasound-guided radiofrequency ablation.

BACKGROUND: To evaluate the perinatal outcomes in women with selective termination using ultrasound-guided radiofrequency ablation (RFA). METHODS: Complicated monochorionic (MC) twin pregnancies and multiple pregnancies with an indication for selective termination by ultrasound-guided coagulation of the umbilical cord with RFA under local anesthesia between July 2013 and Jan 2020 were reviewed. We analyzed the indications, gestational age at the time of the procedure, cycles of RFA, duration of the procedure, and perinatal outcome. RESULTS: Three hundred and thirteen patients were treated during this period. Seven of whom were lost of follow-up. The remaining 306 cases, including 266 pairs of monochorionic diamniotic (MCDA) twins (86.93%), two pairs of monoamniotic twins (0.65%), 30 dichorionic triamniotic (DCTA) triplets (1%), and three monochorionic triamniotic (MCTA) triplets (0.98%), were analyzed. Indications included twin-to-twin transfusion syndrome (TTTS) (n = 91), selective fetal growth restriction (sFGR) (n = 83), severe discordant structural malformation (n = 78), multifetal pregnancy reduction (MFPR) (n = 78), twin reverse arterial perfusion sequence (TRAPS) (n = 19), and twin anemia-polycythemia sequence (TAPS) (n = 3). Upon comparison of RFA performed before and after 20 weeks, the co-twin loss rate (20.9% vs. 21.5%), the incidence of preterm premature rupture of membranes (PPROM) within 24 h (1.5% vs. 1.2%), and the median gestational age at delivery [35.93 (28-38) weeks vs. 36 (28.54-38.14) weeks] were similar (p > 0.05). CONCLUSIONS: RFA is a reasonable option when indicated in multiple pregnancies and complicated monochorionic pregnancies. In our experience, the overall survival rate was 78.76% with RFA in selective feticide, and early treatment increases the likelihood of survival for the remaining fetus because the fetal loss rate is similar before and after 20 weeks.

The application of late amniocentesis: a retrospective study in a tertiary fetal medicine center in China.

BACKGROUND: To assess the indications and complications of late amniocentesis and the advanced genetic test results in a tertiary university fetal medical medicine unit. METHODS: In this retrospective study, women that underwent amniocentesis at 24+ 0 to 39+ 4 weeks, between January 2014 and December 2019, were recruited. Indications, complications, genetic test results, and pregnancy outcomes were reported for each pregnancy and compared with those who underwent the traditional amniocentesis at 16+ 0 to 23+ 6 weeks (control group). Information was retrieved from patient medical records, checked by research staff, and analyzed. RESULTS: Of the 1287 women (1321 fetuses) included in the late amniocentesis group, late detected sonographic abnormalities (85.5%) were the most common indication. The overall incidence of preterm birth and intrauterine demise after amniocentesis were 2.5 and 1.3%, respectively. Sixty-nine fetuses with aneuploidy (5.3%) and seventy-two fetuses with pathogenic copy number variations (5.5%) were identified by chromosomal microarray analysis. The maximal diagnostic yield (70%) was in the subgroup of fetuses with the abnormal diagnostic test results, followed by abnormal NIPT results (35.7%) and multiple abnormalities (23.8%). And 35.4% of the pregnancies were finally terminated. CONCLUSIONS: Due to the high detection rates of advanced genetic technologies and the safety of the invasive procedure (3.9% vs 4.0%), it is reasonable to recommend late amniocentesis as an effective and reliable method to detect late-onset fetal abnormalities. However, chromosomal microarray and whole-exome sequencing may result in uncertain results like variants of uncertain significance. Comprehensive genetic counseling is necessary.

Urinary trace elements in association with premature ovarian insufficiency and reproductive hormones in a Chinese population.

Homeostasis disturbance of trace elements has been linked to adverse reproductive consequences, including premature ovarian insufficiency (POI) in women, but limited evidence has been reported so far. This case-control study evaluated the associations between 5 common urinary trace elements [copper (Cu), manganese (Mn), Iron (Fe), Selenium (Se), and zinc (Zn)] and the odds for POI. Urinary concentrations of these 5 metals and serum levels of POI-related reproductive hormones of 169 cases and 209 healthy controls were measured. The urinary levels of Cu and Se in women with POI were significantly higher than those in the controls. The positive associations were observed between Cu levels and the odds of POI [for the medium tertile: odds ratio (OR) = 3.79, 95% CI: 1.98-7.27, p < 0.001; for the highest tertile: OR = 3.85, 95% CI: 2.00-7.41, p < 0.001]. The highest tertile of urinary Se levels was associated with increasing POI risk (for the highest tertile: OR = 2.54, 95% CI: 1.38-4.70, compared with the lowest tertile, p for trend = 0.001). In POI patients, urinary concentrations of Zn and Fe were negatively associated with serum levels of follicle-stimulating hormone (FSH). Our findings suggested that higher exposure levels of Cu and Se might lead to an increased risk of POI.

A Structural Overview of Vascular Endothelial Growth Factors Pharmacological Ligands: From Macromolecules to Designed Peptidomimetics.

The vascular endothelial growth factor (VEGF) family of cytokines plays a key role in vasculogenesis, angiogenesis, and lymphangiogenesis. VEGF-A is the main member of this family, alongside placental growth factor (PlGF), VEGF-B/C/D in mammals, and VEGF-E/F in other organisms. To study the activities of these growth factors under physiological and pathological conditions, resulting in therapeutic applications in cancer and age-related macular degeneration, blocking ligands have been developed. These have mostly been large biomolecules like antibodies. Ligands with high affinities, at least in the nanomolar range, and accurate structural data from X-ray crystallography and NMR spectroscopy have been described. They constitute the main focus of this overview, which evidences similarities and differences in their binding modes. For VEGF-A ligands, and to a limited extent also for PlGF, a transition is now observed towards developing smaller ligands like nanobodies and peptides. These include unnatural amino acids and chemical modifications for designed and improved properties, such as serum stability and greater affinity. However, this review also highlights the scarcity of such small molecular entities and the striking lack of small organic molecule ligands. It also shows the gap between the rather large array of ligands targeting VEGF-A and the general absence of ligands binding other VEGF members, besides some antibodies. Future developments in these directions are expected in the upcoming years, and the study of these growth factors and their promising therapeutic applications will be welcomed.

Urinary cadmium concentrations and risk of primary ovarian insufficiency in women: a case-control study.

Cadmium, a toxic heavy metal that occurs in the environment in large quantities through human activities, has been shown to have adverse effects on female reproductive health. However, the association between cadmium exposure and primary ovarian insufficiency (POI), one of the most prevalent ovarian diseases in women, has not been examined yet. This case-control study involving 169 POI cases and 209 healthy controls was conducted in Zhejiang Province, China. The urinary concentrations of cadmium were determined by inductively coupled plasma mass spectrometry (ICP-MS). In addition, serum levels of reproductive hormones, including follicle-stimulating hormone (FSH), luteinizing hormone (LH), anti-Mullerian hormone (AMH) and estradiol, were measured. The median concentration of urinary cadmium in POI cases (0.43 µg/L, 0.58 µg/g for creatinine adjustment) was significantly higher than that of controls (0.29 µg/L, 0.43 µg/g for creatinine adjustment). The results of binary logistic regression models showed that the concentrations of urinary cadmium were positively significantly correlated with the odds ratio (ORs) of POI before the adjustment of confounders. After the adjustment, a significantly positive association was still present between the increased concentrations of cadmium and the ORs of POI (2.50, 95% CIs: 1.34-4.65 for the third tertile, p for trend = 0.001). The serum levels of FSH and LH were positively associated with urinary cadmium, while AMH and estradiol levels were inversely correlated. To the best of our knowledge, this is the first reported positive association of cadmium exposure with the risk of POI in women.

Exposure to polycyclic aromatic hydrocarbons and risk for premature ovarian failure and reproductive hormones imbalance.

Polycyclic aromatic hydrocarbons (PAHs) are a typical class of persistent organic pollutants that is ubiquitous worldwide. Previous animal studies suggested that PAHs had adverse effects on female reproduction. However, the human data regarding relationship of PAHs exposure with women reproductive health, such as ovarian dysfunction, are scarce. In this case-control study, the associations of serum levels of PAHs with the risk of premature ovarian failure (POF) and reproductive hormones in Chinese women were investigated, with recruiting 157 POF patients and 217 healthy women. The serum levels of 12 types of PAHs, as well as reproductive hormones, including follicle-stimulating hormone, luteinizing hormone and anti-mullerian hormone, were determined. In the logistic regression models, most individual PAH congeners showed significantly positive correlations with the risk of POF (p < 0.05), except for fluorine and pyrene. Benzo(a)pyrene (BaP), as the most carcinogenic PAH congener, was observed to be significantly positively associated with the risk of POF. After adjustment for age, body mass index, educational levels and household income, per one-unit increase in the log-transformed BaP concentration was significantly correlated with 2.191-fold increased risk of POF (OR = 2.191, 95%CI: 1.634-2.938, p < 0.05). To the best of our knowledge, this is the first study to report an association between internal exposure levels of PAHs and the increased risk of POF in women.

Identification and characterization of potent and selective inhibitors targeting protein tyrosine phosphatase 1B (PTP1B).

Protein tyrosine phosphatase 1B (PTP1B) plays an important role in the negative regulation of insulin and leptin signaling. The development of small molecular inhibitors targeting PTP1B has been validated as a potential therapeutic strategy for Type 2 diabetes (T2D). In this work, we have identified a series of compounds containing dihydropyridine thione and particular chiral structure as novel PTP1B inhibitors. Among those, compound 4b showed moderate activity with IC50 value of 3.33 µM and meanwhile with good selectivity (>30-fold) against TCPTP. The further MOA study of PTP1B demonstrated that compounds 4b is a substrate-competitive inhibitor. The binding mode analysis suggested that compound 4b simultaneously occupies the active site and the second phosphotyrosine (pTyr) binding site of PTP1B. Furthermore, the cell viability assay of compound 4b showed tolerable cytotoxicity in L02 cells, thus 4b may be prospectively used to further in vivo study.

The identification of novel small-molecule inhibitors targeting WDR5-MLL1 interaction through fluorescence polarization based high-throughput screening.

The protein-protein interaction between WDR5 (WD40 repeat protein 5) and MLL1 (mixed-lineage leukemia 1) is important for maintaining optimal H3K4 methyltransferase activity of MLL1. Dysregulation of MLL1 catalytic function is relevant to mixed-lineage leukemia, and targeting WDR5-MLL1 interaction could be a promising therapeutic strategy for leukemia harboring MLL1 fusion proteins. To date, several peptidomimetic and non-peptidomimetic small-molecule inhibitors targeting WDR5-MLL1 interaction have been reported, yet the discovery walk of new drugs inhibiting MLL1 methytransferase activity is still in its infancy. It's urgent to find other small-molecule WDR5-MLL1 inhibitors with novel scaffolds. In this study, through fluorescence polarization (FP)-based high throughput screening, several small-molecule inhibitors with potent inhibitory activities in vitro against WDR5-MLL1 interaction were discovered. Nuclear Magnetic Resonance (NMR) assays were carried out to confirm the direct binding between hit compounds and WDR5. Subsequent similarity-based analog searching of the 4 hits led to several inhibitors with better activity, among them, DC_M5_2 displayed highest inhibitory activity with IC50 values of 9.63 ±â€¯1.46 µM. Furthermore, a molecular docking study was performed and disclosed the binding modes and interaction mechanisms between two most potent inhibitors and WDR5.

Identification of Selective, Cell Active Inhibitors of Protein Arginine Methyltransferase 5 through Structure-Based Virtual Screening and Biological Assays.

Protein arginine methyltransferase 5 (PRMT5), a type II PRMT enzyme, is reported as an important therapeutic target in leukemia and lymphoma. In the present study, based on the combination of virtual screening and biochemical validations, we discovered a series of small-molecule inhibitors targeting PRMT5. Among those, DC_Y134 exhibited the most potent activity with IC50 value of 1.7 µM and displayed good selectivity against other methyltransferases. Further treatment with DC_Y134 inhibited the proliferation of several hematological malignancy cell lines by causing cell cycle arrest and apoptosis. Western blot assays indicated that DC_Y134 reduced the cellular symmetrically dimethylated levels. In addition, we analyzed the binding mode of DC_Y134 through molecular docking, which revealed that DC_Y134 occupies the binding site of substrate arginine and explained the selectivity of this inhibitor. Taken together, compound DC_Y134 could be used to elucidate the biological roles of PRMT5 and serve as a lead compound for treatment of hematologic malignancies.

Pyrethroid Pesticide Exposure and Risk of Primary Ovarian Insufficiency in Chinese Women.

Pyrethroids are a class of widely used insecticides. Female animal studies suggested that pyrethroid exposure impaired ovarian function, which resulted in similar symptoms of primary ovarian insufficiency (POI). However, it is still unknown whether this association applies to women. In this case-control study, a total of 172 POI patients and 247 control women were recruited in Zhejiang, China. The urinary concentrations of metabolites of pyrethroids, 3-phenoxybenzoic acid (3-PBA) and 4-fluoro-3-phenoxybenzoic acid (4-F-3-PBA), as well as the serum concentrations of follicle-stimulating hormone (FSH), luteinizing hormone (LH) and anti-Mullerian hormone (AMH) were determined. The associations of pyrethroid metabolites with POI and POI-related hormones were accessed using unconditional logistic regression. Higher urinary levels of 3-PBA were significantly associated with increased risk of POI [adjusted odds ratio (OR) = 2.344, 95% CI: 1.193-4.607 for the highest vs lowest quartile of 3-PBA, p = 0.013]. Stratified analyses showed that each log increase in urinary 3-PBA concentration was significantly associated with an induction in odds of 51.0% being in the highest quartile of FSH and 28.6% being in the highest quartile of LH levels, whereas a 25.9% reduction in odds of being in the highest quartile of AMH levels (All p for trend <0.05). To our knowledge, this is the first case-control study to report an association of pyrethroid exposure with increased risk of POI in women.