Tumor-repopulating cells evade ferroptosis via PCK2-dependent phospholipid remodeling.

Whether stem-cell-like cancer cells avert ferroptosis to mediate therapy resistance remains unclear. In this study, using a soft fibrin gel culture system, we found that tumor-repopulating cells (TRCs) with stem-cell-like cancer cell characteristics resist chemotherapy and radiotherapy by decreasing ferroptosis sensitivity. Mechanistically, through quantitative mass spectrometry and lipidomic analysis, we determined that mitochondria metabolic kinase PCK2 phosphorylates and activates ACSL4 to drive ferroptosis-associated phospholipid remodeling. TRCs downregulate the PCK2 expression to confer themselves on a structural ferroptosis-resistant state. Notably, in addition to confirming the role of PCK2-pACSL4(T679) in multiple preclinical models, we discovered that higher PCK2 and pACSL4(T679) levels are correlated with better response to chemotherapy and radiotherapy as well as lower distant metastasis in nasopharyngeal carcinoma cohorts.

Outcome of first or second transplantation using unrelated umbilical cord blood without ATG conditioning regimen for pediatric bone marrow failure disorders.

BACKGROUND: Unrelated umbilical cord blood transplantation (UCBT) for bone marrow failure (BMF) disorders using conditioning regimens without Anti-Thymocyte Globulin (ATG) has been used as an alternative transplantation for emerging patients without matched-sibling donors. Experience with this transplant modality in children is limited, especially as a secondary treatment for transplant failure patients. PROCEDURE: We retrospectively reviewed 17 consecutive bone marrow failure patients who underwent unrelated umbilical cord blood transplantation in our center and received conditioning regimens of Total Body Irradiation (TBI) or Busulfan (BU) + Fludarabine (FLU) + Cyclophosphamide (CY). RESULTS: Among the 17 BMF patients, 15 patients were treated with first cord blood transplantation and another 2 with secondary cord blood transplantation because of graft failure after first haploidentical stem cell transplantation at days +38 and +82. All patients engrafted with a median donor cell chimerism of 50 % at days +7 (range, 16 %-99.95 %) and finally rose to 100 % at days +30. Median time to neutrophil engraftment was 19 days (range, 12-30) and time to platelet engraftment was 32 days (range, 18-61). Pre-engraftment syndrome (PES) was found in 16 patients (94.11 %, 16/17). Cumulative incidence of grades II to IV acute GVHD was 58.8 % (95 % CI: 32.7-84.9 %), and 17.6 % (95 % CI: 2.6-37.9 %) of patients developed chronic GVHD. The 3-year overall survival (OS) and failure-free survival (FFS) rates were 92.86 ± 6.88 %. CONCLUSION: UCBT is an effective alternative treatment for bone marrow failure pediatric patients. TBI/BU + FLU + CY regimen ensure a high engraftment rate for unrelated umbilical cord blood transplantation, which overcomes the difficulty of graft failure. Secondary salvage use of cord blood transplantation may still be useful for patients who have failed after other transplantation.

Minimal residual disease monitoring in childhood Philadelphia chromosome-positive acute lymphoblastic leukemia: prognostic significance and correlation between multiparameter flow cytometry and real-time quantitative polymerase chain reaction

Not available.

Decitabine-containing conditioning improved outcomes for children with higher-risk myelodysplastic syndrome undergoing allogeneic hematopoietic stem cell transplantation.

Myelodysplastic syndrome (MDS) is a rare clonal hematopoietic disorder in children. The risk stratification system and treatment strategy for adults are unfit for children. The role of hypomethylating agents (HMAs) in higher-risk childhood MDS has not been identified. This study aimed to investigate the outcomes of hematopoietic stem cell transplantation (HSCT) in children with higher-risk MDS at one single center. A retrospective study was conducted in children with higher-risk MDS undergoing HSCT between September 2019 and March 2023 at Blood Diseases Hospital CAMS. The clinical characteristics and transplantation information were reviewed and analyzed. A total of 27 patients were analyzed, including 11 with MDS with excess blasts (MDS-EB), 14 with MDS-EB in transformation (MDS-EBt) or acute myeloid leukemia with myelodysplasia-related changes (AML-MRC), and 2 with therapy-related MDS/AML (t-MDS/AML). Eight patients harbored monosomy 7. Before transplantation, induction therapy was administered to 25 patients, and 19 of them achieved bone marrow blasts <5% before HSCT. The stem cell source was unmanipulated-related bone marrow or peripheral blood stem cells for nineteen patients and unrelated cord blood for eight. All patients received decitabine-containing and Bu/Cy-based myeloablative conditioning; 26 patients achieved initial engraftment. The cumulative incidences of grade II-IV and grade III-IV acute graft-versus-host disease (GvHD) at 100 days were 65.4% and 42.3%, respectively. The incidence of cGvHD was 38.5%. The median follow-up was 26 (range 4-49) months after transplantation. By the end of follow-up, two patients died of complications and two died of disease progression. The probability of 3-year overall survival (OS) was 84.8% (95%CI, 71.1 to 98.5%). In summary, decitabine-containing myeloablative conditioning resulted in excellent outcomes for children with higher-risk MDS undergoing allogeneic HSCT.

GDF15 as a key disease target and biomarker: linking chronic lung diseases and ageing.

Growth differentiation factor 15 (GDF15), a member of the transforming growth factor-beta superfamily, is expressed in several human organs. In particular, it is highly expressed in the placenta, prostate, and liver. The expression of GDF15 increases under cellular stress and pathological conditions. Although numerous transcription factors directly up-regulate the expression of GDF15, the receptors and downstream mediators of GDF15 signal transduction in most tissues have not yet been determined. Glial cell-derived neurotrophic factor family receptor α-like protein was recently identified as a specific receptor that plays a mediating role in anorexia. However, the specific receptors of GDF15 in other tissues and organs remain unclear. As a marker of cell stress, GDF15 appears to exert different effects under different pathological conditions. Cell senescence may be an important pathogenetic process and could be used to assess the progression of various lung diseases, including COVID-19. As a key member of the senescence-associated secretory phenotype protein repertoire, GDF15 seems to be associated with mitochondrial dysfunction, although the specific molecular mechanism linking GDF15 expression with ageing remains to be elucidated. Here, we focus on research progress linking GDF15 expression with the pathogenesis of various chronic lung diseases, including neonatal bronchopulmonary dysplasia, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, and pulmonary hypertension, suggesting that GDF15 may be a key biomarker for diagnosis and prognosis. Thus, in this review, we aimed to provide new insights into the molecular biological mechanism and emerging clinical data associated with GDF15 in lung-related diseases, while highlighting promising research and clinical prospects.

[Relationship Between Hearing Loss and Cognitive Function in Elderly Chinese People: A Study Based on Propensity Score Matching]. / åŸºäºŽå€¾å‘å¾—åˆ†åŒ¹é æŽ¢è®¨ä¸­å›½è€å¹´äººå¬åŠ›æŸå¤±ä¸Žè®¤çŸ¥åŠŸèƒ½ä¹‹é—´çš„å ³ç³».

Objective: To explore the relationship between hearing loss and cognitive function in the elderly population through propensity score matching method. Methods: We analyzed the data of 7605 participants aged 60 and above who were included in the 2018 China Health and Retirement Longitudinal Study (CHARLS). The non-substitutable 1∶1 nearest neighbor matching method without caliper value was used for propensity score matching and G-computation was used to estimate the average treatment effect (ATE) of hearing loss on all dimensions of cognitive function. Results: Before matching, there were 3626 (47.68%) women, with 1409 (18.53%) of whom suffering from hearing loss and 3031 (39.86%) of whom suffering from cognitive impairment. After matching, 1409 subjects were included in the hearing loss group and 1409, in the normal hearing group, with both groups sharing similar distribution of basic demographic characteristics. The results for the average treatment effect of the population indicated that the cognitive function scores of the hearing loss group were lower than those of the normal hearing group, with the overall cognitive function being 0.593 points lower (95% confidence intervel [CI]: －0.916-－0.257, P<0.001), orientation being 0.183 points lower (95% CI: －0.302-－0.055, P=0.004), immediate memory being 0.150 points lower (95% CI: －0.218-－0.085, P<0.001), and language skills being 0.178 points lower (95% CI: －0.303-－0.058, P=0.006). The prevalence of cognitive impairment of the hearing loss group was 4.2% higher than that of the normal hearing group (95% CI: 0.007-0.077, P=0.020). Conclusion: Hearing loss adversely affects the orientation, memory, and language skills of the elderly population and forms a potential risk factor for cognitive impairment in the elderly population.

[Analysis of Influencing Factors of Hyperuricemia in Tibetan Population in Nagqu City, Tibet]. / è¥¿è—é‚£æ›²å¸‚è—æ—äººç¾¤é«˜å°¿é ¸è¡€ç—‡å½±å“å› ç´ åˆ†æž.

Objective: To analyze the prevalence of hyperuricemia (HUA) among the Tibetan population in Nagqu City, Tibet and to uncover the relevant influencing factors. Methods: From July 2020 to August 2021, 763 Tibetan natives from Bangor County (specifically Xinji Township and Jiaqiong Township) and Seni District (specificially Sexiong Township), Nagqu City were investigated by multi-stage cluster random sampling method and the prevalence of HUA was studied by retrospective analysis. Chi-square test and multiple logistic regression were used to analyze the influencing factors of HUA prevalence. Results: The overall prevalence of HUA among the Tibetan population in the three townships of Nagqu City was 19.66% (150/763). In particular, the prevalence in men was 35.00%, while that in women was 8.58%, showing significant difference (P<0.05). According to the results of univariate analysis, there were significant differences in the distribution of sex, abnormal liver function, abnormal hemoglobin, hyperlipidemia, high level of low-density lipoprotein, hypertriglyceridemia, hypercholesterolemia, abnormal creatinine, hyperhomocysteinemia, obesity, and hypertension between HUA and non-HUA patients (P<0.05). Multiple logistic regression showed that female sex (odds ratio [OR]=0.195, 95% confidence interval [CI]: 0.120-0.315) was a protective factor for HUA, while abnormal liver function (OR=2.812, 95% CI: 1.685-4.692), abnormal creatinine (OR=7.374, 95% CI: 1.446-37.620), high level of low-density lipoprotein (OR=2.357, 95% CI: 1.011-5.492), and hyperlipidemia (OR=3.056, 95% CI: 1.886-4.951) were independent risk factors. Conclusion: The prevalence of HUA is relatively high in Nagqu city and the prevalence of HUA is much higher in men than that in women. Male sex, abnormal liver function, abnormal creatinine, elevated low-density lipoprotein, and hyperlipidemia may be the risk factors for HUA in the local Tibetan population.

[Prevalence and Influencing Factors of Isolated Diastolic Hypertension in Tibetan Population in Tibet]. / è¥¿è—åœ°åŒºè—æ—äººç¾¤å•çº¯èˆ’å¼ æœŸé«˜è¡€åŽ‹çš„æ‚£ç— çŽ°çŠ¶åŠå ¶å½±å“å› ç´ åˆ†æž.

Objective: To investigate the prevalence and influencing factors of isolated diastolic hypertension (IDH) in the Tibetan population in Tibet and to provide some evidence for the prevention and control of hypertension and other related diseases in high-altitude areas. Methods: A multistage stratified whole-group random sampling method was used to enroll participants from Ngari Prefecture, Nagqu City, Shannan City, and Lhasa City, Tibet. A total of 3918 native Tibetans with complete data were enrolled in the survey between June 2020 and August 2023. The participants were aged from 18 to 80. The demographic data, life habits, and chronic disease prevalence of the participants were collected. Fasting venous blood samples were collected to perform the routine blood tests and blood biochemistry tests. The prevalence of IDH in subgroups with different characteristics was analyzed and the influencing factors were analyzed by multivariate logistic regression, accordingly. The predictive value of influencing factors on the prevalence of IDH was analyzed by the receiver operating characteristic (ROC) curve and the findings were compared with those of the previous prediction models for IDH. Results: The prevalence of hypertension in the participants was 33.7% (n=1321), among which, 395 had IDH, accounting for 29.9% of the hypertensive patients. The results of multivariate regression showed that age, heart rate, body mass index, waist circumference, hemoglobin, and low-density lipoprotein cholesterol were associated with risks of developing IDH (P<0.05). The area under the ROC curve (AUC) was 0.71, which indicated improved accuracy for predicting the risks for IDH in comparison with previous predictive models for IDH. Among the influencing factors, BMI showed the best predictive value for IDH risks. Conclusion: The prevalence of IDH is high among Tibetans in Tibet, suggesting the necessity for rational allocation of health resources in accordance. Compared with the previous IDH prediction models, the model proposed in this study is more suited for the Tibetan population. Targeted interventions should be carried out for the high-risk populations, such as young and middle-aged adults and populations suffering from overweight/obesity, central obesity, high-altitude polycythemia, and dyslipidemia, so as to effectively control the occurrence and development of IDH.

Rapid Formation of Intramolecular Disulfide Bridges using Light: An Efficient Method to Control the Conformation and Function of Bioactive Peptides.

Disulfide bonds are widely found in natural peptides and play a pivotal role in stabilizing their secondary structures, which are highly associated with their biological functions. Herein, we introduce a light-mediated strategy to effectively control the formation of disulfides. Our strategy is based on 2-nitroveratryl (oNv), a widely used photolabile motif, which serves both as a photocaging group and an oxidant (after photolysis). We demonstrated that irradiation of oNv-caged thiols with UV light could release free thiols that are rapidly oxidized by locally released byproduct nitrosoarene, leading to a "break-to-bond" fashion. This strategy is highlighted by the in situ restoration of the antimicrobial peptide tachyplesin I (TPI) from its external disulfide-caged analogue TPI-1. TPI-1 exhibits a distorted structure and a diminished function. However, upon irradiation, the ß-hairpin structure and membrane activity of TPI were largely restored via rapid intramolecular disulfide formation. Our study proposes a powerful method to regulate the conformation and function of peptides in a spatiotemporal manner, which has significant potential for the design of disulfide-centered light-responsive systems.

Prognostic factors of childhood acute lymphoblastic leukemia with TCF3::PBX1 in CCCG-ALL-2015: A multicenter study.

BACKGROUND: Contemporary risk-directed treatment has improved the outcome of patients with acute lymphoblastic leukemia (ALL) and TCF3::PBX1 fusion. In this study, the authors seek to identify prognostic factors that can be used to further improve outcome. METHODS: The authors studied 384 patients with this genotype treated on Chinese Children's Cancer Group ALL-2015 protocol between January 1, 2015 and December 31, 2019. All patients provisionally received intensified chemotherapy in the intermediate-risk arm without prophylactic cranial irradiation; those with high minimal residual disease (MRD) ≥1% at day 46 (end) of remission induction were candidates for hematopoietic cell transplantation. RESULTS: The overall 5-year event-free survival was 84.4% (95% confidence interval [CI], 80.6-88.3) and 5-year overall survival 88.9% (95% CI, 85.5-92.4). Independent factors associated with lower 5-year event-free survival were male sex (80.4%, [95% CI, 74.8-86.4] vs. 88.9%, [95% CI, 84.1-93.9] in female, p = .03) and positive day 46 MRD (≥0.01%) (62.1%, [95% CI, 44.2-87.4] vs. 87.1%, [95% CI, 83.4-90.9] in patients with negative MRD, p < .001). The presence of testicular leukemia at diagnosis (n = 10) was associated with particularly dismal 5-year event-free survival (33.3% [95% CI, 11.6-96.1] vs. 83.0% [95% CI, 77.5-88.9] in the other 192 male patients, p < .001) and was an independent risk factor (hazard ratio [HR], 5.7; [95% CI, 2.2-14.5], p < .001). CONCLUSIONS: These data suggest that the presence of positive MRD after intensive remission induction and testicular leukemia at diagnosis are indicators for new molecular therapeutics or immunotherapy in patients with TCF3::PBX1 ALL.

Alzheimer Disease Biomarkers: Moving from CSF to Plasma for Reliable Detection of Amyloid and tau Pathology.

BACKGROUND: Development of validated biomarkers to detect early Alzheimer disease (AD) neuropathology is needed for therapeutic AD trials. Abnormal concentrations of "core" AD biomarkers, cerebrospinal fluid (CSF) amyloid beta1-42, total tau, and phosphorylated tau correlate well with neuroimaging biomarkers and autopsy findings. Nevertheless, given the limitations of established CSF and neuroimaging biomarkers, accelerated development of blood-based AD biomarkers is underway. CONTENT: Here we describe the clinical significance of CSF and plasma AD biomarkers to detect disease pathology throughout the Alzheimer continuum and correlate with imaging biomarkers. Use of the AT(N) classification by CSF and imaging biomarkers provides a more objective biologically based diagnosis of AD than clinical diagnosis alone. Significant progress in measuring CSF AD biomarkers using extensively validated highly automated assay systems has facilitated their transition from research use only to approved in vitro diagnostics tests for clinical use. We summarize development of plasma AD biomarkers as screening tools for enrollment and monitoring participants in therapeutic trials and ultimately in clinical care. Finally, we discuss the challenges for AD biomarkers use in clinical trials and precision medicine, emphasizing the possible ethnocultural differences in the levels of AD biomarkers. SUMMARY: CSF AD biomarker measurements using fully automated analytical platforms is possible. Building on this experience, validated blood-based biomarker tests are being implemented on highly automated immunoassay and mass spectrometry platforms. The progress made developing analytically and clinically validated plasma AD biomarkers within the AT(N) classification scheme can accelerate use of AD biomarkers in therapeutic trials and routine clinical practice.

Phospholipase iPLA2ß averts ferroptosis by eliminating a redox lipid death signal.

Ferroptosis, triggered by discoordination of iron, thiols and lipids, leads to the accumulation of 15-hydroperoxy (Hp)-arachidonoyl-phosphatidylethanolamine (15-HpETE-PE), generated by complexes of 15-lipoxygenase (15-LOX) and a scaffold protein, phosphatidylethanolamine (PE)-binding protein (PEBP)1. As the Ca2+-independent phospholipase A2ß (iPLA2ß, PLA2G6 or PNPLA9 gene) can preferentially hydrolyze peroxidized phospholipids, it may eliminate the ferroptotic 15-HpETE-PE death signal. Here, we demonstrate that by hydrolyzing 15-HpETE-PE, iPLA2ß averts ferroptosis, whereas its genetic or pharmacological inactivation sensitizes cells to ferroptosis. Given that PLA2G6 mutations relate to neurodegeneration, we examined fibroblasts from a patient with a Parkinson's disease (PD)-associated mutation (fPDR747W) and found selectively decreased 15-HpETE-PE-hydrolyzing activity, 15-HpETE-PE accumulation and elevated sensitivity to ferroptosis. CRISPR-Cas9-engineered Pnpla9R748W/R748W mice exhibited progressive parkinsonian motor deficits and 15-HpETE-PE accumulation. Elevated 15-HpETE-PE levels were also detected in midbrains of rotenone-infused parkinsonian rats and α-synuclein-mutant SncaA53T mice, with decreased iPLA2ß expression and a PD-relevant phenotype. Thus, iPLA2ß is a new ferroptosis regulator, and its mutations may be implicated in PD pathogenesis.

Electroacupuncture Ameliorates Hypothalamic‒Pituitary‒Adrenal Axis Dysfunction Induced by Surgical Trauma in Mice Through the Hypothalamic Oxytocin System.

Electroacupuncture (EA) can effectively reduce surgical stress reactions and promote postoperative recovery, but the mechanisms remain unclear. The present study aims to examine the effects of EA on the hyperactivity of the hypothalamic‒pituitary‒adrenal (HPA) axis and investigate its potential mechanisms. Male C57BL/6 mice were subjected to partial hepatectomy (HT). The results showed that HT increased the concentrations of corticotrophin-releasing hormone (CRH), corticosterone (CORT), and adrenocorticotropic hormone (ACTH) in the peripheral blood and upregulated the expression of CRH and glucocorticoid receptors (GR) proteins in the hypothalamus. EA treatment significantly inhibited the hyperactivity of the HPA axis by decreasing the concentration of CRH, CORT, and ACTH in peripheral blood and downregulating the expression of CRH and GR in the hypothalamus. Moreover, EA treatment reversed the HT-induced downregulation of oxytocin (OXT) and oxytocin receptor (OXTR) in the hypothalamus. Furthermore, intracerebroventricular injection of the OXTR antagonist atosiban blocked the effects of EA. Thus, our findings implied that EA mitigated surgical stress-induced HPA axis dysfunction by activating the OXT/OXTR signaling pathway.

ALOX5 inhibition protects against dopaminergic neurons undergoing ferroptosis.

Oxidative disruption of dopaminergic neurons is regarded as a crucial pathogenesis in Parkinson's disease (PD), eventually causing neurodegenerative progression. (-)-Clausenamide (Clau) is an alkaloid isolated from plant Clausena lansium (Lour.), which is well-known as a scavenger of lipid peroxide products and exhibiting neuroprotective activities both in vivo and in vitro, yet with the in-depth molecular mechanism unrevealed. In this study, we evaluated the protective effects and mechanisms of Clau on dopaminergic neuron. Our results showed that Clau directly interacted with the Ser663 of ALOX5, the PKCα-phosphorylation site, and thus prevented the nuclear translocation of ALOX5, which was essential for catalyzing the production of toxic lipids 5-HETE. LC-MS/MS-based phospholipidomics analysis demonstrated that the oxidized membrane lipids were involved in triggering ferroptotic death in dopaminergic neurons. Furthermore, the inhibition of ALOX5 was found to significantly improving behavioral defects in PD mouse model, which was confirmed associated with the effects of attenuating the accumulation of lipid peroxides and neuronal damages. Collectively, our findings provide an attractive strategy for PD therapy by targeting ALOX5 and preventing ferroptosis in dopaminergic neurons.

Competing-risks analysis for evaluating the prognosis of patients with microinvasive cutaneous squamous cell carcinoma based on the SEER database.

BACKGROUND: Utilizing the traditional Cox regression model to identify the factors affecting the risk of mortality due to microinvasive cutaneous squamous cell carcinoma (micSCC) may produce skewed results. Since cause-specific mortality can guide clinical decision-making, this study employed the Fine-Gray model based on the Surveillance, Epidemiology, and End Results (SEER) database to identify significant predictive variables for the risk of micSCC-related mortality. METHODS: This study used the information of patients with micSCC who were listed in the SEER database during 2000-2015. Cox regression and Fine-Gray models were utilized for the multivariable analysis, and Gray's test and the cumulative incidence function were used for the univariable analyses. RESULTS: There were 100 patients who died from other reasons and 38 who died from micSCC among the 1259 qualified patients with micSCC. Most were female, white, married, had localized metastasis, etc. According to the univariable Gray's test (P < 0.05), the cumulative incidence rate for events of interest was strongly associated with age, sex, marital status, American Joint Committee on Cancer staging, radiation status, summary stage, chemotherapy status, surgery status, and tumor size. Multivariable Cox regression analysis and multivariable competing-risks analysis indicated that age, tumor size, and income were independent risk variables for the prognosis of patients with micSCC. In both age and tumor size variables, the competing-risks model showed a slight decrease in the hazard ratio and a slight narrowing of the 95% confidence interval compared with the Cox regression model. However, this pattern is not evident in the income variable. CONCLUSIONS: This study established a Fine-Gray model for identifying the independent risk factors that influence the risk of mortality among patients with micSCC. This study uncovers that, in the context of competing risks, age, tumor size, and income serve as independent risk factors influencing the risk of mortality due to micSCC among patients. Our findings have the potential to provide more accurate risk assessments for patient outcomes and contribute to the development of individualized treatment plans.

Dual functional antioxidant and butyrylcholinesterase inhibitors for the treatment of Alzheimer's disease: Design, synthesis and evaluation of novel melatonin-alkylbenzylamine hybrids.

Here, we have designed and synthesized a series of melatonin-alkylbenzylamine hybrids as multitarget agents for the treatment of Alzheimer's disease (AD). Most of them exhibited a potent multifunctional profile involving cholinesterase inhibition and antioxidant effects. Among these compounds, compound 5 was most the potent antioxidant (ORAC = 5.13) and also an excellent selective inhibitor of BuChE (huBuChE IC50 = 1.20 µM, huAChE IC50 = 177.49 µM, SI = 147.91). Moreover, kinetic study indicated compound 5 was a mixed-type inhibitor for huBuChE. Furthermore, it could induce expression of the Nrf2 as well as its downstream markers at the protein level in cells. More importantly, compound 5 display no acute toxicity in mice at doses up to 2500 mg/kg. And we found compound 5 could improve memory function of scopolamine-induced amnesia mice. These results highlighted compound 5 as a possible hit molecule for further investigation of new anti-AD drugs.

Novel 2,6-disubstituted benzofuran-3-one analogues improve cerebral ischemia/reperfusion injury via neuroprotective and antioxidative effects.

There are no highly effective and safe medicines for clinical treatment of ischemic stroke, although the natural product 3-n-butylphthalide (NBP) has been approved in China for mild and moderate ischemic stroke. To discover more potent anti-cerebral ischemic agents and overcome the low stability by phthalide derivatives, benzofuran-3-one was selected as a core moiety and two types of nitric oxide (NO)-donating groups were incorporated into the structure. In this work, a series of 2,6-disubstituted benzofuran-3-one derivatives were designed and synthesised as NBP analogues, and tested as neuroprotective and antioxidative agents. Compounds 5 (without an NO donor) and 16 (with an NO donor) displayed more potent neuroprotective effects than the established clinical drugs Edaravone and NBP. More importantly, 5 and 16 also exhibited good antioxidative activity without cytotoxicity in rat primary neuronal and PC12 cells. Most active compounds showed good blood-brain barrier permeability in a parallel artificial membrane permeability assay. Furthermore, compound 5 reduced the ischemic infarct area significantly in rats subjected to ischemia/reperfusion injury, downregulated ionised calcium-binding adaptor molecule 1 and glial fibrillary acidic protein in inflammatory cells, and upregulated nerve growth factor.

Reducing lipid peroxidation attenuates stress-induced susceptibility to herpes simplex virus type 1.

Psychological stress increases the susceptibility to herpes simplex virus type 1 (HSV-1) infection. There is no effective intervention due to the unknown pathogenesis mechanisms. In this study we explored the molecular mechanisms underlying stress-induced HSV-1 susceptibility and the antiviral effect of a natural compound rosmarinic acid (RA) in vivo and in vitro. Mice were administered RA (11.7, 23.4 mg·kg-1·d-1, i.g.) or acyclovir (ACV, 206 mg·kg-1·d-1, i.g.) for 23 days. The mice were subjected to restraint stress for 7 days followed by intranasal infection with HSV-1 on D7. At the end of RA or ACV treatment, mouse plasma samples and brain tissues were collected for analysis. We showed that both RA and ACV treatment significantly decreased stress-augmented mortality and alleviated eye swelling and neurological symptoms in HSV-1-infected mice. In SH-SY5Y cells and PC12 cells exposed to the stress hormone corticosterone (CORT) plus HSV-1, RA (100 µM) significantly increased the cell viability, and inhibited CORT-induced elevation in the expression of viral proteins and genes. We demonstrated that CORT (50 µM) triggered lipoxygenase 15 (ALOX15)-mediated redox imbalance in the neuronal cells, increasing the level of 4-HNE-conjugated STING, which impaired STING translocation from the endoplasmic reticulum to Golgi; the abnormality of STING-mediated innate immunity led to HSV-1 susceptibility. We revealed that RA was an inhibitor of lipid peroxidation by directly targeting ALOX15, thus RA could rescue stress-weakened neuronal innate immune response, thereby reducing HSV-1 susceptibility in vivo and in vitro. This study illustrates the critical role of lipid peroxidation in stress-induced HSV-1 susceptibility and reveals the potential for developing RA as an effective intervention in anti-HSV-1 therapy.

Influencing factors of bone mass abnormalities among postmenopausal women in Tibet, China.

BACKGROUND: This study aimed to provide a reference for the prevention and treatment of abnormal bone mass in postmenopausal women by analysing the current situation and influencing factors of bone mass abnormalities in Tibet. METHODS: A total of 229 postmenopausal Tibetan women were randomly selected from six counties by a multistage cluster random sampling method. Multiple logistic regression was utilized to analyse the status and influencing factors of bone mass abnormalities in postmenopausal Tibetan women. RESULTS: Among 229 postmenopausal Tibetan women, the prevalence of osteopenia and osteoporosis was 54.6% and 9.6%, respectively. Age {odds ratio (OR) = 0.022 [95% confidence interval (CI) = 0.003 ~ 0.163]}, BMI [OR = 441.902 (20.899,9343.717)], altitude [OR = 18.818 (1.391,254.585)], and creatinine (CREA) levels [OR = 0.895 (0.825 ~ 0.971)] were significantly associated with the risk of osteoporosis. CONCLUSION: Postmenopausal Tibetan women had high rates of abnormal bone mass. Age, BMI, altitude and CREA levels were associated with osteoporosis. It is suggested that relevant departments should take targeted measures to promote health education on the prevention of osteoporosis in the general population and increase the screening of high-risk groups for osteoporosis to improve the bone health of postmenopausal Tibetan women.

The Chinese version of informant AD8 for mild cognitive impairment and dementia screening in community-dwelling older adults.

BACKGROUND: Conducting routine mild cognitive impairment (MCI) and dementia screening for older adults in the community is important, which not only can improve our understanding of these diseases but also can increase early detection and treatment. METHODS: To analyze the reliability and validity of the informant AD8 and explore the cut-off values for screening MCI and dementia in the community-dwelling older adults, this study adopted a multi-stage cluster sampling method to recruit 327 participants aged 60 and over in communities. The informant AD8 and Clinical Dementia Rating (CDR) scales were used to evaluate cognitive function of the subjects, and the receiver operating characteristic curves (ROC) was conducted to test the screening efficacy. RESULTS: Among the 327 participants, 33.0% of them met the criteria of MCI, and 3.4% of them met the criteria of dementia. The area under the receiver operating characteristic curve (AUC) of the informant AD8 for screening dementia was 0.974, with a screening cut-off of three, sensitivity of 90.9% and specificity of 89.0%. But it has a poor discriminability in MCI screening [AUC = 0.645, 95% confidence interval (CI): 0.578-0.711]. CONCLUSIONS: This study suggests that the informant AD8 is an ideal and useful tool for dementia screening in community-dwelling older adults. However, it is less capable to distinguish older adults with MCI from those with normal cognitive function.