Hepatic IRE1α-XBP1 signaling promotes GDF15-mediated anorexia and body weight loss in chemotherapy.

Platinum-based chemotherapy drugs can lead to the development of anorexia, a detrimental effect on the overall health of cancer patients. However, managing chemotherapy-induced anorexia and subsequent weight loss remains challenging due to limited effective therapeutic strategies. Growth differentiation factor 15 (GDF15) has recently gained significant attention in the context of chemotherapy-induced anorexia. Here, we report that hepatic GDF15 plays a crucial role in regulating body weight in response to chemo drugs cisplatin and doxorubicin. Cisplatin and doxorubicin treatments induce hepatic Gdf15 expression and elevate circulating GDF15 levels, leading to hunger suppression and subsequent weight loss. Mechanistically, selective activation by chemotherapy of hepatic IRE1α-XBP1 pathway of the unfolded protein response (UPR) upregulates Gdf15 expression. Genetic and pharmacological inactivation of IRE1α is sufficient to ameliorate chemotherapy-induced anorexia and body weight loss. These results identify hepatic IRE1α as a molecular driver of GDF15-mediated anorexia and suggest that blocking IRE1α RNase activity offers a therapeutic strategy to alleviate the adverse anorexia effects in chemotherapy.

Effectiveness of nurse-delivered stepwise swallowing training on dysphagia in patients with Alzheimer's disease: A multi-center randomized controlled trial.

BACKGROUND: Although swallowing exercises are a fundamental treatment for dysphagia, few studies have evaluated the effectiveness of swallowing training in patients with Alzheimer's disease. METHODS: We recruited 93 patients with Alzheimer's disease from three hospitals in Guangdong, China. This was a parallel armed randomized controlled trial that randomly assigned patients to intervention (n = 48) and control (n = 45) groups. The intervention group adopted systematic stepwise swallowing training for four weeks based on routine dysphagia care. The control group implemented routine dysphagia care, including diet and posture management and health education about swallowing dysfunction. The swallowing function was the primary outcome, which was assessed using the Water Swallowing Test and Standard Swallowing Assessment. An abnormal eating behavior questionnaire was used to assess the incidence of aberrant eating behavior in patients with Alzheimer's disease. The Mini-Nutritional Assessment Short Form and Barthel index were adopted to evaluate the nutritional status and ability to carry out daily activities between groups. SPSS software was used to perform the chi-square test, t-test, and generalized estimation equation for data analysis. RESULTS: We analyzed the effects of the stepwise swallowing training program using the generalized estimating equation method. The intervention group exhibited greater improvements in their swallowing function (Water Swallowing Test: ß = -3.133, 95 % CI: -4.113, -2.154, P < 0.001; Standard Swallowing Assessment: ß = -5.813, 95 % CI: -7.782, -3.844, P < 0.001), abnormal eating behaviors (abnormal eating behavior questionnaire: ß = -13.324, 95 % CI: -21.643, -5.005, P = 0.002), daily function (Barthel index: ß = 11.280, 95 % CI: 4.021, 18.540, P = 0.002), and nutritional status (Mini-Nutritional Assessment Short Form: ß = 2.402, 95 % CI: 1.313, 3.490, P < 0.001) over time than the routine-care group in the fourth week. CONCLUSIONS: Stepwise swallowing training is a safe and effective intervention for managing dysphagia and other related symptoms in patients with Alzheimer's disease.

Physical condition and activity of daily living among aging inpatients with mental disorders in Guangzhou, China: a cross-sectional study.

BACKGROUND: The number of elderly with mental disorders is increasing, but few studies have been concerned with the physical condition and activities of daily living (ADL) of these patients. This study aims to describe the physical condition and ADL of patients with mental illnesses (PMI) from different age groups, which provides evidence to improve mental health services for PMI. METHODS: In this prospective cross-sectional study, the samples were divided into three groups of less than 60 years old (group 1), 60-74 years old (group 2), and over 75 years old (group 3) for comparison. Participants' ADL and physical condition were measure by Barthel Index (BI), Functional Activities Questionnaire (FAQ), Standardised swallowing assessment (SSA) and Short Form of Mini Nutrition Assessment (MNA-SF). The Brief Psychiatric Rating Scale (BPRS) and the Mini-Mental State Examination (MMSE) were used to measure psychological condition. RESULTS: Totally, 392 participants had been recruited, meanwhile 86% of them were diagnosed with at least one physical disease. There were statistically significant differences in the three groups of participants in BI (F = 50.603, P < 0.001), FAQ (F = 40.332, P < 0.001), SSA (F = 28.574, P < 0.001), and MNA-SF (F = 18.366, P < 0.001). Group 2 and group 3 had significantly lower scores in BI and FAQ than group 1, and the SSA scores were significantly higher than the participants in group 1. In the negative symptoms subscale of BPRS, the mean score of group 3 was significantly higher than groups 1 and 2. Negative symptom subscale has different degrees of correlation with BI (r = -0.537), FAQ (r = 0.643), SSA (r = 0.480), MNA (r = -0.325) and MMSE (r = 0.607). In addition, the participants with comorbidities were related to BI (r = -0.364). CONCLUSION: Somatic comorbidities play a pivotal role in the clinical characteristics of elderly patients with mental illness, thus greater effort should be paid to elderly patients suffering from mental illness with dysphagia, malnutrition, and cognitive decline. Further, the negative symptoms of elderly patients with mental disorders also deserve attention.

Repair effect of the poly (D,L-lactic acid) nanoparticle containing tauroursodeoxycholic acid-eluting stents on endothelial injury after stent implantation.

Background: Chronic endoplasmic reticulum stress (ERS) plays a crucial role in cardiovascular diseases. Thus, it can be considered a therapeutic target for these diseases. In this study, poly (D,L-lactic acid) (PDLLA) nanoparticle-eluting stents loaded with tauroursodeoxycholic acid (TUDCA), an ER stress inhibitor, was fabricated to assess their ability to reduce endothelial cell apoptosis and promote re-endothelialization after stent implantation. Materials and methods: PDLLA nanoparticles loaded with TUDCA were prepared via the emulsification-solvent evaporation method. The cumulative release rates of TUDCA were measured in vitro via high-performance liquid chromatography. The carotid arteries of rabbits were subsequently implanted with stents in vivo. The rabbits were then sacrificed after 4 weeks for scanning electron microscopy. Meanwhile, TUDCA concentration in the homogenate of the peripheral blood and distal vascular tissue after stent implantation was measured. The effect of TUDCA on ERS, apoptosis, and human umbilical vein endothelial cell (HUVEC) function was investigated in vitro by performing cell migration assay, wound healing assay, cell proliferation assays, endoplasmic reticulum (ER)-specific fluorescence staining, immunofluorescence, and western blotting. Results: TUDCA nanoparticles were released slowly over 28 days. In addition, TUDCA-eluting stents enhanced re-endothelialization and accelerated the recovery of endotheliocytes in vivo. ERS and apoptosis significantly increased in H2O2-treated HUVECs in vitro. Meanwhile, TUDCA reduced apoptosis and improved function by inhibiting ERS in H2O2-treated HUVECs. Decreased rates of apoptosis and ERS were observed after silencing XBP-1s in H2O2-treated HUVECs. Conclusion: TUDCA can inhibit apoptosis and promote re-endothelialization after stent implantation by inhibiting IRE/XBP1s-related ERS. These results indicate the potential therapeutic application of TUDCA as a drug-coated stent.

Elevated homocysteine levels, white matter abnormalities and cognitive impairment in patients with late-life depression.

Background: Cognitive impairment in late-life depression (LLD) is considered to be caused by neurodegenerative changes. Elevated homocysteine (Hcy) levels may be linked to cognitive abnormalities associated with LLD. The important role of white matter (WM) damage in cognitive impairment and pathogenesis in patients with LLD has been widely reported. However, no research has explored the interrelationships of these features in patients with LLD. Objective: The goal of the study was to examine the interrelationship between Hcy levels, cognition, and variations in WM microstructure detected by diffusion tensor imaging (DTI) in patients with LLD. Methods: We recruited 89 healthy controls (HCs) and 113 patients with LLD; then, we measured the plasma Hcy levels of participants in both groups. All individuals performed a battery of neuropsychological tests to measure cognitive ability. Seventy-four patients with LLD and 68 HCs experienced a DTI magnetic resonance imaging (MRI) scan. Results: Patients with LLD showed significantly lower fractional anisotropy (FA) values in the bilateral inferior longitudinal fasciculus than those of healthy participants. Only in LLD patients was Hcy concentration inversely associated to FA values in the forceps minor. Finally, multiple regression analyses showed that an interaction between Hcy levels and FA values in the right cingulum of the cingulate cortex and right inferior longitudinal fasciculus were independent contributors to the executive function of patients with LLD. Conclusion: Our results highlight the complex interplay between elevated homocysteine levels and WM abnormalities in the pathophysiology of LLD-related cognitive impairment, consistent with the neurodegeneration hypothesis.

Ononin alleviates endoplasmic reticulum stress in doxorubicin-induced cardiotoxicity by activating SIRT3.

Doxorubicin (DOX) is a potent anthracycline antineoplastic drug. However, its dose-dependent cardiotoxicity limits its clinical application. Ononin is a natural isoflavone glycoside that is crucial in modulating apoptosis-related signaling pathways. In this study, we assessed the possible cardioprotective effects of ononin in DOX-induced cardiotoxicity and elucidated the underlying molecular mechanisms. In vitro and in vivo assessments were performed using DOX-treated H9C2 cells and rats, respectively. First, DOX was injected into the tail veins of Wistar rats to induce cardiomyopathy. Next, rats in the DOX + Ononin30 and DOX + Ononin60 groups were intragastrically administered ononin two weeks before DOX treatment. H9C2 cells were treated with vehicle or DOX with or without ononin. Next, 3-TYP was used to determine the relationship between endoplasmic reticulum (ER) stress and sirtuin 3 (SIRT3) expression. Ononin treatment ameliorated DOX-induced myocardial injury as determined by echocardiography. Furthermore, ononin partially restored DOX-induced cardiac dysfunction; the left ventricular ejection fraction (LVEF) and left ventricular systolic fractional shortening (LVFS) increased after pre-treatment with ononin. Further, ononin suppressed DOX-induced ER stress and apoptosis in rat cardiomyocytes and H9C2 cells. The Bax/Bcl-2 ratio and 78-kD glucose-regulated protein (GRP78) and CCAAT enhancer-binding protein (CHOP) expression levels were higher in the DOX-treated group than in the control group but ononin treatment improved these parameters. These effects are associated with SIRT3 activity. Moreover, 3-TYP blocked the ononin-mediated protective effects. Hence, ononin positively affected DOX-induced cardiotoxicity by inhibiting ER stress and apoptosis, possibly mediated by stimulation of the SIRT3 pathway.

Evaluating the effectiveness of stepwise swallowing training on dysphagia in patients with Alzheimer's disease: study protocol for a randomized controlled trial.

BACKGROUND: The high prevalence of dysphagia among Alzheimer's disease (AD) patients has become a public health and economic concern. Therefore, effective and accessible dysphagia treatments are needed. As a fundamental rehabilitation of dysphagia, swallowing muscle exercises have received increased attention. Stepwise swallowing training (SST), integrated with all swallowing organs movement, is expected to improve swallowing dysfunction among AD patients. By using a randomized controlled trial design, we propose a multi-center research to evaluate the effectiveness of SST program among AD patients. METHODS: A multi-center exploratory randomized controlled trial, with a 4-week follow-up period, will be conducted in three major public psychiatric hospitals in Guangdong, China. Participants in the control group will be assigned to routine dysphagia care, while participants in the intervention group will undergo the same nursing care and additionally receive the SST program. The SST program includes five sections of swallowing organs training: lip movement, facial movement, tongue movement, mandibular movement, and neck movement. Primary outcomes evaluate the swallowing function, namely, Water Swallowing Test (WTS) and Standard Swallowing Assessment (SSA). Secondary outcomes aim at measuring the improvement of negative impacts of dysphagia, namely eating behavior, ability of daily activity, and nutritional status. Data will be collected at baseline (T1), at 2 weeks (T2, intervention), and 4 weeks after intervention (T3, follow-up). DISCUSSION: This study will offer trial-based evidence of the effectiveness of SST in relieving dysphagia among AD patients. SST program is expected to improve both the swallowing function and reduce the negative impacts of dysphagia, with an exploration of acceptability in the SST program. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2200056481 . Prospectively registered on 6 February 2022.

METTL14 suppresses pyroptosis and diabetic cardiomyopathy by downregulating TINCR lncRNA.

N6-methyladenosine (m6A) is one of the most important epigenetic regulation of RNAs, such as lncRNAs. However, the underlying regulatory mechanism of m6A in diabetic cardiomyopathy (DCM) is very limited. In this study, we sought to define the role of METTL14-mediated m6A modification in pyroptosis and DCM progression. DCM rat model was established and qRT-PCR, western blot, and immunohistochemistry (IHC) were used to detect the expression of METTL14 and TINCR. Gain-and-loss functional experiments were performed to define the role of METTL14-TINCR-NLRP3 axis in pyroptosis and DCM. RNA pulldown and RNA immunoprecipitation (RIP) assays were carried out to verify the underlying interaction. Our results showed that pyroptosis was tightly involved in DCM progression. METTL14 was downregulated in cardiomyocytes and hear tissues of DCM rat tissues. Functionally, METTL14 suppressed pyroptosis and DCM via downregulating lncRNA TINCR, which further decreased the expression of key pyroptosis-related protein, NLRP3. Mechanistically, METTL14 increased m6A methylation level of TINCR gene, resulting in its downregulation. Moreover, the m6A reader protein YTHDF2 was essential for m6A methylation and mediated the degradation of TINCR. Finally, TINCR positively regulated NLRP3 by increasing its mRNA stability. To conclude, our work revealed the novel role of METTL14-mediated m6A methylation and lncRNA regulation in pyroptosis and DCM, which could help extend our understanding the epigenetic regulation of pyroptosis in DCM progression.

Predictors of everyday functional impairment in older patients with schizophrenia: A cross-sectional study.

Objective: This study investigates the prevalence of everyday functional impairment among older adults with schizophrenia and builds a predictive model of functional decline. Methods: A total of 113 hospitalized older patients enrolled in this study. Functional impairment is defined according to the Functional Activities Questionnaire (FAQ). Patients who scored <9 could function independently daily, while those who scored ≥9 had problems in everyday functional activities. Data collected include sociodemographic characteristics, depressive symptoms, social support, and physical comorbidities, which were classified according to the eight anatomical systems of the human body. Results: The sample comprised 75% female participants with a mean age of 63.74 ± 7.42 years old. A total of 33.6% had a functional impairment, while cognitive impairment was present in 63.7%. Independent participants had better urinary system and respiratory system health (P < 0.05). After adjusting for the potential confounders of age, disease course, physical comorbidities, psychiatric symptoms, the ability to independently carry out daily activities, and cognitive function, we found that impaired everyday function is associated with poor cognition, depressive symptoms, first admission, psychiatric symptoms (especially positive symptoms), ADL, and respiratory and urinary system diseases. Conclusion: Everyday functional capacity is predicted by disease course, admission time, cognition, depressive symptoms, severity of psychosis, ability to carry out daily activities, and respiratory and urinary system health status. Urinary system diseases contribute significantly to the prediction of impaired function. Future studies should focus on health status, drug use, and everyday functional recovery in older patients with schizophrenia.

Longitudinal Association Between Cognition and Depression in Patients With Late-Life Depression: A Cross-Lagged Design Study.

Objectives: Although previous studies have extensively confirmed the cross-sectional relationship between cognitive impairment and depression in depressed elderly patients, the findings of their longitudinal associations are still mixed. The purpose of this study was to explore the two-way causal relationship between depression symptoms and cognition in patients with late-life depression (LLD). Methods: A total of 90 patients with LLD were assessed across two time points (baseline and 1-year follow up) on measures of 3 aspects of cognition and depressive symptoms. The data were then fitted to a structural equation model to examine two cross-lagged effects. Results: Depressive symptoms predicted a decline in executive function (ß = 0.864, p = 0.049) but not vice versa. Moreover, depressive symptoms were predicted by a decline in scores of working memory test (ß = -0.406, p = 0.023), respectively. None of the relationships between the two factors was bidirectional. Conclusion: These results provide robust evidence that the relationship between cognition and depressive symptoms is unidirectional. Depressive symptoms may be a risk factor for cognitive decline. The decrease of information processing speed predicts depressive symptoms.

Dihydrolycorine Attenuates Cardiac Fibrosis and Dysfunction by Downregulating Runx1 following Myocardial Infarction.

In spite of early interventions to treat acute myocardial infarction (MI), the occurrence of adverse cardiac remodeling following heart failure due to acute MI remains a clinical challenge. Thus, there is an increasing demand for the development of novel therapeutic agents capable of inhibiting the development of pathological ventricular remodeling. RNA-seq data analysis of acute MI rat models from GEO revealed that Runx1 was the most differentially expressed MI-related gene. In this study, we demonstrated that increased Runx1 expression under pathological conditions results in decreased cardiac contractile function. We identified dihydrolycorine, an alkaloid lycorine, as a promising inhibitor of Runx1. Our results showed that treatment with this drug could prevent adverse cardiac remodeling, as indicated by the downregulation of fibrotic genes using western blotting (collagen I, TGFß, and p-smad3), downregulation of the apoptosis gene Bax, upregulation of the apoptosis gene Bcl-2, and improved cardiac functions, such as LVEF, LVSF, LVESD, and LVEDD. Additionally, dihydrolycorine treatment could rescue cardiomyocyte hypertrophy as demonstrated by wheat germ agglutinin staining, increased expression levels of the punctuate gap junction protein connexin 43, and decreased α-SMA expression, resulting in cardiomyocyte fibrosis in immunofluorescence staining. Molecular docking, binding modeling, and pull-down assays were used to identify potential dihydrolycorine-binding sites in Runx1. When Ad-sh-Runx1 was transfected into hypoxia-cardiomyocytes or injected into the hearts of MI rats, the cardioprotective effects of dihydrolycorine were abolished, and the normal electrophysiological activity of cardiomyocytes was disrupted. Taken together, the results of the present study indicate that dihydrolycorine may inhibit adverse cardiac remodeling after MI through the reduction of Runx1, suggesting that dihydrolycorine-mediated-Runx1 regulation might represent a novel therapeutic approach for adverse cardiac remodeling after MI.

Yellow Wine Polyphenolic Compound Protects Against Doxorubicin-Induced Cardiotoxicity by Modulating the Composition and Metabolic Function of the Gut Microbiota.

BACKGROUND: Dietary polyphenols help to prevent cardiovascular diseases, and interactions between polyphenols and gut microbiota are known to exist. In this study, we speculated that gut microbiota-mediated metabolite regulation might contribute to the anticardiotoxic effects of yellow wine polyphenolic compound (YWPC) in doxorubicin (DOX)-treated rats. METHODS: 16S-rDNA sequencing was performed to analyze the effects of YWPC on the gut microbiota in DOX-treated rats (n=6). Antibiotics were used to investigate the contribution of the altered microbiome to the role of YWPC (n=6). Plasma metabolomics were also analyzed by untargeted gas chromatography-mass spectrometry systems. RESULTS: YWPC ameliorated DOX-mediated cardiotoxicity, as evidenced by increased cardiac and mitochondrial function and reduced levels of inflammation and myocardial apoptosis (P<0.05 for all). The low abundance of Escherichia-Shigella, Dubosiella, and Allobaculum, along with enrichment of Muribaculaceae_unclassified, Ralstonia, and Rikenellaceae_RC9_gut_group in the gut, suggested that YWPC ameliorated DOX-induced microbial dysbiosis. YWPC also influenced the levels of metabolites altered by DOX, resulting in lower arachidonic acid and linoleic acid metabolism and higher tryptophan metabolite levels (P<0.05 for all). Correlational studies indicated that YWPC alleviated DOX-induced inflammation and mitochondrial dysfunction by modulating the gut microbial community and its associated metabolites. Antibiotic treatment exacerbated cardiotoxicity in DOX-treated rats, and its effect on the gut microbiota partly abolished the anticardiotoxic effects of YWPC, suggesting that the microbiota is required for the cardioprotective role of YWPC. CONCLUSIONS: YWPC protected against DOX-induced cardiotoxicity in a gut microbiota-dependent manner. This supports the use of dietary polyphenols as a therapeutic approach for the treatment of cardiovascular diseases via microbiota regulation.

Inhibition of the long non-coding RNA ZFAS1 attenuates ferroptosis by sponging miR-150-5p and activates CCND2 against diabetic cardiomyopathy.

Diabetic cardiomyopathy (DbCM) is responsible for increased morbidity and mortality in patients with diabetes and heart failure. However, the pathogenesis of DbCM has not yet been identified. Here, we investigated the important role of lncRNA-ZFAS1 in the pathological process of DbCM, which is associated with ferroptosis. Microarray data analysis of DbCM in patients or mouse models from GEO revealed the significance of ZFAS1 and the significant downregulation of miR-150-5p and CCND2. Briefly, DbCM was established in high glucose (HG)-treated cardiomyocytes and db/db mice to form in vitro and in vivo models. Ad-ZFAS1, Ad-sh-ZFAS1, mimic miR-150-5p, Ad-CCND2 and Ad-sh-CCND2 were intracoronarily administered to the mouse model or transfected into HG-treated cardiomyocytes to determine whether ZFAS1 regulates miR-150-5p and CCND2 in ferroptosis. The effect of ZFAS1 on the left ventricular myocardial tissues of db/db mice and HG-treated cardiomyocytes, ferroptosis and apoptosis was determined by Masson staining, immunohistochemical staining, Western blotting, monobromobimane staining, immunofluorescence staining and JC-1 staining. The relationships among ZFAS1, miR-150-5p and CCND2 were evaluated using dual-luciferase reporter assays and RNA pull-down assays. Inhibition of ZFAS1 led to reduced collagen deposition, decreased cardiomyocyte apoptosis and ferroptosis, and attenuated DbCM progression. ZFAS1 sponges miR-150-5p to downregulate CCND2 expression. Ad-sh-ZFAS1, miR-150-5p mimic, and Ad-CCND2 transfection attenuated ferroptosis and DbCM development both in vitro and in vivo. However, transfection with Ad-ZFAS1 could reverse the positive effects of miR-150-5p mimic and Ad-CCND2 in vitro and in vivo. lncRNA-ZFAS1 acted as a ceRNA to sponge miR-150-5p and downregulate CCND2 to promote cardiomyocyte ferroptosis and DbCM development. Thus, ZFAS1 inhibition could be a promising therapeutic target for the treatment and prevention of DbCM.

Olfactory Dysfunction Is Already Present with Subjective Cognitive Decline and Deepens with Disease Severity in the Alzheimer's Disease Spectrum.

BACKGROUND: Odor identification dysfunction occurs early in Alzheimer's disease (AD) and is considered a preclinical symptom along with subjective cognitive decline (SCD). Nevertheless, whether subjects with SCD are co-symptomatic with odor identification dysfunction remains unclear. OBJECTIVE: To compare the degree of odor identification dysfunction and assess the relation between odor identification and cognitive performance in the AD spectrum (including SCD, mild cognitive impairment (MCI), and AD). METHODS: Patients (84 SCD, 129 MCI, 52 AD) and 35 controls underwent the Sniffin' Sticks Screen 16 test and comprehensive neuropsychological examination. RESULTS: Odor identification scores were progressively lower moving from normal older adult to SCD, MCI, and AD. Additionally,the proportion of odor identification dysfunction were increasingly higher in the AD spectrum (p for trend <0.001), but no significant difference was found in the proportion of subjective olfactory dysfunction. No significant correlation was found between odor identification and cognition in the normal older adults and SCD subjects, but odor identification correlated with global cognition in the MCI (r = 0.199, p = 0.033) and in the AD (r = 0.300, p = 0.036) patients. Multiple linear regression showed that odor identification dysfunction was most strongly associated with memory among different cognitive subdomains and was most strongly associated with immediate verbal recall among different memory subdomains. CONCLUSION: Odor identification dysfunction is already present with SCD and deepens with disease severity in the AD spectrum, and it may contribute to predicting cognitive decline and identifying SCD subjects who are at risk of developing AD.

Abnormal Serum Bilirubin/Albumin Concentrations in Dementia Patients With Aß Deposition and the Benefit of Intravenous Albumin Infusion for Alzheimer's Disease Treatment.

BACKGROUND: Our previous study in animal models revealed that bilirubin could induce Aß formation and deposition. Bilirubin may be important in neurodegenerative dementia with Aß deposition. Hence, lowering the concentration of the free bilirubin capable of crossing the blood brain-barrier may benefit the treatment of Alzheimer's disease (AD). OBJECTIVES: The objectives of this study were to examine the change in the serum bilirubin and albumin concentrations of dementia patients with Aß deposition, and to determine the effects of intravenous administration of albumin in the treatment of AD. METHODS: Bilirubin and albumin concentrations in dementia patients with Aß deposition were examined. Cell viability and apoptosis were determined in dopaminergic neuron-like cells MN9D treated with bilirubin in the presence of diverse concentrations of serum. Human albumin at a dose of 10 g every 2 weeks for 24 weeks was administered intravenously to AD patients to examine the effect of albumin on AD symptoms. RESULTS: Significantly higher indirect bilirubin (IBIL) concentrations, lower albumin concentrations, and higher ratio of IBIL to albumin (IBIL/ALB) were observed in dementia patients with Aß deposition, including AD, dementia with Lewy bodies, and general paresis of insane. In vitro assays showed that bilirubin-induced injury in cultured dopaminergic neuron-like cells negatively depends on the concentration of serum in the culture medium. General linear model with repeated measures analysis indicated a main effect of group on the change in albumin concentrations and Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory scale (ADCS-ADL) scores, and the main effect of time and group, and group-by-time interaction on the change of Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) scores. Analysis of the combined data of the entire 28 weeks of assessment period using the area under curve convincingly showed significantly improvements in the change of albumin concentrations, ADCS-ADL scores, and CDR-SB scores. CONCLUSION: IBIL and the IBIL/ALB ratio are significantly higher in dementia patients with Aß deposition, and intravenous administration of albumin is beneficial to AD treatment. TRIAL REGISTRATION: The intervention study was registered at http://www.chictr.org.cn (ChiCTR-IOR-17011539). Date of registration: June 1, 2017.

Interactive effects of elevated homocysteine and late-life depression on cognitive impairment.

BACKGROUND: Both an elevated homocysteine (Hcy) level and depression are risk factors for cognitive impairment in the general population, but no study has analyzed whether the coexistence of an elevated Hcy level and late-life depression (LLD) is associated with worse cognitive performance. OBJECTIVE: We aimed to investigate the relationship between Hcy levels and cognitive function in individuals with LLD and whether the coexistence of an elevated Hcy level and LLD is associated with worse cognitive performance. METHODS: A total of 113 LLD patients and 89 normal controls underwent a standardized clinical interview and comprehensive neuropsychological assessment battery. Plasma concentrations of Hcy were detected. Factorial analyses were performed to examine the impact of the coexistence of an elevated Hcy level and LLD on cognitive performance. RESULTS: Plasma Hcy levels in patients with LLD were significantly higher than that in normal controls. Only for LLD patients, Hcy level was negatively correlated with global cognition, executive function, attention, and visual space. The factorial analysis showed that there was a significant interactive effect of Hcy level (normal and elevated levels) and LLD (with and without LLD) on global cognition. In post hoc comparisons, the elderly individuals with both elevated Hcy levels and LLD tended to have the worst global cognitive function compared with those with LLD or elevated Hcy levels alone. CONCLUSIONS: The coexistence of an elevated Hcy level and LLD was associated with worse cognitive performance. Early intervention should be initiated to protect cognition in LLD patients with elevated Hcy levels.

Fucoidan from Fucus vesiculosus attenuates doxorubicin-induced acute cardiotoxicity by regulating JAK2/STAT3-mediated apoptosis and autophagy.

Doxorubicin (DOX) is well-known for its potent antitumor activity but limited by its multiple and serious adverse effects. A major adverse effect is acute cardiotoxicity; yet, its mechanism has not been elucidated. Fucoidan is a multifunctional and nontoxic polysaccharide that is widely studied because of its favorable biological activities and safety. Hence, we proposed that fucoidan may play a protective role in DOX-induced acute cardiotoxicity without causing additional side effects. Sprague-Dawley rats were injected intraperitoneally with a single high dose of DOX to induce acute cardiac injury. Fucoidan was administered orally before DOX injection and AG490, a JAK2 inhibitor, was applied to verify the participation of the JAK2/STAT3 pathway. In vitro, H9C2 cells were treated with the same drugs at different concentrations and intervention times. in vivo and in vitro results demonstrated that DOX administration induced myocardial damage accompanied by acceleratory apoptosis and deficient autophagy in heart tissues or cells, which could be significantly improved by fucoidan supplement. AG490 partly abolished the cardioprotective effects of fucoidan, suggesting the involvement of JAK2 signaling. Additionally, western blotting revealed DOX-induced JAK2/STAT3 pathway activation, which was enhanced by fucoidan and weaken by AG490. Hence, fucoidan exerted a favorable effect on DOX-induced cardiotoxicity by enhancing autophagy and suppressing apoptosis in a JAK2/STAT3-dependent manner, which may provide a promising and novel therapeutic strategy against negative chemotherapy-induced effects.

Icariin Ameliorates Diabetic Cardiomyopathy Through Apelin/Sirt3 Signalling to Improve Mitochondrial Dysfunction.

Myocardial contractile dysfunction in diabetic cardiomyocytes is a significant promoter of heart failure. Herein, we investigated the effect of icariin, a flavonoid monomer isolated from Epimedium, on diabetic cardiomyopathy (DCM) and explored the mechanisms underlying its unique pharmacological cardioprotective functions. High glucose (HG) conditions were simulated in vitro using cardiomyocytes isolated from neonatal C57 mice, while DCM was stimulated in vivo in db/db mice. Mice and cardiomyocytes were treated with icariin, with or without overexpression or silencing of Apelin and Sirt3 via transfection with adenoviral vectors (Ad-RNA) and specific small hairpin RNAs (Ad-sh-RNA), respectively. Icariin markedly improved mitochondrial function both in vivo and in vitro, as evidenced by an increased level of mitochondrial-related proteins via western blot analysis (PGC-1α, Mfn2, and Cyt-b) and an increased mitochondrial membrane potential, as observed via JC-1 staining. Further, icariin treatment decreased cardiac fibrogenesis (Masson staining), and inhibited apoptosis (TUNEL staining). Together, these changes improved cardiac function, according to multiple transthoracic echocardiography parameters, including LVEF, LVSF, LVESD, and LVEDD. Moreover, icariin significantly activated Apelin and Sirt3, which were inhibited by HG and DCM. Importantly, when Ad-sh-Apelin and Ad-sh-Sirt3 were transfected in cardiomyocytes or injected into the heart of db/db mice, the cardioprotective effects of icariin were abolished and mitochondrial homeostasis was disrupted. Further, it was postulated that since Ad-Apelin induced different results following increased Sirt3 expression, icariin may have attenuated DCM development by preventing mitochondrial dysfunction through the Apelin/Sirt3 pathway. Hence, protection against mitochondrial dysfunction using icariin may prove to be a promising therapeutic strategy against DCM in diabetes.

Adjunctive intranasal esketamine for major depressive disorder: A systematic review of randomized double-blind controlled-placebo studies.

OBJECTIVES: This is a meta-analysis of randomized double-blind controlled-placebo trials (RCTs) examining the effectiveness, tolerability, and safety of intranasal esketamine in treating major depressive disorder (MDD). METHODS: Standardized mean difference (SMD), risk ratio (RR) and their 95% confidence intervals (CIs) were calculated using RevMan version 5.3. RESULTS: Four RCTs with 7 active arms covering 708 patients with MDD on intranasal esketamine (n = 419) and placebo (n = 289) were included. Compared with placebo, adjunctive intranasal esketamine was associated with significantly greater study-defined response (RR=1.39, 95%CI: 1.18 to 1.64, P<0.0001) and remission (RR=1.42, 95%CI: 1.17 to 1.72, P = 0.0004) at endpoint assessment. Intranasal esketamine had greater study-defined response starting at 2 h (RR= 2.77, 95%CI: 1.62 to 4.76, P = 0.0002), peaking at 24 h (RR=5.42, 95%CI: 1.38 to 21.20, P = 0.02), and at least lasting for 28 days (RR=1.36, 95%CI: 1.16 to 1.58, P = 0.0001). Similarly, intranasal esketamine had significantly greater study-defined remission starting at 2 h (RR=7.71, 95%CI: 2.16 to 27.55, P = 0.002), peaking at 24 h (RR=6.87, 95%CI: 1.55 to 30.35, P = 0.01), and lasting for 28 days (RR=1.38, 95%CI: 1.11 to 1.72, P = 0.004). Intranasal esketamine had a significantly higher rate of discontinuation due to intolerability (RR=3.50, 95%CI: 1.38 to 8.86, P = 0.008). Discontinuation due to any reasons and inefficacy were similar between the two groups. CONCLUSION: Intranasal esketamine appears to have an ultra-rapid antidepressant effect for MDD, at least lasting for 28 days. The long-term therapeutic effect and safety of intranasal esketamine need to be further examined in large-scale RCTs.