Esketamine induces apoptosis of nasopharyngeal carcinoma cells through the PERK/CHOP pathway.

Nasopharyngeal carcinoma, a malignant tumor prevalent in southeast Asia and north Africa, still lacks effective treatment. Esketamine, an N-methyl-D-aspartatic acid (NMDA) receptor (NMDAR) antagonist, is widely used in clinical anesthesia. Emerging evidence suggests that esketamine plays an important role in inhibiting tumor cell activity. However, the underlying mechanisms of esketamine on nasopharyngeal carcinoma remain unknown. In this study, we found that esketamine inhibited the proliferation and migration of nasopharyngeal carcinoma cells. Mechanically, transcriptome sequencing and subsequent verification experiments revealed that esketamine promoted the apoptosis of nasopharyngeal carcinoma cells through endoplasmic reticulum stress PERK/ATF4/CHOP signaling pathway mediated by NMDAR. Additionally, when combined with esketamine, the inhibitory effect of cisplatin on the proliferation of nasopharyngeal carcinoma cells was significantly enhanced. These findings provide new insights into future anti-nasopharyngeal carcinoma clinical strategies via targeting the NMDAR/PERK/CHOP axis alone or in combination with cisplatin.

Cyano Decoration of π-Bridge to Boost Photoluminescence and Electroluminescence Quantum Yields of Triazine/Carbazole Based Blue TADF Emitter.

In general, a large donor-acceptor dihedral angle is required to guarantee sufficient frontier molecular orbitals separation for thermally activated delayed fluorescence (TADF) emitters, which is intrinsically unfavorable for the radiative transition. We present a molecular design method favoring both reverse intersystem crossing (RISC) and radiative transitions even at a moderate D-A angle. A blue TADF emitter TrzBuCz-CN was designed with triazine/tert-butylcarbazole as donor/acceptor and cyano (CN) incorporated on the phenylene bridge. In comparison with the methyl decoration in similar way (TrzBuCz-Me), CN decoration reduced the D-A dihedral angle from 70° to 60°, which is intrinsically not favorable for sufficient FMO separation, but unexpectedly reduced the singlet and triplet energy gap (ΔEST ) and thus facilitated TADF feature by pulling down the lowest singlet state energy. While the reduced distorsion instead improved the HOMO-LUMO overlap and boosted the fluorescence quantum yield from 41 % to 94 %. The blue organic light-emitting diode of TrzBuCz-CN exhibited an external quantum efficiency of 13.7 % with emission peak at 466 nm, greatly superior to 6.0 % of TrzBuCz-Me. The result provides a feasible design strategy to facilitate both RISC and radiation processes by CN decoration of the linking bridge of TADF emitters.

Effects of an intraoperative intravenous Bolus Dose of Dexmedetomidine on postoperative catheter-related bladder discomfort in male patients undergoing transurethral resection of bladder tumors: a randomized, double-blind, controlled trial.

PURPOSE: To investigate whether the effect of intravenous bolus doses of dexmedetomidine on postoperative catheter-related bladder discomfort (CRBD) was dose-dependent in male patients undergoing transurethral resection of bladder tumors (TURBT). METHODS: The study protocol was registered at the Chinese Clinical Trial Registry (ChiCTR 2,000,034,657, date of registration: July 14, 2020). Adult male patients were randomized to one of four groups: placebo (Group C); dexmedetomidine 0.2 µg/kg (Group D 0.2); dexmedetomidine 0.5 µg/kg (Group D 0.5); or dexmedetomidine 1 µg/kg (Group D 1). The primary outcome was the incidence of moderate-to-severe CRBD at 0, 1, 6, 24, and 48 h postoperatively. RESULTS: The incidence of moderate-to-severe CRBD was significantly lower in Group D 0.5 and Group D 1 than in Group C at 0 h (13% vs. 40%, P = 0.006; 8% vs. 40%, P = 0.001), 1 h (15% vs. 53%, P < 0.001; 13% vs. 53%, P < 0.001), and 6 h (10% vs. 32%, P = 0.025; 8% vs. 32%, P = 0.009) postoperatively. Compared with baseline, both the MAP and HR were significantly lower in Group D 1 at 1 min ([94 ± 15] vs. [104 ± 13] mm Hg, P = 0.003; [64 ± 13] vs. [73 ± 13] bpm, P = 0.001) and 30 min ([93 ± 10] vs. [104 ± 13] mm Hg, P < 0.001; [58 ± 9] vs. [73 ± 13] bpm, P < 0.001) postextubation. CONCLUSION: The effect of intravenous bolus doses of dexmedetomidine on postoperative CRBD was dose-independent, whereas intravenous administration of 0.5 µg/kg dexmedetomidine reduced the early postoperative incidence of CRBD with minimal side effects. TRIAL REGISTRATION: Clinical trial number and registry URL: ChiCTR 2,000,034,657, http://www.chictr.org.cn , date of registration: July 14, 2020.

Sleep-disordered breathing and nocturnal hypoxemia in chronic thromboembolic pulmonary disease.

BACKGROUND AND AIMS: Sleep-disordered breathing (SDB) and nocturnal hypoxemia were known to be present in patients with chronic thromboembolic pulmonary hypertension (CTEPH), but the difference between SDB and nocturnal hypoxemia in patients who have chronic thromboembolic pulmonary disease (CTEPD) with or without pulmonary hypertension (PH) at rest remains unknown. METHODS: Patients who had CTEPH (n = 80) or CTEPD without PH (n = 40) and who had undergone sleep studies from July 2020 to October 2022 at Shanghai Pulmonary Hospital were enrolled. Nocturnal mean SpO2 (Mean SpO2) <90% was defined as nocturnal hypoxemia, and the percentage of time with a saturation below 90% (T90%) exceeding 10% was used to evaluate the severity of nocturnal hypoxemia. Logistic and linear regression analyses were performed to investigate the difference and potential predictor of SDB or nocturnal hypoxemia between CTEPH and CTEPD without PH. RESULTS: SDB was similarly prevalent in CTEPH and CTEPD without PH (P = 0.104), both characterised by obstructive sleep apnoea (OSA). Twenty-two patients with CTEPH were diagnosed with nocturnal hypoxemia, whereas only three were diagnosed with CTEPD without PH (P = 0.021). T90% was positively associated with mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance in patients with CTEPH and CTEPD without PH (P < 0.001); T90% was also negatively related to cardiac output in these patients. Single-breath carbon monoxide diffusing capacity, sex and mPAP were all correlated with nocturnal hypoxemia in CTEPH and CTEPD without PH (all P < 0.05). CONCLUSION: Nocturnal hypoxemia was worse in CTEPD with PH; T90%, but not SDB, was independently correlated with the hemodynamics in CTEPD with or without PH.

Traditional Uses, Chemical Constituents and Pharmacological Activities of the Toona sinensis Plant.

Toona sinensis (A. Juss.) Roem., which is widely distributed in China, is a homologous plant resource of medicine and food. The leaves, seeds, barks, buds and pericarps of T. sinensis can be used as medicine with traditional efficacy. Due to its extensive use in traditional medicine in the ancient world, the T. sinensis plant has significant development potential. In this review, 206 compounds, including triterpenoids (1-133), sesquiterpenoids (134-135), diterpenoids (136-142), sterols (143-147), phenols (148-167), flavonoids (168-186), phenylpropanoids (187-192) and others (193-206), are isolated from the T. sinensis plant. The mass spectrum cracking laws of representative compounds (64, 128, 129, 154-156, 175, 177, 179 and 183) are reviewed, which are conducive to the discovery of novel active substances. Modern pharmacological studies have shown that T. sinensis extracts and their compounds have antidiabetic, antidiabetic nephropathy, antioxidant, anti-inflammatory, antitumor, hepatoprotective, antiviral, antibacterial, immunopotentiation and other biological activities. The traditional uses, chemical constituents, compound cracking laws and pharmacological activities of different parts of T. sinensis are reviewed, laying the foundation for improving the development and utilization of its medicinal value.

Study on Design, Synthesis and Herbicidal Activity of Novel 6-Indazolyl-2-picolinic Acids.

Thirty-eight new 4-amino-3,5-dicholo-6-(1H-indazolyl)-2-picolinic acids and 4-amino-3,5-dicholo-6-(2H-indazolyl)-2-picolinic acids were designed by scaffold hopping and synthesized to discover potential herbicidal molecules. All the new compounds were tested to determine their inhibitory activities against Arabidopsis thaliana and the root growth of five weeds. In general, the synthesized compounds exhibited excellent inhibition properties and showed good inhibitory effects on weed root growth. In particular, compound 5a showed significantly greater root inhibitory activity than picloram in Brassica napus and Abutilon theophrasti Medicus at the concentration of 10 µM. The majority of compounds exhibited a 100% post-emergence herbicidal effect at 250 g/ha against Amaranthus retroflexus and Chenopodium album. We also found that 6-indazolyl-2-picolinic acids could induce the up-regulation of auxin genes ACS7 and NCED3, while auxin influx, efflux and auxin response factor were down-regulated, indicating that 6-indazolyl-2-picolinic acids promoted ethylene release and ABA production to cause plant death in a short period, which is different in mode from other picolinic acids.

Imaging Features in BMPR2 Mutation-associated Pulmonary Arterial Hypertension.

Background Germline mutation in the BMPR2 gene is common in patients with pulmonary arterial hypertension (PAH). However, its association with imaging findings in these patients is, to the knowledge of the authors, unknown. Purpose To characterize distinctive pulmonary vascular abnormalities at CT and pulmonary artery angiography in patients with and without BMPR2 mutation. Materials and Methods In this retrospective study, chest CT scans, pulmonary artery angiograms, and genetic test data were acquired for patients diagnosed with idiopathic PAH (IPAH) or heritable PAH (HPAH) between January 2010 and December 2021. Perivascular halo, neovascularity, centrilobular ground-glass opacity (GGO), and panlobular GGO were evaluated at CT and graded on a four-point severity scale by four independent readers. Clinical characteristics and imaging features between patients with BMPR2 mutation and noncarriers were analyzed using the Kendall rank-order coefficient and the Kruskal-Wallis test. Results This study included 82 patients with BMPR2 mutation (mean age, 38 years ± 15 [SD]; 34 men; 72 patients with IPAH and 10 patients with HPAH) and 193 patients without the mutation, all with IPAH (mean age, 41 years ± 15; 53 men). A total of 115 patients (42%; 115 of 275) had neovascularity, and 56 patients (20%; 56 of 275) had perivascular halo at CT, and so-called frost crystals were observed on pulmonary artery angiograms in 14 of 53 (26%) patients. Compared with patients without BMPR2 mutation, patients with BMPR2 mutation more frequently showed two distinctive radiographic manifestations, perivascular halo and neovascularity (38% [31 of 82] vs 13% [25 of 193] in perivascular halo [P < .001] and 60% [49 of 82] vs 34% [66 of 193] in neovascularity [P < .001], respectively). "Frost crystals" were more frequent in patients with BMPR2 mutation compared with noncarriers (53% [10 of 19] vs 12% [four of 34]; P < .01). Severe perivascular halo frequently coexisted with severe neovascularity in patients with BMPR2 mutation. Conclusion Patients with PAH with BMPR2 mutation showed distinctive features at CT, specifically perivascular halo and neovascularity. This suggested a link between the genetic, pulmonary, and systemic manifestations that underly the pathogenesis of PAH. © RSNA, 2023 Supplemental material is available for this article.

Design, Synthesis, Fungicidal and Insecticidal Activities of Novel Diamide Compounds Combining Pyrazolyl and Polyfluoro-Substituted Phenyl into Alanine or 2-Aminobutyric Acid Skeletons.

Thirty novel diamide compounds combining pyrazolyl and polyfluoro-substituted phenyl groups into alanine or 2-aminobutyric acid skeletons were designed and synthesized with pyflubumide as the lead compound to develop potent and environmentally friendly pesticides. The preliminary bioassay results indicated that the new compounds containing the para-hexa/heptafluoroisopropylphenyl moiety exhibit fungicidal, insecticidal, and acaricidal activities. This is the first time that the para-hexa/heptafluoroisopropylphenyl group is a key fragment of the fungicidal activity of new N-phenyl amide compounds. Most of the target compounds exhibited moderate to good insecticidal activity against Aphis craccivora at a concentration of 400 µg/mL, and some showed moderate activity at a concentration of 200 µg/mL; in particular, compounds I-4, II-a-10, and III-26 displayed higher than 78% lethal rates at 200 µg/mL. Compound II-a-14 exhibited a 61.1% inhibition at 200 µg/mL for Tetranychus cinnabarinus. In addition, some of the target compounds exhibited good insecticidal activities against Plutella xylostella at a concentration of 200 µg/mL; the mortalities of compounds I-1, and II-a-15 were 76.7% and 70.0%, respectively. Preliminary analysis of the structure-activity relationship (SAR) indicated that the insecticidal and acaricidal activities varied significantly depending on the type of substituent and substitution pattern. The fungicidal activity results showed that compounds I-1, II-a-10, II-a-17, and III-26 exhibited good antifungal effects. Enzymatic activity experiments and in vivo efficacy of compound II-a-10 were conducted and discussed.

Design, Synthesis, Herbicidal Activity, and Structure-Activity Relationship Study of Novel 6-(5-Aryl-Substituted-1-Pyrazolyl)-2-Picolinic Acid as Potential Herbicides.

Picolinic acid and picolinate compounds are a remarkable class of synthetic auxin herbicides. In recent years, two new picolinate compounds, halauxifen-methyl (ArylexTM active) and florpyrauxifen-benzyl (RinskorTM active), have been launched as novel herbicides. Using their structural skeleton as a template, 33 4-amino-3,5-dicholor-6-(5-aryl-substituted-1-pytazolyl)-2-picolinic acid compounds were designed and synthesized for the discovery of compounds with potent herbicidal activity. The compounds were tested for inhibitory activity against the growth of Arabidopsis thaliana roots, and the results demonstrated that the IC50 value of compound V-7 was 45 times lower than that of the halauxifen-methyl commercial herbicide. Molecular docking analyses revealed that compound V-7 docked with the receptor auxin-signaling F-box protein 5 (AFB5) more intensively than picloram. An adaptive three-dimensional quantitative structure-activity relationship model was constructed from these IC50 values to guide the next step of the synthetic strategy. Herbicidal tests of the new compounds indicated that compound V-8 exhibited better post-emergence herbicidal activity than picloram at a dosage of 300 gha-1, and it was also safe for corn, wheat, and sorghum at this dosage. These results demonstrated that 6-(5-aryl-substituted-1-pyrazolyl)-2-picolinic acid compounds could be used as potential lead structures in the discovery of novel synthetic auxin herbicides.

Integrative analysis of m3C associated genes reveals METTL2A as a potential oncogene in breast Cancer.

RNA methylation modifications, especially m6A mRNA modification, are known to be extensively involved in tumor development. However, the relationship between N3-methylcytidine (m3C) related genes and tumorigenesis has rarely been studied. In this research, we found that m3C-related genes were expressed at different levels and affected patients' prognosis across multiple cancer types from The Cancer Genome Atlas and multi-omics levels. Importantly, methyltransferase-like proteins 2A (METTL2A) had a high amplification frequency (~ 7%) in patients with breast invasive carcinoma (BRCA), and its overexpression was an independent predictor of poor overall survival. Enrichment analysis of associated genes revealed that METTL2A may activate DNA synthesis and cell proliferation pathways in BRCA cells. Through drug sensitivity analysis, Trifluridine, PD407824, and Taselisib were shown to be effective drugs for METTL2A-positive BRCA patients. Overall, our research conducts a holistic view of the expression level and prognostic signature of m3C-related genes with multiple malignancies. Importantly, METTL2A has been intensely explored as a potential oncogene in BRCA, to aid the development of potential drug agents for precision therapy in breast cancer patients.

Peak oxygen uptake is a strong prognostic predictor for pulmonary hypertension due to left heart disease.

BACKGROUND: Pulmonary hypertension in left heart disease (PH-LHD), which includes combined post- and precapillary PH (Cpc-PH) and isolated postcapillary PH (Ipc-PH), differs significantly in prognosis. We aimed to assess whether cardiopulmonary exercise testing (CPET) predicts the long-term survival of patients with PH-LHD. METHODS: A single-center observational cohort enrolled 89 patients with PH-LHD who had undergone right heart catherization and CPET (mean pulmonary arterial pressure > 20 mm Hg and pulmonary artery wedge pressure ≥ 15 mm Hg) between 2013 and 2021. A receiver operating characteristic curve was plotted to determine the cutoff value of all-cause death. Survival was estimated using the Kaplan-Meier method and analyzed using the log-rank test. The Cox proportional hazards model was performed to determine the association between CPET and all-cause death. RESULTS: Seventeen patients died within a mean of 2.2 ± 1.3 years. Compared with survivors, nonsurvivors displayed a significantly worse 6-min walk distance, workload, exercise time and peak oxygen consumption (VO2)/kg with a trend of a lower oxygen uptake efficiency slope (OUES) adjusted by Bonferroni's correction. Multivariate Cox regression revealed that the peak VO2/kg was significantly associated with all-cause death after adjusting for Cpc-PH/Ipc-PH. Compared with Cpc-PH patients with a peak VO2/kg ≥ 10.7 ml kg-1 min-1, Ipc-PH patients with a peak VO2/kg < 10.7 ml kg-1 min-1 had a worse survival (P < 0.001). CONCLUSIONS: The peak VO2/kg is independently associated with all-cause death in patients with PH-LHD. The peak VO2/kg can also be analyzed together with Cpc-PH/Ipc-PH to better indicate the prognosis of patients with PH-LHD.

Effects of Etco2 on the Minimum Alveolar Concentration of Sevoflurane that Blunts the Adrenergic Response to Surgical Incision: A Prospective, Randomized, Double-Blinded Trial.

BACKGROUND: CO2 has anesthetic potency and effectively influences the circulatory system. We investigated the effects of Etco2 on the minimum alveolar concentration of sevoflurane that blunts the adrenergic response to surgical incision (MAC-BAR) in patients undergoing radical surgery for gastric carcinoma. METHODS: Ninety patients undergoing radical gastric-carcinoma surgery under general anesthesia were enrolled and randomly assigned into 3 groups. After intubation, the Etco2 in group L (n = 30), group N (n = 30), and group H (n = 30) was adjusted to 25 mm Hg ≤ Etco2 <30 mm Hg, 30 mm Hg ≤ Etco2 < 40 mm Hg, and 40 mm Hg ≤ Etco2 < 45 mm Hg, respectively, by changes in controlled ventilation. Hemodynamics and depth of anesthesia were observed before and after skin incision. The MAC-BAR of sevoflurane for each group was determined using an up-and-down sequential-allocation technique. RESULTS: To obtain 7 crossovers, 25, 26, and 26 patients were used in group L, group N, and group H, respectively. The MAC-BAR of sevoflurane using the up-and-down method for group H was significantly lower than that for group L (2.3% [95% confidence interval {CI}, 2.2-2.4] vs 2.9% [95% CI, 2.7-3.0]; difference, -0.6% [95% CI, -0.7 to -0.4], P < .001) and group N (2.3% [95% CI, 2.2-2.4] vs 2.8% [95% CI, 2.8-2.9]; difference, -0.5% [95% CI, -0.7 to -0.4], P < .001), while no significant difference was found between group L and group N (P = 1.000). CONCLUSIONS: Higher Etco2 levels (Etco2 values equal to 40 mm Hg or higher) can effectively decrease the MAC-BAR of sevoflurane in patients undergoing radical surgery for gastric carcinoma.

Peroxiredoxin 6 mediates the protective function of curcumin pretreatment in acute lung injury induced by serum from patients undergoing one-lung ventilation in vitro.

BACKGROUND: Curcumin has attracted much attention due to its wide range of therapeutic effects. In this study, we used serum collected from patients undergoing one-lung ventilation (OLV) to establish an in vitro acute lung injury (ALI) model to explore the potential protective mechanism of curcumin on ALI. Our study provides a new reference for the prevention and treatment of ALI induced by OLV. METHODS: A549 cells were treated with 20% serum from patients undergoing OLV to establish an in vitro ALI model. Curcumin, at a dose of 40 µg/ml, was administered two hours prior to this model. The levels of inflammation and oxidative stress markers were observed by Western blot, qRT-PCR, ELISA and reactive oxygen species assay. Additionally, the expression of peroxiredoxin 6 (Prdx6) and proteins involved in the NF-κB signaling pathway was evaluated. RESULTS: Twenty percent of serum collected from patients undergoing OLV downregulated the expression of Prdx6, leading to the activation of the NF-κB signaling pathway, which was associated with the subsequent overproduction of inflammatory cytokines and reactive oxygen species. Pretreatment with curcumin restored Prdx6 downregulation and inhibited NF-κB pathway activation by suppressing the nuclear translocation of P65, eventually reducing inflammation and oxidative stress damage in A549 cells. CONCLUSIONS: Prdx6 mediated the protective function of curcumin by inhibiting the activation of the NF-κB pathway in ALI in vitro.

The Different Effects of Direct Bilirubin on Portopulmonary Hypertension and Idiopathic Pulmonary Arterial Hypertension.

Background: To observe different roles of direct bilirubin (Dbil) on portopulmonary hypertension (POPH) and idiopathic pulmonary arterial hypertension (IPAH). Methods: Thirty incident patients with POPH and 180 with IPAH (matched by the WHO functional classification in a 1 : 6 ratio) between March 2010 and December 2020 were included. The receiver operating curve and Kaplan-Meier method were applied to estimate the ability to distinguish between the two and survival, respectively. Univariate and forward multiple stepwise regression analyses were performed to access the relationship between pulmonary vascular resistance (PVR) and clinical indices. Results: Compared to IPAH, the POPH group had better hemodynamics including PVR (7.08 ± 3.95 vs. 14.89 ± 7.11, P < 0.001) and higher total bilirubin (Tbil) and Dbil. Tbil and Dbil had a negative correlation with PVR in the POPH group (r = -0.394, P=0.031; r = -0.364, P=0.048, respectively) but positive correlation in the IPAH group (r = 0.218, P=0.003; r = 0.178, P=0.018, respectively). Increased neutrophil counts (r = 0.394, P=0.031) and elevated NT-proBNP (r = 0.433, P < 0.001) would help predict the elevation of PVR in POPH and IPAH groups independent of Dbil, respectively. Dbil could distinguish POPH from IPAH (AUC = 0.799, P=0.009), and the ability was elevated when taking aspartate aminotransferase together (AUC = 0.835, P < 0.001). The overall survival was better in POPH than in IPAH (7 dead cases of POPH and 96 of IPAH, P=0.002). Survival was better in POPH than in IPAH in the group of Dbil ≥7 µmol/L (P=0.001) but showed no significant difference between POPH and IPAH in the group of Dbil <7 µmol/L (P=0.192). Conclusions: The POPH group had a better hemodynamic profile than IPAH. Dbil was associated oppositely with the elevation of PVR in POPH and IPAH. Patients with POPH had better survival than those with IPAH in the total cohort and in the group of Dbil ≥7 µmol/L, but limited dead cases of POPH should be noted.

Effect of body weight on bleeding events of aspirin in ischemic stroke or transient ischemic attack patients.

WHAT IS KNOWN AND OBJECTIVES: Bleeding is the most common adverse reaction to aspirin and can lead to drug discontinuation or even be life-threatening in the secondary prevention of stroke or transient ischemic attack. The aim of this study was to evaluate risk factors for bleeding adverse reaction of aspirin in ischemic stroke or transient ischemic attack. METHODS: This retrospective analysis included patients treated with aspirin (100 mg) as a secondary prevention for ischemic stroke or transient ischemic attack. The bleeding events that occurred during the first year were collected, including gastrointestinal, skin, nasal cavity, gum, and urinary tract bleeding events. Then, univariate and multivariate logistic regression analyses were used to identify independent factors associated with bleeding events of aspirin. RESULTS AND DISCUSSION: A total of 578 patients were enrolled in this study, and 58 patients developed bleeding during the first year of secondary prevention. Body weight and combination with selective serotonin reuptake inhibitors were found to be significant risk factors for overall bleeding (p = 0.025 and 0.012). Body weight below 60 kg was a risk factor for overall bleeding and gastrointestinal bleeding events. WHAT IS NEW AND CONCLUSION: Patients weighing less than 60 kg were at increased risk of bleeding with 100 mg aspirin for secondary prevention of cerebral infarction transient ischemic attack.

Constitutional delay of growth and puberty in female mice is induced by circadian rhythm disruption in utero.

Constitutional delay of growth and puberty (CDGP) refers to the late onset of puberty. CDGP is associated with poor psychosocial outcomes and elevated risk of cardiovascular and osteoporotic diseases, especially in women. The environmental factors that contribute to CDGP are poorly understood. Here, we investigated the effects of chronic circadian disturbance (CCD) during the fetal stage on the pubertal development of female mice. Compared to non-stressed female (NS-F) mice that were not exposed to CCD in utero, adolescent CCD female (CCD-F) mice exhibited phenotypes that were consistent with CDGP, including lower body weight, reduced levels of circulating gonadal hormones, decreased expression of gonadal hormones and steroid synthesis-related enzymes in the ovary and hypothalamus, irregular estrus cycles, and tardive vaginal introitus initial opening (VO) days (equivalent to the menarche). Phenotypic differences in the above-noted parameters were not observed in CCD-F mice once they had reached adulthood. The expression of genes involved in fatty acid metabolism was perturbed in the ovary and hypothalamus of CCD-F mice. In addition, the ovaries of these animals exhibited altered diurnal expression profiles of circadian clock genes. Together, our findings not only suggest that CCD during fetal development may result in delayed puberty in female mice, they also offer insights on potential mechanisms that underlie CDGP.

B cells and tumor immune escape. / Bç»†èƒžä¸Žè‚¿ç˜¤å ç–«é€ƒé€¸.

B lymphocyte is an important component of the human immune system and it has a role in the process of the body's specific immunity. In recent years, the research on B cells and tumor immune escape has rapidly progressed. Studies have shown that different types of B cells play different roles in tumor microenvironment through a variety of mechanisms. B cells in the tertiary lymphatic structure promote anti-tumor immunity, while regulatory B cells promote tumor immune escape. Antibody drugs targeting B cells are a promising direction for tumor immunotherapy.

The role of mRNA in the development, diagnosis, treatment and prognosis of neural tumors.

Neural tumors can generally be divided into central nervous system tumors and peripheral nervous tumors. Because this type of tumor is located in the nerve, even benign tumors are often difficult to remove by surgery. In addition, the majority of neural tumors are malignant, and it is particular the same for the central nervous system tumors. Even treated with the means such as chemotherapy and radiotherapy, they are also difficult to completely cure. In recent years, an increasingly number of studies have focused on the use of mRNA to treat tumors, representing an emerging gene therapy. The use of mRNA can use the expression of some functional proteins for the treatment of genetic disorders or tissue repair, and it can also be applied to immunotherapy through the expression of antigens, antibodies or receptors. Therefore, although these therapies are not fully-fledged enough, they have a broad research prospect. In addition, there are many ways to treat tumors using mRNA vaccines and exosomes carrying mRNA, which have drawn much attention. In this study, we reviewed the current research on the role of mRNA in the development, diagnosis, treatment and prognosis of neural tumors, and examine the future research prospects of mRNA in neural tumors and the opportunities and challenges that will arise in the future application of clinical treatment.

Effects of an Intraoperative Intravenous Bolus Dose of Dexmedetomidine on Remifentanil-Induced Postinfusion Hyperalgesia in Patients Undergoing Thyroidectomy: A Double-Blind Randomized Controlled Trial.

BACKGROUND: Consecutive exposure to high-dose remifentanil during anesthesia may induce remifentanil-induced postinfusion hyperalgesia (RPH). Dexmedetomidine, a highly selective α2-adrenergic receptor agonist, may have synergistic effects with opioids and aid in perioperative pain management. In this study, we hypothesized that an intraoperative bolus dose of intravenous dexmedetomidine could alleviate RPH in patients undergoing thyroidectomy under general anesthesia. METHODS: Ninety patients undergoing thyroidectomy were randomly assigned to 1 of 3 groups: placebo, normal saline (group P); low-dose dexmedetomidine 0.2 µg·kg-1 (group LD); or high-dose dexmedetomidine 0.5 µg·kg-1 (group HD). Remifentanil was infused at a rate of 0.30 µg·kg-1·minute-1. Mechanical pain thresholds were measured using an Electronic von Frey device preoperatively and at 30 minutes, 6 hours, 24 hours, and 48 hours after surgery and were analyzed with 2-way repeated-measures analysis of variance (ANOVA) followed by Bonferroni post hoc comparison. We also recorded postoperative pain scores, the incidence of receiving rescue analgesics, and side effects up to 48 hours after surgery. RESULTS: The mechanical pain thresholds around the skin incision were significantly higher in group LD compared to group P 30 minutes and 6 hours after surgery (mean ± standard deviation: [65.0 ± 25.2] vs [49.6 ± 24.4] g, mean difference [95% confidence interval]: 15.4 [0.3-30.5] g, P = .045 at 30 minutes; [65.9 ± 24.5] vs [49.3 ± 26.1] g, 16.6 [1.1-32.1] g, P = .032 at 6 hours). The pain thresholds around the skin incision were significantly higher in group HD compared to group P 30 minutes and 6 hours after surgery ([67.8 ± 21.7] vs [49.6 ± 24.4] g, 18.2 [3.1-33.3] g, P = .013 at 30 minutes; [68.3 ± 22.5] vs [49.3 ± 26.1] g, 19.0 [3.5-34.5] g, P = .011 at 6 hours). The incidence of hyperalgesia around the skin incision was lower in group HD than in group P 30 minutes and 6 hours after surgery (4 [13%] vs 14 [48%], P = .012 at 30 minutes, 4 [13%] vs 12 [41%], P = .045 at 6 hours), although no significant difference was observed between group LD and group P. Postoperative pain scores, the incidence of rescue analgesic demand, and postoperative side effects were not significantly different between the groups. CONCLUSIONS: An intraoperative intravenous bolus dose of dexmedetomidine 0.5 µg·kg-1 alleviates remifentanil-induced hyperalgesia in patients undergoing thyroidectomy without a significant difference in side effects.

Protective effects of Lepidium draba L. leaves extract on testis histopathology, oxidative stress indicators, serum reproductive hormones and inflammatory signalling in oxymetholone-treated rat.

This study was aimed to investigate the protective effects of Lepidium draba L. (L. draba) extract on oxymetholone (OM)-induced testicular injury in rat. Six groups of n = 5 adult male rats were used as; 1: control, 2: OM (5 mg/kg OM orally), 3, 4 and 5: L. draba extract (100, 200 and 400 mg kg-1  day-1 ) +OM (5 mg kg-1  day-1 OM) and 6:400 mg/kg/d L. draba extract for 30 days. Serum testosterone (T), follicle-stimulating hormone (FSH) and luteinising hormone (LH), inflammatory cytokines (IL-6, IL-10, TNF-α, IL-1ß), oxidative stress (OS) indicators [superoxide dismutase, catalase, glutathione peroxidase and nitric oxide (NO)], apoptotic related genes (Bcl-2, p53, caspase-3 (c3) and Bax) were investigated. OM significantly increased the serum levels of T, proinflammatory cytokines and pro-apoptotic genes expression. Also, it decreased LH and FSH, sperm viability, count and motility. L. draba extract especially could markedly normalise the serum levels of LH and FSH, and T, restore serum antioxidant enzymes and suppressed the pro-inflammatory cytokines. Also, germ cells apoptosis was inhibited against via downregulating the p53, c3, Bax and upregulating Bcl-2. It concluded that L. draba extract could protect the function and structure of testis against OM-induced testicular toxicity via its antioxidant and anti-inflammatory properties.