The relationship of cardiovascular disease risk, clozapine antipsychotic use and cognitive function in a large Chinese schizophrenia cohort.

OBJECTIVE: This study explores the intricate relationship between clozapine use, cardiovascular disease (CVD) risk, and cognitive function in patients with schizophrenia (SCZ). METHODS: A cohort comprising 765 patients was stratified based on clozapine usage. Data on demographics, clinical characteristics, and glycolipid metabolism were collected. The Framingham Risk Score and vascular age were calculated using gender-specific Cox regression calculators. Cognitive function was assessed with the Repeatable Battery for Assessment of Neuropsychological Status. RESULTS: Among the patients, 34.6 % were clozapine users. Clozapine users exhibited lower systolic blood pressure, high-density lipoprotein cholesterol and total cholesterol (all ps < 0.05). Furthermore, clozapine users exhibited higher PANSS scores, along with lower scores in RBANS scores (all ps < 0.05). Correlation analysis revealed positive correlation between CVD risk in non-clozapine users and negative symptom scores (r = 0.074, p = 0.043), and negative correlation with positive symptom scores and RBANS scores (r = -0.121, p = 0.001; r = -0.091, p = 0.028). Multivariate stepwise regression analysis indicated that attention scores as predictive factors for increased CVD risk in clozapine users (B = -0.08, 95 %CI = -0.11 to -0.03, p = 0.003). CONCLUSIONS: Patients with SCZ using clozapine exhibit more severe clinical symptoms and cognitive impairments. Attention emerges as a predictor for increased CVD risk in clozapine users.

Immunoinflammatory features and cognitive function in treatment-resistant schizophrenia: unraveling distinct patterns in clozapine-resistant patients.

Patients with treatment-resistant schizophrenia (TRS), particularly those resistant to clozapine (CTRS), pose a clinical challenge due to limited response to standard antipsychotic treatments. Inflammatory factors like tumor necrosis factor-alpha (TNF-α), interleukin 2 (IL-2), and interleukin 6 (IL-6) are implicated in schizophrenia's pathophysiology. Our study examines cognitive function, psychopathological symptoms and inflammatory factors in TRS patients, focusing on differences between CTRS and non-CTRS individuals, as well as healthy controls. A cohort of 115 TRS patients and 84 healthy controls were recruited, assessing IL-2, IL-6 and TNF-α. The Positive and Negative Syndrome Scale (PANSS) was applied to assess psychopathological symptoms, while the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was applied to assess cognitive functioning. CTRS patients showed lower visuospatial constructional score (p = 0.015), higher PANSS scores, higher levels of IL-2 and reduced TNF-α than non-CTRS patients (p < 0.05). Notably, IL-2 was independently associated with psychopathology symptoms in CTRS patients (Beta = 0.268, t = 2.075, p = 0.042), while IL-6 was associated with psychopathology symptoms in non-CTRS patients (Beta = - 0.327, t = - 2.109, p = 0.042). Sex-specific analysis in CTRS patients revealed IL-2 associations with PANSS total and positive symptoms in females, and TNF-α associations with PANSS positive symptoms in males. Furthermore, IL-2, IL-6, and TNF-α displayed potential diagnostic value in TRS patients and CTRS patients (p < 0.05). Clozapine­resistant symptoms represent an independent endophenotype in schizophrenia with distinctive immunoinflammatory characteristics, potentially influenced by sex.

Sex-dependent associations of serum BDNF, glycolipid metabolism and cognitive impairments in Parkinson's disease with depression: a comprehensive analysis.

Brain-derived neurotrophic factor (BDNF) and glycolipid metabolism have been implicated in cognitive impairments and depression among Parkinson's disease (PD). However, the role of sex differences in this relationship remains elusive. This study aimed to investigate the potential sex differences in the link between serum BDNF levels, glycolipid metabolism and cognitive performance among depressive PD patients. PD patients comprising 108 individuals with depression and 108 without depression were recruited for this study. Cognitive function was assessed using the Montreal Cognitive Assessment Beijing version (MOCA-BJ). The severity of depressive symptoms was assessed using the Hamilton Depression Rating Scale (HAMD-17), while motor symptoms were evaluated using the Revised Hoehn and Yahr rating scale (H-Y) and the Unified Parkinson's Disease Rating Scale Part III (UPDRS-III). Laboratory testing and enzyme-linked immunosorbent assay (ELISA) are used to measure serum levels of glycolipid metabolism and BDNF. Females showed superior performance in delayed recall (all p < 0.05), male PD patients exhibited higher scores in naming tasks compared to females in non-depression group. There was no sex differences in serum BDNF levels between depression and non-depression groups. Liner regression analysis indicated BDNF as an independent risk factor for language deficits in male PD patients with depression (p < 0.05), while cholesterol (CHOL) emerged as a cognitive influencing factor, particularly in delayed recall among male PD patients with depression (p < 0.05). Our study reveals extensive cognitive impairments in PD patients with depression. Moreover, BDNF and CHOL may contribute to the pathological mechanisms underlying cognitive deficits, particularly in male patients with depression.

Association of cytokines levels, psychopathology and cognition among CR-TRS patients with metabolic syndrome.

Clozapine-resistant treatment-refractory schizophrenia (CR-TRS) patients face significant clinical challenges. While links between metabolic syndrome (MetS) and inflammatory cytokines in schizophrenia have been established, the relationship between MetS and cytokine levels in CR-TRS patients remains unexplored. This study aimed to investigate the relationship between cytokines levels, clinical symptoms and cognitive impairments in CR-TRS patients, both with and without MetS. The study included 69 CR-TRS patients (31with MetS and 38 without MetS) and 84 healthy controls. The levels of IL-2, IL-6, TNF-α and routine biochemical parameters were measured. Psychopathological symptoms and cognitive function were assessed using the Positive and Negative Syndrome Scale (PANSS) and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), respectively. We found that CR-TRS patients with MetS displayed lower cognitive function scores compared to those without MetS, even when accounting for potential confounders. TNF-α levels were significantly higher in CRTRS patients with MetS compared to those without MetS, demonstrating substantial pathophysiological potential for CR-TRS patients with MetS via receiver operating characteristic curve (ROC). In CR-TRS patients without MetS, IL-2 independently contributed to the total score and general psychopathology subscore of PANSS. Additionally, IL-6 exhibited an independent contribution to the positive subscore of PANSS. In terms of cognition function, IL-6 independently contributed to the delayed memory of RBANS in CR-TRS patients without MetS. TNF-α could potentially serve as a predictive marker for distinguishing between CR-TRS patients with/without MetS, while IL-2 and IL-6 could independently contribute to psychopathological symptoms or cognitive function in CRTRS patients without MetS. Our study provided insights into the potential interplay between cytokines, clinical symptoms and cognitive impairments in CR-TRS patients with/without MetS.

Worse psychological traits associated with higher probability of emotional problems during the Omicron pandemic in Tianjin, China

Background and Objectives: Individuals with specific psychological weaknesses are prone to mental problems during the coronavirus pandemic. This self-rating study assessed the combined effects of infection-related stress, resilience, worry, and loneliness on the likelihood of depression and anxiety among infected and non-infected individuals during the Tianjin Pandemic in 2022.MethodsIndividuals infected with Omicron (n = 249) and health residents (n = 415) were recruited from two hospitals and communities in Tianjin. Each respondent completed the following on-site assessment: Self-developed Scale of Demographics, Zung Self-Rating Depression Scale (SDS), Zung Self-Rating Anxiety Scale (SAS), the Connor-Davidson Resilience Scale (CD-RISC), De Jong Gierveld Scale (DJGLS), and the Penn State Worry Questionnaire (PSWQ). The respondents were categorized into depression or non-depression group by SDS scores, and anxiety or non-anxiety group by SAS scores.ResultsThe overall scores of CD-RISC, DJGJLS, and PSWQ were significantly different both between the depression group and non-depression groups and between the anxiety group and non-anxiety groups. The greater likelihood of depression was associated with lower overall scores of CD-RISC and higher scores of PSWQ; the greater likelihood of anxiety was associated with higher scores of PSWQ. The likelihood of depression was also positively associated with having infection-related stress and three demographics. (AU)

Organotin benzohydroxamate derivatives (OTBH) target colchicine-binding site exerting potent antitumor activity both in vitro and vivo revealed by quantitative proteomic analysis.

The activity of four typical organotin benzohydroxamate compounds (OTBH) with the different electronegativity of fluorine and chlorine atoms was assessed both in vitro and in vivo, revealing that they all exhibited notable antitumor effects. Furthermore, it was discovered that the biochemical capacity against cancer was influenced by their substituents' electronegativity and structural symmetry. For instance, benzohydroxamate derivatives with single chlorine at the fourth site on the benzene ring, two normal­butyl organic ligands, a symmetrical structure, and so on ([n-Bu2Sn[{4-ClC6H4C(O)NHO}2] (OTBH-1)) had stronger antitumor activity than others. Furthermore, the quantitative proteomic analysis discovered 203 proteins in HepG2 cells and 146 proteins in rat liver tissues that were differently identified before and after administration. Simultaneously, bioinformatics analysis of differentially expressed proteins demonstrated that the antiproliferative effects involved in the microtubule-based process, tight junction and its downstream apoptosis pathways. As predicted analytically, molecular docking indicated that ''-O-'' were the target docking atoms for the colchicine-binding site; meanwhile, this site was additionally verified by the EBI competition experiment and the microtubule assembly inhibition test. In conclusion, these derivatives promising for developing microtubule-targeting agents (MTAs) were shown to target the colchicine-binding site, impair cancer cell microtubule networks, and then halt mitosis and trigger apoptosis.

Effects of aerobic exercise performed during pregnancy on hypertension and gestational diabetes: a systematic review and meta-analysis.

INTRODUCTION: Gestational diabetes mellitus (GDM) and gestational hypertension (GH) are the most common pregnancy complications, predisposing to adverse pregnancy outcomes and being a major cause of maternal morbidity and mortality, often associated with significantly higher health risks for the mother and her offspring. The aim of this study was to systematically evaluate the effects of aerobic exercise performed during pregnancy on GDM, GH, and pregnancy outcomes. EVIDENCE ACQUISITION: The databases PubMed, EMbase, Web of Science, China Knowledge Network, Wan fang, and Wipu were searched for clinical randomized controlled trials of exercise interventions on GDM, GH, and pregnancy outcomes, and data were analyzed and systematically evaluated using RevMan 5.3 according to the inclusion and exclusion criteria. EVIDENCE SYNTHESIS: Meta-analysis showed that, in terms of pregnancy complications, aerobic exercise intervention reduced the incidence of maternal GDM better than the control group, with a statistically significant difference (OR=0.39, 95% CI: 0.30, 0.50, P<0.00001); aerobic exercise intervention reduced the incidence of maternal GH better than the control group, with a statistically significant difference (OR=0.38, 95% CI: 0.27, 0.54, P<0.00001). CONCLUSIONS: The results in pregnancy suggest that aerobic exercise is advantageous for pregnant women, as it reduces the incidence of GDM and GH and improves the incidence of adverse pregnancy outcomes to a certain extent.

Worse psychological traits associated with higher probability of emotional problems during the Omicron pandemic in Tianjin, China.

Background and Objectives: Individuals with specific psychological weaknesses are prone to mental problems during the coronavirus pandemic. This self-rating study assessed the combined effects of infection-related stress, resilience, worry, and loneliness on the likelihood of depression and anxiety among infected and non-infected individuals during the Tianjin Pandemic in 2022. Methods: Individuals infected with Omicron (n = 249) and health residents (n = 415) were recruited from two hospitals and communities in Tianjin. Each respondent completed the following on-site assessment: Self-developed Scale of Demographics, Zung Self-Rating Depression Scale (SDS), Zung Self-Rating Anxiety Scale (SAS), the Connor-Davidson Resilience Scale (CD-RISC), De Jong Gierveld Scale (DJGLS), and the Penn State Worry Questionnaire (PSWQ). The respondents were categorized into depression or non-depression group by SDS scores, and anxiety or non-anxiety group by SAS scores. Results: The overall scores of CD-RISC, DJGJLS, and PSWQ were significantly different both between the depression group and non-depression groups and between the anxiety group and non-anxiety groups. The greater likelihood of depression was associated with lower overall scores of CD-RISC and higher scores of PSWQ; the greater likelihood of anxiety was associated with higher scores of PSWQ. The likelihood of depression was also positively associated with having infection-related stress and three demographics. Conclusions: This on-site study demonstrates the importance of specific traits in a small-scale pandemic: the worse resilience and the greater worry propensity related to the higher probability of depression, and the greater propensity of worry related to the higher probability of anxiety. Moreover, those experiencing infection-related stress, being male, living alone, and being unemployed are more likely to have depressive problems.

HSPA1A, HSPA2, and HSPA8 Are Potential Molecular Biomarkers for Prognosis among HSP70 Family in Alzheimer's Disease.

Alzheimer's disease (AD) is a chronic neurodegenerative disease, which leads to impairment of cognition and memory. The heat shock protein 70 (HSP70) family plays an important role in the pathogenesis of AD. It is known to regulate protein misfolding in a variety of diseases, including inhibition of Aß aggregation and NFT formation in AD. As yet, the diagnostic molecular markers of AD remain unclear. Herein, we sought to investigate molecular markers of HSP70 family that can affect diagnosis and treatment in AD through computational analysis. In this study, the intersection between HSP70 family members and immune molecules was taken to screen immune-related HSP70 family genes. Based on the datasets from the NCBI-Gene Expression Omnibus (GEO) database, we found that the expression levels of HSPA1A and HSPA2 were significantly increased in AD samples, while HSPA8 significantly decreased. Surprisingly, the combination of the 3 hub genes had a good diagnosis of AD via receiver operating characteristic curve (ROC). Moreover, the clinical value of the 3 hub genes was further assessed by the Spearman correlation analysis with AD-related genes, ß-secretase activity, and γ-secretase activity. In terms of immune cell infiltration, we showed that the distribution of seven immune cell types (macrophages M2, neutrophils, T cells CD4 memory activated, macrophages M0, NK cells activated, plasma cells, and T cells follicular helper) was associated with the occurrence of AD by CIBERSORT. Furthermore, our data suggested that EP300, MYC, TP53, JUN, CREBBP, and ESR1 might be key transcription factors (TFs) for the 3 hub genes. In general, these findings suggest that HSPA1A, HSPA2, and HSPA8 are potential molecular biomarkers for prognosis among HSP70 family in AD, and it provides a new perspective on diagnostic and therapeutic targets for AD.

The multifunctional Prussian blue/graphitic carbon nitride nanocomposites for fluorescence imaging-guided photothermal and photodynamic combination therapy.

Cancer has been regarded as one of the most intractable diseases worldwide and threatens human health and life. Photothermal/Photodynamic therapy (PTT and PDT) have emerged as reliable and effective strategies in cancer treatment with the superiorities of non-invasiveness, slight side effects, and high treatment efficiency. Herein, a nanocomposite (PBCN) was fabricated via electrostatic interaction between Prussian blue nanoparticles (PBNPs) and graphitic carbon nitride (g-C3N4), and the resulting PBCN possessed good photothermal properties and excellent photodynamic effects with 808 nm irradiation. Furthermore, it exhibits excellent fluorescence imaging ability in cells, highlighting its potential as a powerful imaging agent in the biomedical field. Combination with a photothermal material, photosensitizer, and fluorescence imaging agent would thus allow PBCN to realize fluorescence imaging-guided PTT/PDT, showing an outstanding theranostic effect on cancer cells.

Probiotic Bifidobacterium lactis V9 attenuates hepatic steatosis and inflammation in rats with non-alcoholic fatty liver disease.

Both steatosis and inflammation are key pathological events in the progression of non-alcoholic fatty liver disease (NAFLD). Probiotics are beneficial for the prevention and treatment of NAFLD. Bifidobacterium animalis subsp. lactis V9 (V9) is a newly isolated strain with favorable probiotic properties. The study aims to evaluate the effects and mechanisms of V9 on the hepatic steatosis and inflammatory responses in a rat model of NAFLD induced by high-fat diets (HFD). Our results showed that administration of V9 significantly attenuated the HFD-induced increases in alanine transaminase (ALT) and aspartate aminotransferase (AST) levels, resulting in alleviated hepatic steatosis. V9 supplementation reduced the accumulation of hepatic triglyceride and free fatty acid,while increasing the levels of glycogen. Serum levels of glucose were also decreased in HFD rats administrated with V9. Meanwhile, the transcription of SREBP-1c and FAS was reduced, and the hepatic expression of phosphorylated-AMPK and PPAR-α was restored after V9 administration. V9 suppressed the production of inflammatory cytokines (e.g. IL-6, IL-1ß, and TNF-α) in HFD-fed rats. The anti-inflammatory effects of V9 was found to be associated with the inhibition of hepatic expression of TLR4, TLR9, NLRP3, and ASC mRNA. Furthermore, the activation of ERK, JNK, AKT and NF-κB were suppressed by V9 treatment. These results indicate that Bifidobacterium lactis V9 improves NAFLD by regulating de novo lipid synthesis and suppressing inflammation through AMPK and TLR-NF-κB pathways, respectively.

Chloramphenicol/sulfobutyl ether-ß-cyclodextrin complexes in an ophthalmic delivery system: prolonged residence time and enhanced bioavailability in the conjunctival sac.

Objective: Conventional chloramphenicol (CHL) eye drops are widely used anti-infection formulations for acute bacterial conjunctivitis. However, the therapeutic effects are limited by insufficient concentration in the conjunctival sac. Hence, the objective of this study is to formulate and develop novel CHL eye drops with improved topical concentrations by increasing the solubility and decreasing the transcorneal penetration. Research design and methods: CHL was included in the sulfobutyl ether-ß-cyclodextrin (SBE-ß-CD) using the freeze-drying method. Eye drops containing CHL/SBE-ß-CD complexes were prepared and evaluated for in vitro and in vivo studies. Results: The formation of CHL/SBE-ß-CD inclusion was confirmed by DSC, XRD, NMR, and SEM. The aqueous solubility of CHL was significantly enhanced, and the drug transcorneal penetration was inhibited after inclusion. The CHL/SBE-ß-CD displayed sustained release profiles. The tear fluid elimination kinetic study showed that the CHL/SBE-ß-CD eye drops had better ability to prolong the residence time, and significantly increase CHL concentration in the conjunctival sac. Besides, it was shown that CHL/SBE-ß-CD eye drops were nonirritating to rabbits' eyes. Conclusions: The SBE-ß-CD inclusions offer a potential alternative strategy for ocular administration of poorly water-soluble drugs in the conjunctival sac.

Seabuckthorn berry polysaccharide extracts protect against acetaminophen induced hepatotoxicity in mice via activating the Nrf-2/HO-1-SOD-2 signaling pathway.

BACKGROUND: Oxidative stress is concomitant with acetaminophen (APAP)-induced hepatotoxicity, which has been highlighted as therapeutic targets for such diseases. The berries of Seabuckthorn (Hippophae rhamnoides L.) have been traditionally used in Tibetan medicine for thousands of years. The effect of Seabuckthorn berry polysaccharide on drug- induced liver injury (DILI) has not yet been elucidated. PURPOSE: This study aims to investigate the protective effects and mechanisms of Seabuckthorn polysaccharide (SP) against APAP-induced hepatotoxicity. STUDY DESIGN: Sixty C57BL/6 mice were randomly divided into six groups (n = 10 per group), namely the control group (Ctrl), APAP-induced-liver injury group (APAP), NAC pretreated group (NAC), 100 mg/kg SP pretreated group (APAP/SP100), 200 mg/kg SP pretreated group (APAP/SP200) and 200 mg/kg SP pretreated group without APAP challenge (SP200). SP was given orally to mice for 30 consecutive days prior to APAP exposure (300 mg/kg). NAC (150 mg/kg) was administrated 1 h before APAP challenge. METHODS: ALT and AST were detected 16 h after APAP treatment; Hepatic expression of GSH, SOD, NO, iNOS and GSH-Px were examined. The expression of p-JNK, Bcl-2/Bax, p62, Keap-1 and SOD-2 was detected by Western blotting. The expression of Nrf-2 and its target genes HO-1, GCLC and NQO-1 were analyzed by RT-PCR and Western blotting. RESULTS: Pretreatment with SP led to decreased levels of ALT and AST in APAP mice, without affecting APAP metabolism. This was accompanied by diminished liver injuries, increased levels of GSH and GSH-Px, reduced NO and iNOS expression. SP increased the activity of SOD as well as SOD-2 expression in APAP mice. SP suppressed APAP-induced JNK phosphorylation and increased the ratio of Bcl-2/Bax. Furthermore, SP decreased the expression of Keap-1 and increased the nuclear expression of Nrf-2. The expression of Nrf-2 target gene HO-1 was increased by SP pretreatment in APAP mice. CONCLUSION: SP alleviates APAP-induced hepatotoxicity. The protective effects of SP are associated with the activation of the Nrf-2/HO-1-SOD-2 signaling pathway.

Electrochemical detection of protein kinase activity based on carboxypeptidase Y digestion triggered signal amplification.

An effective assay method for monitoring protein kinase activity and screening inhibitors is greatly beneficial to kinase-related drug discovery, early diagnosis of diseases, and therapeutic effect evaluation. Herein, we develop a simple electrochemical method for detecting the activity of casein kinase II (CK2) based on phosphorylation against carboxypeptidase Y (CPY) digestion triggered signal amplification, where CK2 catalyzed phosphorylation event protects the substrate peptide from the digestion of CPY, maintains the repulsive force of the substrate peptide towards the redox probe, and results in a weak electrochemical signal. Whereas, without phosphorylation, the substrate peptide is digested by CPY and a strong electrochemical signal is obtained. The detection feasibility is demonstrated for the assay of CK2 activity with low detection limit of 0.047unit/mL. Moreover, the biosensor was used for the analysis of kinase inhibition. Based on the electrochemical signal dependent inhibitor concentration, the IC50 value of ellagic acid was estimated to be 39.77nM. The proposed method is also successfully applied to analyze CK2 activity in cell lysates, proving the applicability in complex biological samples.