Development of a certified reference material for D-phenylalanine with evaluation of enantiomeric purity.

D-Phenylalanine (D-Phe) is a small chiral organic molecule that is both an important pharmaceutical intermediate and used as a calibrator for quantifying amino acids in liquid chromatography-circular dichroism. We have developed a process for a national certified reference material (CRM) for D-Phe following ISO 17034:2016. The identity of D-Phe was confirmed using mass spectrometry (MS) and nuclear magnetic resonance (NMR), infrared, and ultraviolet (UV) spectroscopy. The absolute optical conformation was also determined using circular dichroism (CD) spectroscopy and optical rotation measurements. Impurities were identified via liquid chromatography (LC) with a UV-Vis detector and a charged aerosol detector (CAD) and LC-MS. Both mass balance and quantitative NMR were employed for value assessment, and the associated uncertainty was evaluated. The certified purity was determined to be 0.995 ± 0.003 g/g, a validation that was confirmed by CD using L-Phe CRM as a calibrator. Twenty milligrams of raw material was packed in sealed brown glass tubes for storage, and no inhomogeneity was observed. Stability tests revealed that the D-Phe CRM remained stable at -20 °C for at least 26 months, at 4 °C for at least 14 days, and at 25 °C and 60 °C for at least 7 days. The D-Phe CRM can be used to ensure the accuracy and reliability of D-Phe quantitation in the pharmaceutical field and also as a calibrator to ensure traceability to the International System of Units (SI) for L-Phe quantitation and protein purity analysis using LC-CD methods. The approach outlined in this paper also has potential for use in the development of other chiral CRMs.

Calycosin inhibits the proliferation and metastasis of renal cell carcinoma through the MAZ/HAS2 signaling pathway.

Calycosin (Caly), a flavonoid compound, demonstrates a variety of beneficial properties. However, the specific mechanisms behind Caly's anticancer effects remain largely unexplored. Network pharmacology was used to explore the potential targets of Caly in renal cancer. Additionally, RNA-seq sequencing was used to detect changes in genes in renal cancer cells after Caly treatment. Validation was carried out through quantitative reverse transcription-PCR and Western blot analysis. The luciferase reporter assay was applied to pinpoint the interaction site between MAZ and HAS2. Furthermore, the immunoprecipitation assay was utilized to examine the ubiquitination and degradation of MAZ. In vivo experiments using cell line-derived xenograft mouse models were performed to assess Calycosin's impact on cancer growth. Network pharmacology research suggests Caly plays a role in promoting apoptosis and inhibiting cell adhesion in renal cancer. In vitro, Caly has been observed to suppress proliferation, colony formation, and metastasis of renal cancer cells while also triggering apoptosis. Additionally, it appears to diminish hyaluronic acid synthesis by downregulating HAS2 expression. MAZ is identified as a transcriptional regulator of HAS2 expression. Calycosin further facilitates the degradation of MAZ via the ubiquitin-proteasome pathway. Notably, Caly demonstrates efficacy in reducing the growth of renal cell carcinoma xenograft tumors in vivo. Our findings indicate that Caly suppresses the proliferation, metastasis, and progression of renal cell carcinoma through its action on the MAZ/HAS2 signaling pathway. Thus, Caly represents a promising therapeutic candidate for the treatment of renal cell carcinoma.

ZC3H13-Mediated m6A Modification Ameliorates Acute Myocardial Infarction through Preventing Inflammation, Oxidative Stress and Ferroptosis by Targeting lncRNA93358.

BACKGROUND: Acute myocardial infarction (AMI) is a life-threatening event that is associated with RNA modification and programmed cell death (PCD). This study attempted to investigate the impacts of zinc finger CCCH domain-containing protein 13 (ZC3H13)-mediated N6-methyladenosine (m6A) on ferroptosis in AMI. METHODS: The infarcted areas and cardiac function were evaluated, and the expression level of ZC3H13 was measured in AMI rats that were induced by isoproterenol. Meanwhile, oxygen glucose deprivation (OGD) in vitro model was induced to investigate the alterations on inflammation, oxidative stress and ferroptosis. The m6A modification site of lncRNA93358 modified by ZC3H13 was predicted using bioinformatics, and the interaction between ZC3H13 and lncRNA93358 was verified using the dual-luciferase reporter assays. ZC3H13 was overexpressed and lncRNA93358 was silenced to study their regulatory role in cell death, inflammation, oxidative stress and ferroptosis in AMI. RESULTS: Significant decreased expression of ZC3H13 was observed in AMI rats, with impaired cardiac function, enhanced inflammation and oxidative stress. ZC3H13 targeted the modification site GGACC of lncRNA93358 and downregulated lncRNA93358. Silencing lncRNA93358 inhibited cell death, reduced the levels of inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1ß, suppressed oxidative stress-related indicators (lactate dehydrogenase (LDH), reactive oxygen species (ROS), glutathione (GSH) and malondialdehyde (MDA), as well as downregulated ferroptosis-related acyl-CoA synthetase long chain family member 4 (ACSL4), prostaglandin-endoperoxide synthase 2 (PTGS2) and glutathione peroxidase 4 (GPX4). The effect of silencing lncRNA93358 was further enhanced by overexpression of ZC3H13. CONCLUSION: This study reveals the ZC3H13-mediated epigenetic RNA modification targeting lncRNA93358 and suggests that ZC3H13 overexpression may be a promising approach for AMI treatment.

Electroreductive deuteroarylation of alkenes enabled by an organo-mediator.

Electroreduction mediated by organo-mediators has emerged as a concise and effective strategy, holding significant potential in the site-specific introduction of deuterium. In this study, we present an environmentally friendly electroreduction approach for anti-Markovnikov selective deuteroarylation of alkenes and aryl iodides with D2O as the deuterium source. The key to the protocol lies in the employment of a catalytic amount of 2,2'-bipyiridine as an efficient organo-mediator, which facilitates the generation of aryl radicals by assisting in the cleavage of the C-X (X = I or Br) bonds in aryl halides. Because its reduction potential matches that of aryl iodides, the organo-mediator can control the chemoselectivity of the reaction and avoid the side reactions of competitive substrate deuteration. These phenomena are theoretically supported by CV experiments and DFT calculations. Our protocol provides a series of mono-deuterated alkylarenes with excellent deuterium incorporation through two single-electron reductions (SER), without requiring metal catalysts, external reductants, and sacrificial anodes.

Gestational organophosphate esters (OPEs) exposure in association with placental DNA methylation levels of peroxisome proliferator-activated receptors (PPARs) signaling pathway-related genes.

BACKGROUND: Organophosphate esters (OPEs) exposure could affect offspring health. However, the underlying mechanisms are not well documented. OBJECTIVES: Based on a birth cohort study, we aimed to investigate the associations among gestational OPEs exposure, placental DNA methylation levels of peroxisome proliferator-activated receptor (PPAR) signaling pathway-related genes, and fetal growth. METHODS: We measured the concentrations of eight OPE metabolites in maternal urine samples and neonatal anthropometric measurements in 733 mother-child pairs. In 327 placental samples, we assessed the DNA methylation levels of 14 genes which were involved in the PPARs signaling pathway and expressed in placenta. Multiple linear regression models were used to examine the associations of OPEs exposure with placental DNA methylation, and of OPEs and placental DNA methylation with neonatal anthropometric measurements. Causal mediation analyses were conducted to examine the potential mediating role of placental DNA methylation in the pathway between OPEs exposure and fetal growth. RESULTS: We observed a general pattern of OPEs exposure being associated with hypermethylation of candidate genes, with statistically significant associations identified for several OPEs with RXRA, ACAA1, ACADL, ACADM, PLTP, and NR1H3 methylation. Further, gestational exposure to BCIPP, DPP, BBOEP, ∑NCl-OPEs, and ∑OPEs tended to be associated with lower anthropometric measurements, with more significant associations observed on arm circumference, and abdominal and back skinfold thickness. Notably, RXRA, ACAA1, ACOX1, CPT2, ACADM, and NR1H3 methylation tended to be associated with lower neonatal anthropometric measurements, especially for abdominal and back skinfold thickness. Moreover, mediation analyses showed that 19.42 % of the total effect of DPP on the back skinfold thickness was mediated by changes in RXRA methylation, and there was a significant indirect effect of RXRA methylation. CONCLUSIONS: Gestational OPEs exposure could disrupt the placental DNA methylation levels of PPAR signaling pathway-related genes, which might contribute to the effect of OPEs on fetal growth.

A Strategy for Anode Recovery and Upgrading by In Situ Growth of Iron-Based Oxides on Microwave-Puffed Graphite.

Faced with the increasing volume of retired lithium-ion batteries (LIBs), recycling and reusing the spent graphite (SG) is of great significance for resource sustainability. Here, a facile method for transforming the SG into a carbon framework as well as loading Fe2O3 to form a composite anode with a sandwich structure is proposed. Taking advantage of the fact that the layer spacing of the spent graphite naturally expands, impurities and intercalants are eliminated through microwave thermal shock to produce microwave-puffed graphite (MPG) with a distinct three-dimensional structure. Based on the mechanism of microwave-induced gasification intercalation, a Fe2O3-MPG intercalation compound (Fe2O3-MPGIC) anode material was constructed by introducing iron precursors between the framework layers and subsequently converting them into Fe2O3 through annealing. The Fe2O3-MPGIC anode exhibits a high reversible capacity of 1000.6 mAh g-1 at 200 mA g-1 after 100 cycles and a good cycling stability of 504.4 mAh g-1 at 2000 mA g-1 after 500 cycles. This work can provide a reference for the feasible recycling of SG and development of high-performance anode materials for LIBs.

Machine Learning-based Framework Develops a Tumor Thrombus Coagulation Signature in Multicenter Cohorts for Renal Cancer.

Background: Renal cell carcinoma (RCC) is frequently accompanied by tumor thrombus in the venous system with an extremely dismal prognosis. The current Tumor Node Metastasis (TNM) stage and Mayo clinical classification do not appropriately identify preference-sensitive treatment. Therefore, there is an urgent need to develop a better ideal model for precision medicine. Methods: In this study, we developed a coagulation tumor thrombus signature for RCC with 10 machine-learning algorithms (101 combinations) based on a novel computational framework using multiple independent cohorts. Results: The established tumor thrombus coagulation-related risk stratification (TTCRRS) signature comprises 10 prognostic coagulation-related genes (CRGs). This signature could predict survival outcomes in public and in-house protein cohorts and showed high performance compared to 129 published signatures. Additionally, the TTCRRS signature was significantly related to some immune landscapes, immunotherapy response, and chemotherapy. Furthermore, we also screened out hub genes, transcription factors, and small compounds based on the TTCRRS signature. Meanwhile, CYP51A1 can regulate the proliferation and migration properties of RCC. Conclusions: The TTCRRS signature can complement the traditional anatomic TNM staging system and Mayo clinical stratification and provide clinicians with more therapeutic options.

The Role of Placental DNA Methylation at Reproduction-Related Genes in Associations between Prenatal Bisphenol Analogues Exposure and the Digit Ratio in Children at Age 4: A Birth Cohort Study.

Placental DNA methylation (DNAm) may be a potential mechanism underlying the effects of prenatal bisphenol analogues (BPs) exposure on reproductive health. Based on the Shanghai-Minhang Birth Cohort Study (S-MBCS), this study investigated associations of placental DNAm at reproduction-related genes with prenatal BPs exposure and children's digit ratios at age 4 using multiple linear regression models, and mediation analysis was further used to examine the mediating role of placental DNAm in the associations between prenatal BPs exposure and digit ratios among 345 mother-child pairs. Prenatal exposure to bisphenol A (BPA) was associated with hypermethylation at Protocadherin 8 (PCDH8), RBMX Like 2 (RBMXL2), and Sperm Acrosome Associated 1 (SPACA1), while bisphenol F (BPF) exposure was associated with higher methylation levels of Fibroblast Growth Factor 13 (FGF13). Consistent patterns were found in associations between higher DNAm at the 4 genes and increased digit ratios. Further mediation analysis showed that about 15% of the effect of BPF exposure on increased digit ratios was mediated by placental FGF13 methylation. In conclusion, the altered placental DNAm status might be a mediator underlying the feminizing effect of prenatal BPs exposure.

Effect of Drug-Coated Balloon Versus Stent Angioplasty in Patients With Symptomatic Intracranial Atherosclerotic Stenosis.

BACKGROUND AND OBJECTIVES: Drug-coated balloons (DCBs) have exhibited promising results in coronary and peripheral artery diseases, but conclusive evidence is lacking in intracranial vasculature. We assessed the safety and efficacy of DCBs vs stent angioplasty for symptomatic intracranial atherosclerotic stenosis (sICAS) and initially identified patients who might have benefited most from DCB treatment. METHODS: A single-center, retrospective cohort study was conducted from June 2021 to May 2022 with 154 patients with sICAS divided into 2 treatment groups: a DCB group (with or without remedial stenting, n = 47) and a stent group (n = 107). The treatment outcomes were compared using 1:2 propensity score matching. The primary safety end point was perioperative stroke or mortality, and the primary efficacy end point was the rate of target vessel restenosis at 12 months. The degree of luminal change was analyzed as a subgroup, defined as the difference between the degree of stenosis at follow-up and immediately after intervention. RESULTS: One hundred eighteen patients were enrolled using propensity score matching, with 43 patients in the DCB group and 75 in the stent group. The incidence of perioperative adverse events was 2.3% in the DCB group and 8.0% in the stent group (P = .420). At a median follow-up of 12 months, the incidence of restenosis (11.9% [5/43] vs 28.0% [21/75], P = .045) and the median degree of stenosis (30% [20%, 44%] vs 30% [30%, 70%], P = .009, CI [0-0.01, 0.2]) were significantly lower in the DCB group than in the stent group. DCB angioplasty effectively prevented adverse events in the target vessel area and significantly reduced the degree of luminal change in the M1 segment of the middle cerebral artery (0 [0, 15%] vs 10% [0, 50%], P = .016). CONCLUSION: DCB angioplasty might be a safe and effective alternative to stent angioplasty to treat sICAS, particularly among patients with M1 segment of the middle cerebral artery stenosis.

Paris saponin VII reverses resistance to PARP inhibitors by regulating ovarian cancer tumor angiogenesis and glycolysis through the RORα/ECM1/VEGFR2 signaling axis.

The emergence of Poly (ADP-ribose) polymerase inhibitors (PARPi) has marked the beginning of a precise targeted therapy era for ovarian cancer. However, an increasing number of patients are experiencing primary or acquired resistance to PARPi, severely limiting its clinical application. Deciphering the underlying mechanisms of PARPi resistance and discovering new therapeutic targets is an urgent and critical issue to address. In this study, we observed a close correlation between glycolysis, tumor angiogenesis, and PARPi resistance in ovarian cancer. Furthermore, we discovered that the natural compound Paris saponin VII (PS VII) partially reversed PARPi resistance in ovarian cancer and demonstrated synergistic therapeutic effects when combined with PARPi. Additionally, we found that PS VII potentially hindered glycolysis and angiogenesis in PARPi-resistant ovarian cancer cells by binding and stabilizing the expression of RORα, thus further inhibiting ECM1 and interfering with the VEGFR2/FAK/AKT/GSK3ß signaling pathway. Our research provides new targeted treatment for clinical ovarian cancer therapy and brings new hope to patients with PARPi-resistant ovarian cancer, effectively expanding the application of PARPi in clinical treatment.

Associations of prenatal exposure to bisphenols with infant anthropometry: A prospective cohort study.

BACKGROUND: Bisphenols (BPs) have been shown to exhibit developmental toxicities. Epidemiological evidence on prenatal BPs exposure and infant growth primarily confined scopes to specific BPs and birth outcomes, with few studies focusing on infant growth and reporting inconsistent findings. The joint effect of prenatal exposure to BPs mixture on infant growth was rarely studied. OBJECTIVE: This study examined associations of prenatal exposure to individual bisphenol A (BPA) and its analogues (bisphenol F [BPF], bisphenol S [BPS], bisphenol AF [BPAF], and tetrachlorobisphenol A [TCBPA]) and their mixture with infant growth. METHODS: Urinary concentrations of BPs in pregnant women were quantified. Weight, body mass index, skinfold thickness, and circumference measurements of infants were collected at birth, 6 and 12 months of age, rapid growth and overweight were further defined. Multiple linear regression models and Bayesian kernel machine regression models (BKMR) were used to analyze associations of exposure to individual BPs and BPs mixture with infants' anthropometric measurements, and to identify the important components among mixture. The risks for rapid growth and overweight of each BP were determined using modified Poisson regression models. RESULTS: A general profile of higher prenatal BPs exposure (mainly BPA, BPF, and BPS) associated with higher anthropometric measurements and higher risks of overweight during infancy was found. We also observed higher risks of rapid growth in infants following prenatal BPs exposure, with risk ratios ranging from 1.46 to 1.91. The joint effect of BPs mixture and single effect of each BP from the BKMR models were consistent with findings from the linear regression models, further suggesting that associations in girls were generally driven by BPA, BPF, or BPS, while in boys mainly by BPF. CONCLUSION: Prenatal exposure to BPs and their mixture could increase anthropometric measurements of offspring during infancy, with implications of altered growth trajectory in future.

Use of the Tubridge flow diverter in the treatment of intracranial aneurysms: a single center experience.

To investigate the safety and effect of Tubridge flow diverter deployment for the treatment of intracranial aneurysms, 85 patients with intracranial aneurysms treated with the Tubridge flow diverter were retrospectively enrolled. The clinical data including the baseline data, aneurysm parameters before and after treatment, and follow-up outcomes were assessed. Among 85 patients, there were 35 (41.2%) males and 50 females (58.8%) aged 17-77 (mean 56.7 ± 11.1) years with 110 aneurysms. Five (5.9%) patients initially presented with subarachnoid hemorrhage from aneurysm rupture. The aneurysm size was 2-30 (mean 8.6) mm, and the aneurysm neck was 2-10.6 (mean 5.7 ± 2.3) mm. Ninety-three Tubridge stents were deployed. Twenty-five (29.4%) patients experienced adjunctive loose coiling. Blood flow was significantly reduced from entering the aneurysm after stent deployment. Periprocedural complications occurred in three (3.5%) patients, including in-stent thrombosis during embolization in one patient (1.2%), conjunctiva edema on the right in one patient (1.2%), and acute multiple cerebral infarctions in one patient (1.2%). Angiographic follow-up was conducted in 67 (78.8%) patients 3-36 (mean 15.3 ± 5.6) months later. In 11 (16.4% or 11/67) patients, blood flow still entered the aneurysm with the O'Kelly-Marotta (OKM) grade B in two (3.0%) patients and grade C in nine (13.4%), whereas complete occlusion (OKM grade D) was achieved in the other 56 (83.6% or 56/67) aneurysms. In-stent stenosis was present in five (7.5%) patients with approximately 25% stenosis in three (4.5%) patients and 50% in two (3.0%). In conclusion, the Tubridge flow diverter can be safely and efficiently applied in the treatment of small and large intracranial aneurysms, with a low periprocedural complication rate, a high occlusion degree, and a low in-stent stenosis rate at follow-up even though large aneurysms may necessitate a longer surgical time and adjunctive coiling.

Electrochemically Driven para-Selective C(sp2)-H Alkylation Enabled by Activation of Alkyl Halides without Sacrificial Anodes.

With alkyl halides (I, Br, Cl) as a coupling partner, an electrochemically driven strategy for para-selective C(sp2)-H alkylation of electron-deficient arenes (aryl esters, aldehydes, nitriles, and ketones) has been achieved to access diverse alkylated arenes in one step. The reaction enables the activation of alkyl halides in the absence of sacrificial anodes, achieving the formation of C(sp2)-C(sp3) bonds under mild electrolytic conditions. The utility of this protocol is reflected in high site selectivity, broad substrate scope, and scalable.

Associations between maternal urinary kisspeptin in late pregnancy and decreased fetal growth: a pregnancy-birth cohort study.

Background: Kisspeptin has been indicated to be a biomarker of fetal growth. Although some evidence suggested that maternal kisspeptin concentrations in early pregnancy were associated with increased fetal growth, studies are still limited and the effect of kisspeptin in late pregnancy remains unknown. This study aimed to investigate the associations between maternal kisspeptin in late pregnancy and fetal growth. Methods: Based on the Shanghai-Minhang Birth Cohort study, 724 mother-neonate pairs were included in this study. We measured maternal kisspeptin concentrations in the urine samples collected in late pregnancy and neonatal anthropometric indices at birth. The associations between maternal kisspeptin and neonatal anthropometry were investigated using multiple linear regression models. Results: Higher maternal urinary kisspeptin concentrations were associated with lower neonatal birth weight, head circumference, upper arm circumference, abdominal skinfold thickness, triceps skinfold thickness, and back skinfold thickness. The inverse associations were more pronounced for the highest kisspeptin levels versus the lowest. These patterns were consistent in analyses stratified by neonatal sex, with notably stable associations between maternal kisspeptin concentrations and skinfold thickness. Conclusion: The present study suggested that maternal kisspeptin concentrations in late pregnancy might be inversely associated with fetal growth. The physiological mechanisms of maternal kisspeptin might differ from those in early pregnancy. Further studies are required to assess associations between maternal kisspeptin and energy homeostasis and explore the physiological roles of kisspeptin in late pregnancy.

Association between prenatal exposure to per- and polyfluoroalkyl substances and infant anthropometry: A prospective cohort study.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are a group of synthetic organic chemicals with potential endocrine-disrupting effects, and have been found to impair the physical growth of offspring in both experimental and epidemiological studies. We aimed to investigate the effects of prenatal PFAS exposure on repeated measurements of multiple anthropometric indicators in infants. METHOD: PFAS were measured in serum samples collected from pregnant women at 12-16 gestational weeks. We calculated z-scores for the weight-for-age (WAZ), weight-for-length (WLZ), head circumference-for-age (HCZ), arm circumference-for-age (ACZ), triceps skinfold-for-age (TSZ), and subscapular skinfold-for-age (SSZ) at birth, 6 months, and 12 months of age according to the child growth standards of the World Health Organization (WHO) for anthropometric indicators. A total of 964 mother-infant pairs were included. A multivariate linear regression was performed to examine the associations between prenatal PFAS concentrations and anthropometric indicators at each time point. A generalized estimating equation (GEE) model was used to examine the longitudinal effects of PFAS exposure on repeated measurements of anthropometric indicators. Ultimately, a Bayesian kernel machine regression (BKMR) model was used to assess the joint effects of the PFAS mixture on anthropometric indicators. RESULTS: In GEE models, perfluorododecanoic acid (PFDoA) in the high tertile group was associated with increased WAZ/WLZ, with ß values (95% confidence intervals (CI)) of 0.12 (0.00, 0.23) and 0.18 (0.03, 0.32), respectively. Perfluorononanoic acid (PFNA) was associated with increased ACZ in the middle and high tertile groups. The BKMR models also presented the associations of the PFAS mixture with increased WAZ/WLZ throughout infancy, with more profound effects in females. Meanwhile, a pattern of inverse associations was observed between the perfluorooctanoic acid (PFOA) concentrations in the high tertile group and decreased WAZ, WLZ, and HCZ in males. In addition, the associations between PFAS and increased TSZ/SSZ at birth were identified by both linear regression and BKMR models. CONCLUSION: Prenatal PFAS exposure (PFNA and PFDoA) was associated with increased infant anthropometry, especially in female infants, while prenatal PFOA exposure was associated with decreased weight, and head and arm circumference in male infants. The findings indicate that prenatal PFAS exposure may impair the growth trajectory of offspring.

Effects and safety of endovascular recanalization for non-acute symptomatic intracranial vertebral artery occlusion with different risks.

There is no consensus on the optimal treatment for non-acute symptomatic intracranial vertebral artery occlusion, and endovascular recanalization is a challenging procedure. We report our clinical experience of endovascular recanalization in patients with non-acute symptomatic intracranial vertebral artery occlusion to assess the feasibility and safety of endovascular recanalization and determine the candidate patients for this procedure. Ninety-two patients with non-acute symptomatic intracranial vertebral artery occlusion who underwent endovascular recanalization from January 2019 to December 2021 were retrospectively analyzed. we grouped all patients according to imaging examination findings, occlusion length, duration, nature, calcification, and angulation to evaluate the risk of endovascular recanalization. The overall success rate of endovascular recanalization was 83.7% (77/92), and the perioperative complication rate was 10.9% (10/92). Among the 3 classification groups, the recanalization success rate gradually decreased from the low-risk group to the high-risk group (low-risk: 100%, medium-risk: 93.3%, high-risk group: 27.8%, P = .047), while the overall perioperative complication rate showed the opposite trend (0%, 10.0%, 38.9%, respectively, P = .001); the proportion of patients with 90-day modified Rankin Scale scores of 0-2 decreased successively (100%, 83.3%, and 22.2%, respectively, P < .026); 77 patients with successful recanalization were followed; the rate of restenosis/reocclusion increased sequentially (0%, 17.9%, and 80%, respectively, P = .000). Patients in the low- and medium-risk groups showed a good clinical course after endovascular recanalization. Among 88 patients (four patients lost to follow-up), with a median clinical follow-up of 13 months (interquartile range », 7-16), the rate of stroke or death after 30 days was 17.4% (16/92). Endovascular recanalization is safe and feasible for low- and medium-risk patients with non-acute symptomatic intracranial vertebral artery occlusion; it is also an alternative to conservative therapy for the patients.

Liraglutide Reduces Alcohol Consumption, Anxiety, Memory Impairment, and Synapse Loss in Alcohol Dependent Mice.

Glucagon-like peptide 1 (GLP-1) analogues have been commercialized for the management of type 2 diabetes. Recent studies have underscored GLP-1's role as a modulator of alcohol-related behavior. However, the role of the GLP-1 analogue liraglutide on alcohol-withdrawal responses have not been fully elucidated. Liraglutide binds to the G-protein-coupled receptor and activates an adenylyl cyclase and the associated classic growth factor signaling pathway, which acts growth factor-like and neuroprotective properties. The underlying neurobiological mechanisms of liraglutide on alcohol withdrawal remains unknown. This study endeavored to explore the effects of liraglutide on the emotion and memory ability of alcohol-withdrawal mice, and synaptic morphology in the medial prefrontal cortex (mPFC) and the hippocampus (HP), and thus affects the relapse-like drinking of alcohol-withdrawal mice. The alcohol-withdrawal group was reintroduced to a 20% v/v alcohol and water through the two-bottle choice for four consecutive days, a period referred to as alcohol re-drinking. Male C57BL/6J mice were exposed to a regimen of 20% alcohol and water for a duration of 6 weeks. This regimen established the two-bottle choice model of alcohol exposure. Learning capabilities, memory proficiency, and anxiety-like behavior were evaluated using the Morris water maze, open field, and elevated plus maze paradigms. Furthermore, synaptic morphology and the levels of synaptic transport-related proteins were assessed via Golgi staining and Western Blot analysis after a two-week alcohol deprivation period. Alcohol re-drinking of alcohol-withdrawal mice was also evaluated using a two-bottle choice paradigm. Our findings indicate that liraglutide can substantially decrease alcohol consumption and preference (p < 0.05) in the alcohol group and enhance learning and memory performance (p < 0.01), as well as alleviate anxiety-like behavior (p < 0.01) of alcohol-withdrawal mice. Alcohol consumption led to a reduction in dendritic spine density in the mPFC and HP, which was restored to normal levels by liraglutide (p < 0.001). Furthermore, liraglutide was found to augment the levels of synaptic transport-related proteins in mice subjected to alcohol withdrawal (p < 0.01). The study findings corroborate that liraglutide has the potential to mitigate alcohol consumption and ameliorate the memory impairments and anxiety induced by alcohol withdrawal. The therapeutic efficacy of liraglutide might be attributed to its role in counteracting synapse loss in the mPFC and HP regions and thus prevented relapse-like drinking in alcohol-withdrawal mice.

The antinociceptive and anti-alpha-glucosidase effects of glucosides from Hemiphragma heterophyllum Wall.

Hemiphragma heterophyllum Wall. is commonly used in traditional Yi herbal medicine for treating bellyache and toothache. In the current study, an unreported monoterpene glucoside, (S)-thymoquinol O-(6-O-oleuropeoyl)-ß-d-glucopyranoside (1), together with 11 known glucosides were obtained from the whole herb of H. heterophyllum. Their structures were determined based on a detailed analysis of spectroscopic data and acid hydrolysis and methanolysis reactions. Bioassay results showed that compounds 1 and 10 at 40 mg/kg exhibited significant antinociceptive activity in the acetic acid-induced writhing model, with inhibitions of 59.80% and 64.07%, respectively. Moreover, five of the isolates showed moderate anti-α-glucosidase activities with IC50 values ranging from 5.67 to 46.16 µM.

Ventral tegmental area dopaminergic circuits participates in stress-induced chronic postsurgical pain in male mice.

BACKGROUND: Chronic postsurgical pain (CPP) markedly impairs patients' quality of life. Research has shown that chronic stress may extend incisional nociception in male mice. Dopaminergic (DAergic) neurons in the ventral tegmental area (VTA) are integral to stress-related mental disorders (including major depressive disorder, anxiety disorders, and PTSD) and pain. However, the impact of chronic social defeat stress (CSDS) on mesolimbic dopamine (DA) transmission in the development of CPP is yet to be established. It remains uncertain whether the dopamine signals in the rostral anterior cingulate cortex (rACC), which regulate pain, derive from the VTA. This study aims to explore the role of VTA-rACC dopaminergic circuits in a mouse model of CPP induced by CSDS. METHODS: We conducted CSDS on C57BL/6 J wild-type male mice (n = 12-16 mice/group) and DAT-cre male mice (n = 10-12 mice/group). After 10 days of CSDS, a left posterior plantar incision was made to establish a mouse model of CPP. Paw withdrawal thresholds (PWTs) were evaluated using Von-Frey fibre stimulation. The open field test (OFT) and elevated plus maze test (EPM) were used to assess pain-related negative emotions. We used immunofluorescence staining and Western Blot to analyse D1, D2, c-Fos, and TH expression. DAergic fibre projections in the VTA-rACC neural pathway were traced using retrograde tracing and immunofluorescence staining. Optogenetics and Chemogenetics were employed to manipulate DAergic neurons in the VTA and their axons in the rACC. RESULTS: The ipsilateral PWTs in male C57BL/6 J mice significantly decreased after surgery, returning to baseline after seven days. Conversely, in CSDS mice, ipsilateral PWTs remained reduced for at least 30 days post-incision. A significant reduction in TH-positive neurons expressing c-Fos in the VTA of CPP mice was observed 15 days post-incision. Activating DAergic neurons significantly improved ipsilateral PWTs and locomotor performance in the OFT and EPM in CPP mice post-incision. Additionally, D1 expression in the rACC was found to decrease in CPP mice, and this reduction counteracted the increase in PWTs caused by activating DAergic neuron axon terminals in the rACC. CONCLUSION: CSDS results in chronicity of postsurgical nociception and anxiety-like negative emotions, with alterations in DA transmission playing a role in CPP. Specific activation of DAergic neurons mitigates nociceptive responses and anxiety-like bahaviors, possibly mediated by D1 receptors in the rACC.

KIRREL promotes the proliferation of gastric cancer cells and angiogenesis through the PI3K/AKT/mTOR pathway.

Anti-angiogenesis is a promising therapeutic strategy for delaying tumour progression that offers, new hope for gastric cancer targeted therapy. The purpose of this study was to investigate the precise mechanism by which Kin of IRRE-like protein 1 (KIRREL) contributes to the development of gastric cancer, particularly in terms of tumour angiogenesis. Differential expression of KIRREL in tissues and cells was detected using quantitative real-time polymerase chain reaction, western blotting and immunohistochemistry. A bioinformatics analysis was conducted to screen for the function and pathway enrichment of KIRREL in gastric cancer. Lentivirus-induced KIRREL silencing in SNU-5 cells and lentivirus-induced KIRREL overexpression in AGS cells were used to study the effect of KIRREL on the proliferation, cell cycle and angiogenesis of gastric cancer cells. Moreover, the expressions of PI3K, P-PI3K, AKT, P-AKT, mTOR, P-mTOR, HIF-1α and VEGF were also detected. Gastric cancer tissues and cells had high levels of KIRREL expression, which is associated with the proliferation, cell cycle and angiogenesis of gastric cancer cells. After silencing and overexpressing KIRREL in SNU-5 and AGS cells, respectively, the proliferation and angiogenesis of SNU-5 cells were inhibited, while the proliferation and angiogenesis of AGS cells were promoted. According to a bioinformatics analysis of the KIRREL gene, angiogenesis regulation and the PI3K/AKT pathway were highly connected. The PI3K/AKT/mTOR pathway was repressed and stimulated by KIRREL silencing and overexpression, respectively. IGF-1, an AKT agonist, and LY294002, an inhibitor, reversed the effects of KIRREL silencing and overexpression on the PI3K/AKT/mTOR pathway and on gastric cancer cell proliferation and angiogenesis. KIRREL may mediate the proliferation and angiogenesis of gastric cancer cells through the PI3K/AKT/mTOR signalling pathway. These findings could help in the further development of potential anti-angiogenesis targets.