Effects of Otago exercise program on physical function in older adults: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Maintaining physical function is critical for older adults to achieve healthy aging. The Otago exercise program (OEP) has been widely used to prevent falls for older adults. However, the effects of OEP on physical function remain controversial and the possible effects modifiers have not been assessed. OBJECTIVE: To evaluate the effects of OEP on physical function in older adults and to explore potential moderators underlying the effects of OEP. METHODS: We searched five electronic databases and relevant systematic reviews to identify studies. We included randomized controlled trials (RCTs) evaluating the effects of OEP as a single intervention on physical function among older adults aged 65 and over. Meta-analysis was performed using the random-effects model. Standardized mean differences (SMD) for physical function changes, pertinent to balance, strength, and mobility, were outcome measures. Subgroup analyses on exercise protocol and participants' characteristics were performed. RESULTS: Thirteen RCTs consisting of 2402 participants were included in this systematic review and meta-analysis. Results indicated a significant effect of OEP on balance (SMD = 0.59, 95 % CI: 0.22∼0.96), lower body strength (SMD = 0.93, 95 % CI: 0.31∼1.55), and mobility (SMD = -0.59, 95 % CI: -0.95∼-0.22) against control groups. No significant OEP effects were found on upper body strength (MD = 1.48, 95 % CI: -0.58∼3.55). Subgroup analysis revealed that the video-supported delivery mode was more effective for improving balance (P = 0.04) and mobility (P = 0.02) than the face-to-face mode. Session durations over 30 min was more effective on lower body strength (P < 0.001) and mobility (P < 0.001) than those 1-30 min. Program period of 13-26 weeks was more effective on mobility (P = 0.02) than those of 4-12 weeks. However, the effects of OEP on physical function were not associated with age groups, and baseline falling risks. CONCLUSION: The OEP could improve physical function including balance, lower body strength, and mobility in older adults. Implementing the OEP in video-supported, more than 30 min per session and 4-12 weeks may be the most appropriate and effective exercise protocol for improving physical function among older adults. More RCTs with rigorous design and larger scale are needed to further assess the effectiveness of diverse OEP protocols and quantify the dose-effect relationship.

Rectifying METTL4-Mediated N6-Methyladenine Excess in Mitochondrial DNA Alleviates Heart Failure.

BACKGROUND: Myocardial mitochondrial dysfunction underpins the pathogenesis of heart failure (HF), yet therapeutic options to restore myocardial mitochondrial function are scarce. Epigenetic modifications of mitochondrial DNA (mtDNA), such as methylation, play a pivotal role in modulating mitochondrial homeostasis. However, their involvement in HF remains unclear. METHODS: Experimental HF models were established through continuous angiotensin II and phenylephrine (AngII/PE) infusion or prolonged myocardial ischemia/reperfusion injury. The landscape of N6-methyladenine (6mA) methylation within failing cardiomyocyte mtDNA was characterized using high-resolution mass spectrometry and methylated DNA immunoprecipitation sequencing. A tamoxifen-inducible cardiomyocyte-specific Mettl4 knockout mouse model and adeno-associated virus vectors designed for cardiomyocyte-targeted manipulation of METTL4 (methyltransferase-like protein 4) expression were used to ascertain the role of mtDNA 6mA and its methyltransferase METTL4 in HF. RESULTS: METTL4 was predominantly localized within adult cardiomyocyte mitochondria. 6mA modifications were significantly more abundant in mtDNA than in nuclear DNA. Postnatal cardiomyocyte maturation presented with a reduction in 6mA levels within mtDNA, coinciding with a decrease in METTL4 expression. However, an increase in both mtDNA 6mA level and METTL4 expression was observed in failing adult cardiomyocytes, suggesting a shift toward a neonatal-like state. METTL4 preferentially targeted mtDNA promoter regions, which resulted in interference with transcription initiation complex assembly, mtDNA transcriptional stalling, and ultimately mitochondrial dysfunction. Amplifying cardiomyocyte mtDNA 6mA through METTL4 overexpression led to spontaneous mitochondrial dysfunction and HF phenotypes. The transcription factor p53 was identified as a direct regulator of METTL4 transcription in response to HF-provoking stress, thereby revealing a stress-responsive mechanism that controls METTL4 expression and mtDNA 6mA. Cardiomyocyte-specific deletion of the Mettl4 gene eliminated mtDNA 6mA excess, preserved mitochondrial function, and mitigated the development of HF upon continuous infusion of AngII/PE. In addition, specific silencing of METTL4 in cardiomyocytes restored mitochondrial function and offered therapeutic relief in mice with preexisting HF, irrespective of whether the condition was induced by AngII/PE infusion or myocardial ischemia/reperfusion injury. CONCLUSIONS: Our findings identify a pivotal role of cardiomyocyte mtDNA 6mA and the corresponding methyltransferase, METTL4, in the pathogenesis of mitochondrial dysfunction and HF. Targeted suppression of METTL4 to rectify mtDNA 6mA excess emerges as a promising strategy for developing mitochondria-focused HF interventions.

Assessment of Efficacy and Accuracy of Cervical Cytology Screening With Artificial Intelligence Assistive System.

The role of artificial intelligence (AI) in pathology offers many exciting new possibilities for improving patient care. This study contributes to this development by identifying the viability of the AICyte assistive system for cervical screening, and investigating the utility of the system in assisting with workflow and diagnostic capability. In this study, a novel scanner was developed using a Ruiqian WSI-2400, trademarked AICyte assistive system, to create an AI-generated gallery of the most diagnostically relevant images, objects of interest (OOI), and provide categorical assessment, according to Bethesda category, for cervical ThinPrep Pap slides. For validation purposes, 2 pathologists reviewed OOIs from 32,451 cases of ThinPrep Paps independently, and their interpretations were correlated with the original ThinPrep interpretations (OTPI). The analysis was focused on the comparison of reporting rates, correlation between cytological results and histologic follow-up findings, and the assessment of independent AICyte screening utility. Pathologists using the AICyte system had a mean reading time of 55.14 seconds for the first 3000 cases trending down to 12.90 seconds in the last 6000 cases. Overall average reading time was 22.23 seconds per case compared with a manual reading time approximation of 180 seconds. Usage of AICyte compared with OTPI had similar sensitivity (97.89% vs 97.89%) and a statistically significant increase in specificity (16.19% vs 6.77%) for the detection of cervical intraepithelial neoplsia 2 and above lesions. When AICyte was run alone at a 50% negative cutoff value, it was able to read slides with a sensitivity of 99.30% and a specificity of 9.87%. When AICyte was run independently at this cutoff value, no sole case of high-grade squamous intraepithelial lesions/squamous cell carcinoma squamous lesion was missed. AICyte can provide a potential tool to help pathologists in both diagnostic capability and efficiency, which remained reliable compared with the baseline standard. Also unique for AICyte is the development of a negative cutoff value for which AICyte can categorize cases as "not needed for review" to triage cases and lower pathologist workload. This is the largest case number study that pathologists reviewed OOI with an AI-assistive system. The study demonstrates that AI-assistive system can be broadly applied for cervical cancer screening.

Barriers and facilitators to acceptance and implementation of eMental-health intervention among older adults: A qualitative systematic review.

Objective: Electronic mental health interventions are effective but not well promoted currently among older adults. This study sought to systematically review and summarize the barriers and facilitators of accepting and implementing electronic mental health interventions among older adults. Methods: We comprehensively retrieved six electronic databases from January 2012 to September 2022: PubMed, Web of Science, Embase, Scopus, PsycINFO, and CINAHL. The JBI-QARI was used to assess the quality of the research methodology of each publication. Eligible studies underwent data coding and synthesis aligned to inductive and deductive methods. The Consolidated Framework for Implementation Research 2.0 was used as a deductive framework to guide a more structured analysis. Results: The systematic review screened 4309 articles, 17 of which were included (eight with mixed methods and nine with qualitative methods). We identified and extracted the barriers and facilitators of accepting and implementing electronic mental health interventions among older adults: (1) innovation: technology challenges, optimized functions, and contents, security and privacy; (2) outer setting: community engagement and partnerships, financing; (3) inner setting: leadership engagement, available resources, incompatibility, intergenerational support, training and guidance; (4) individuals: perceptions, capability, motivation of older adults and healthcare providers; and (5) implementation process: recruit, external assistance, and team. Conclusion: These findings are critical to optimizing, promoting, and expanding electronic mental health interventions among older adults. The systematic review also provides a reference for better evidence-based implementation strategies in the future.

Development and validation of prediction model for older adults with cognitive frailty.

OBJECTIVE: This study sought to develop and validate a 6-year risk prediction model in older adults with cognitive frailty (CF). METHODS: In the secondary analysis of Chinese Longitudinal Healthy Longevity Survey (CLHLS), participants from the 2011-2018 cohort were included to develop the prediction model. The CF was assessed by the Chinese version of Mini-Mental State Exam (CMMSE) and the modified Fried criteria. The stepwise regression was used to select predictors, and the logistic regression analysis was conducted to construct the model. The model was externally validated using the temporal validation method via the 2005-2011 cohort. The discrimination was measured by the area under the curve (AUC), and the calibration was measured by the calibration plot. A nomogram was conducted to vividly present the prediction model. RESULTS: The development dataset included 2420 participants aged 60 years or above, and 243 participants suffered from CF during a median follow-up period of 6.91 years (interquartile range 5.47-7.10 years). Six predictors, namely, age, sex, residence, body mass index (BMI), exercise, and physical disability, were finally used to develop the model. The model performed well with the AUC of 0.830 and 0.840 in the development and external validation datasets, respectively. CONCLUSION: The study could provide a practical tool to identify older adults with a high risk of CF early. Furthermore, targeting modifiable factors could prevent about half of the new-onset CF during a 6-year follow-up.

Internet-delivered psychological interventions for older adults with depression: A scoping review.

BACKGROUND: Depression is prevalent among older adults, and internet-delivered psychological interventions (IDPIs) have emerged as a promising solution. AIM: To explore the landscape of IDPIs for late-life depression, examining current characteristics, psychotherapies, intervention strategies, facilitators, and barriers. METHOD: Guided by a PRISMA-guided scoping review, we systematically searched five electronic databases. RESULTS: 25 relevant studies were identified. IDPIs were used for treatment, prevention, and assessment. Internet-based cognitive behavioral therapy was the most common psychotherapy. Seven strategies to provide tailored services include psychotherapy courses, professional involvement, mood and progress tracking, virtual community, timed reminders, additional learning resources, and gamification elements. Barriers contained cognitive impairment, low digital literacy, device inaccessibility, limited depression awareness, adherence issues, and acclimation time, while facilitators included prior treatment experience, real-life character stories, strong client-worker bonds, and integration into daily care routines. CONCLUSION: IDPIs present an accessible and convenient avenue for older adults. Future directions suggest exploring minimalist interventions, diverse strategies, and optimized implementation to amplify IDPIs impact among this vulnerable group.

Bidirectional associations between hearing difficulty and cognitive function in Chinese adults: a longitudinal study.

Background: Middle-aged and older adults frequently experience hearing loss and a decline in cognitive function. Although an association between hearing difficulty and cognitive function has been demonstrated, its temporal sequence remains unclear. Therefore, we investigated whether there are bidirectional relationships between hearing difficulty and cognitive function and explored the mediating role of depressive symptoms in this relationship. Method: We used the cross-lagged panel model and the random-intercept cross-lagged panel model to look for any possible two-way link between self-reported hearing difficulty and cognitive function. To investigate depressive symptoms' role in this association, a mediation analysis was conducted. The sample was made up of 4,363 adults aged 45 and above from the China Health and Retirement Longitudinal Study (CHARLS; 2011-2018; 44.83% were women; mean age was 56.16 years). One question was used to determine whether someone had a hearing impairment. The tests of cognitive function included episodic memory and intelligence. The Center for Epidemiologic Studies Depression Scale, which consists of 10 items, was used to measure depressive symptoms. Results: A bidirectional association between hearing and cognition was observed, with cognition predominating (Wald χ2 (1) = 7.241, p < 0.01). At the between-person level, after controlling for potential confounders, worse hearing in 2011 predicted worse cognitive function in 2013 (ß = -0.039, p < 0.01) and vice versa (ß = -0.041, p < 0.01) at the between-person level. Additionally, there was no corresponding cross-lagged effect of cognitive function on hearing difficulty; rather, the more hearing difficulty, the greater the cognitive decline at the within-person level. According to the cross-lagged mediation model, depressive symptoms partially mediates the impact of cognitive function on subsequent hearing difficulty (indirect effect: -0.003, bootstrap 95% confidence interval: -0.005, -0.001, p < 0.05), but not the other way around. Conclusion: These results showed that within-person relationships between hearing impairment and cognitive function were unidirectional, while between-person relationships were reciprocal. Setting mental health first may be able to break the vicious cycle that relates hearing loss to cognitive decline. Comprehensive long-term care requires services that address depressive symptoms and cognitive decline to be integrated with the hearing management.

CSF2RB overexpression promotes the protective effects of mesenchymal stromal cells against ischemic heart injury.

Aims: The invasive intramyocardial injection of mesenchymal stromal cells (MSCs) allows for limited repeat injections and shows poor therapeutic efficacy against ischemic heart failure. Intravenous injection is an alternative method because this route allows for repeated, noninvasive, and easy delivery. However, the lack of targeting of MSCs hinders the ability of these cells to accumulate in the ischemic area after intravenous injections. We investigated whether and how the overexpression of colony-stimulating factor 2 receptor beta subunit (CSF2RB) may regulate the cardiac homing of MSCs and their cardioprotective effects against ischemic heart failure. Methods and Results: Adult mice were subjected to myocardial ischemia/reperfusion (MI/R) or sham operations. We observed significantly higher CSF2 protein expression and secretion by the ischemic heart from 1 day to 2 weeks after MI/R. Mouse adipose tissue-derived MSCs (ADSCs) were infected with adenovirus harboring CSF2RB or control adenovirus. Enhanced green fluorescent protein (EGFP)-labeled ADSCs were intravenously injected into MI/R mice every three days for a total of 7 times. Compared with ADSCs infected with control adenovirus, intravenously delivered ADSCs overexpressing CSF2RB exhibited markedly increased cardiac homing. Histological analysis revealed that CSF2RB overexpression significantly enhanced the ADSC-mediated proangiogenic, antiapoptotic, and antifibrotic effects. More importantly, ADSCs overexpressing CSF2RB significantly increased the left ventricular ejection fraction and cardiac contractility/relaxation in MI/R mice. In vitro experiments demonstrated that CSF2RB overexpression increases the migratory capacity and reduces the hypoxia/reoxygenation-induced apoptosis of ADSCs. We identified STAT5 phosphorylation as the key mechanism underlying the effects of CSF2RB on promoting ADSC migration and inhibiting ADSC apoptosis. RNA sequencing followed by cause-effect analysis revealed that CSF2RB overexpression increases the expression of the ubiquitin ligase RNF4. Coimmunoprecipitation and coimmunostaining experiments showed that RNF4 binds to phosphorylated STAT5. RNF4 knockdown reduced STAT5 phosphorylation as well as the antiapoptotic and promigratory actions of ADSCs overexpressing CSF2RB. Conclusions: We demonstrate for the first time that CSF2RB overexpression optimizes the efficacy of intravenously delivered MSCs in the treatment of ischemic heart injury by increasing the response of the MSCs to a CSF2 gradient and CSF2RB-dependent STAT5/RNF4 activation.

Nomograms for predicting overall survival and cancer-specific survival in patients with invasive micropapillary carcinoma: Based on the SEER database.

BACKGROUND: Invasive micropapillary carcinoma (IMPC) is a rare subtype of breast cancer that lacks a prognostic prediction model. Its treatment and prognostic factors remain controversial. Our study aimed to develop nomograms to predict overall survival (OS) and cancer-specific survival (CSS) in IMPC patients. METHODS: A total of 2149 patients confirmed to have IMPC between 2003 and 2018 were selected from the Surveillance, Epidemiology and End Results (SEER) database. They were divided into training and validation cohorts. Univariate and multivariate Cox regression analyses were used to identify significant independent prognostic factors. The nomograms were used to predict 3- and 5-year OS and CSS. The training and validation cohorts were used to verify the nomograms internally and externally. The predictive capability of the nomograms was evaluated by the consistency index (C-index), calibration curve, receiver operating characteristic (ROC) curve and decision curve analysis (DCA) curve. RESULTS: In the study, 2149 IMPC patients were randomized to a training group (n = 1611) and a validation group (n = 538). Age, T stage, N stage, ER, radiotherapy, and surgery were identified as independent prognostic factors for OS and CSS. These variables were selected to construct nomograms for IMPC. The C-index (0.768 for OS and 0.811 for CSS) and the time-dependent AUC (>0.7) indicated satisfactory discriminative ability of the nomograms. Additionally, DCA showed that the nomograms had higher clinical value than traditional TNM tumor staging. CONCLUSIONS: The models can accurately predict the prognosis of IMPC patients and can aid in providing individualized treatment for patients.

Mesenchymal Stromal Cells Overexpressing Farnesoid X Receptor Exert Cardioprotective Effects Against Acute Ischemic Heart Injury by Binding Endogenous Bile Acids.

Bile acid metabolites have been increasingly recognized as pleiotropic signaling molecules that regulate cardiovascular functions, but their role in mesenchymal stromal cells (MSC)-based therapy has never been investigated. It is found that overexpression of farnesoid X receptor (FXR), a main receptor for bile acids, improves the retention and cardioprotection of adipose tissue-derived MSC (ADSC) administered by intramyocardial injection in mice with myocardial infarction (MI), which shows enhanced antiapoptotic, proangiogenic, and antifibrotic effects. RNA sequencing, LC-MS/MS, and loss-of-function studies reveal that FXR overexpression promotes ADSC paracrine angiogenesis via Angptl4. FXR overexpression improves ADSC survival in vivo but fails in vitro. By performing bile acid-targeted metabolomics using ischemic heart tissue, 19 bile acids are identified. Among them, cholic acid and deoxycholic acid significantly increase Angptl4 secretion from ADSC overexpressing FXR and further improve their proangiogenic capability. Moreover, ADSC overexpressing FXR shows significantly lower apoptosis by upregulating Nqo-1 expression only in the presence of FXR ligands. Retinoid X receptor α is identified as a coactivator of FXR. It is first demonstrated that there is a bile acid pool in the myocardial microenvironment. Targeting the bile acid-FXR axis may be a novel strategy for improving the curative effect of MSC-based therapy for MI.

Transcriptional and Metabolic Responses of Maize Shoots to Long-Term Potassium Deficiency.

Potassium is important for plant growth and crop yield. However, the effects of potassium (K+) deficiency on silage maize biomass yield and how maize shoot feedback mechanisms of K+ deficiency regulate whole plant growth remains largely unknown. Here, the study aims to explore the maize growth, transcriptional and metabolic responses of shoots to long-term potassium deficiency. Under the K+ insufficiency condition, the biomass yield of silage maize decreased. The transcriptome data showed that there were 922 and 1,107 differential expression genes in DH605 and Z58, respectively. In the two varieties, 390 differently expressed overlapping genes were similarly regulated. These genes were considered the fundamental responses to K+ deficiency in maize shoots. Many stress-induced genes are involved in transport, primary and secondary metabolism, regulation, and other processes, which are involved in K+ acquisition and homeostasis. Metabolic profiles indicated that most amino acids, phenolic acids, organic acids, and alkaloids were accumulated in shoots under K+ deficiency conditions and part of the sugars and sugar alcohols also increased. It revealed that putrescine and putrescine derivatives were specifically accumulated under the K+ deficiency condition, which may play a role in the feedback regulation of shoot growth. These results confirmed the importance of K+ on silage maize production and provided a deeper insight into the responses to K+ deficiency in maize shoots.

Small Extracellular Vesicles From Brown Adipose Tissue Mediate Exercise Cardioprotection.

RATIONALE: Long-term exercise provides reliable cardioprotection via mechanisms still incompletely understood. Although traditionally considered a thermogenic tissue, brown adipose tissue (BAT) communicates with remote organs (eg, the heart) through its endocrine function. BAT expands in response to exercise, but its involvement in exercise cardioprotection remains undefined. OBJECTIVE: This study investigated whether small extracellular vesicles (sEVs) secreted by BAT and their contained microRNAs (miRNAs) regulate cardiomyocyte survival and participate in exercise cardioprotection in the context of myocardial ischemia/reperfusion (MI/R) injury. METHODS AND RESULTS: Four weeks of exercise resulted in a significant BAT expansion in mice. Surgical BAT ablation before MI/R weakened the salutary effects of exercise. Adeno-associated virus 9 vectors carrying short hairpin RNA targeting Rab27a (a GTPase required for sEV secretion) or control viruses were injected in situ into the interscapular BAT. Exercise-mediated protection against MI/R injury was greatly attenuated in mice whose BAT sEV secretion was suppressed by Rab27a silencing. Intramyocardial injection of the BAT sEVs ameliorated MI/R injury, revealing the cardioprotective potential of BAT sEVs. Discovery-driven experiments identified miR-125b-5p, miR-128-3p, and miR-30d-5p (referred to as the BAT miRNAs) as essential BAT sEV components for mediating cardioprotection. BAT-specific inhibition of the BAT miRNAs prevented their upregulation in plasma sEVs and hearts of exercised mice and attenuated exercise cardioprotection. Mechanistically, the BAT miRNAs cooperatively suppressed the proapoptotic MAPK (mitogen-associated protein kinase) pathway by targeting a series of molecules (eg, Map3k5, Map2k7, and Map2k4) in the signaling cascade. Delivery of BAT sEVs into hearts or cardiomyocytes suppressed MI/R-related MAPK pathway activation, an effect that disappeared with the combined use of the BAT miRNA inhibitors. CONCLUSIONS: The sEVs secreted by BAT participate in exercise cardioprotection via delivering the cardioprotective miRNAs into the heart. These results provide novel insights into the mechanisms underlying the BAT-cardiomyocyte interaction and highlight BAT sEVs and their contained miRNAs as alternative candidates for exercise cardioprotection.

Irisin Promotes Cardiac Homing of Intravenously Delivered MSCs and Protects against Ischemic Heart Injury.

Few intravenously administered mesenchymal stromal cells (MSCs) engraft to the injured myocardium, thereby limiting their therapeutic efficacy for the treatment of ischemic heart injury. Here, it is found that irisin pretreatment increases the cardiac homing of adipose tissue-derived MSCs (ADSCs) administered by single and multiple intravenous injections to mice with MI/R by more than fivefold, which subsequently increases their antiapoptotic, proangiogenic, and antifibrotic effects in rats and mice that underwent MI/R. RNA sequencing, Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway analysis, and loss-of-function studies identified CSF2RB as a cytokine receptor that facilitates the chemotaxis of irisin-treated ADSCs in the presence of CSF2, a chemokine that is significantly upregulated in the ischemic heart. Cardiac-specific CSF2 knockdown blocked the cardiac homing and cardioprotection abilities of intravenously injected irisin-treated ADSCs in mice subjected to MI/R. Moreover, irisin pretreatment reduced the apoptosis of hydrogen peroxide-induced ADSCs and increased the paracrine proangiogenic effect of ADSCs. ERK1/2-SOD2, and ERK1/2-ANGPTL4 are responsible for the antiapoptotic and paracrine angiogenic effects of irisin-treated ADSCs, respectively. Integrin αV/ß5 is identified as the irisin receptor in ADSCs. These results provide compelling evidence that irisin pretreatment can be an effective means to optimize intravenously delivered MSCs as therapy for ischemic heart injury.

Event-based distributed filtering against deception attacks for sensor networks with quantization effect.

This paper considers a distributed secure filtering problem for a category of time-varying system subject to uncertainty and model-reality mismatch, two-stage deception attacks and bandwidth limitation. Both deception attacks between sensor and corresponding estimator and among estimators appear randomly. To alleviate communication burden, a quantization strategy is introduced before transmitting measurement and estimation signals. An event-triggered mechanism is employed for each estimator node thus only necessary data are transmitted to its neighbour sensors when a setting event occurs. The desired target of the problem to be handled is to devise a series of time-varying filters such that the H∞ secure performance is guaranteed against random deception attacks over a finite time horizon. Sufficient conditions ensuring the existence of time-varying filters under effect of complex factors are derived, where filter gains are obtained by finding the solution of a sequence of recursive matrix inequalities online. Simulation results in both numerical example and industrial continuous-stirred tank reactor system are given to show the validity of the presented methodology.

Metabolomics Analysis Reveals Interaction of Base-Line Chemotherapy and Shiyiwei Shenqi Tablets in Breast Cancer Treatment.

Shiyiwei Shenqi Tablet (SSTs) has been widely used for treatment of different types of cancer including breast cancer. SST has drawn more and more interest due to the low rate of side effects. The aim of this study was to investigate the metabolites in serums of breast cancer patients who received base-line chemotherapy only or combination treatment with SST. An untargeted metabolomics method was developed to investigate the alteration of metabolism in patients' serums using ultra-high-performance liquid chromatography/Q-exactive Orbitrap mass spectrometry. The patients were separated based on the metabolomics data, and further analyses showed that SST treatment can affect the metabolism of glucose, fatty acid, bile acid and amino acid. In particular, SST treatment significantly reduced some short peptides which are potential tumor neoantigens. This study may provide novel insights into the mechanism underlying interaction between SST and base-line chemotherapy in terms of affecting metabolic pathways and thereby changing metabolic products, which might shed new light for clinical medication.

FNDC5/Irisin attenuates diabetic cardiomyopathy in a type 2 diabetes mouse model by activation of integrin αV/ß5-AKT signaling and reduction of oxidative/nitrosative stress.

Irisin, the cleaved form of the fibronectin type III domain containing 5 (FNDC5) protein, is involved in metabolism and inflammation. Recent findings indicated that irisin participated in cardiovascular physiology and pathology. In this study, we investigated the effects of FNDC5/irisin on diabetic cardiomyopathy (DCM) in type 2 diabetic db/db mice. Downregulation of myocardial FNDC5/irisin protein expression and plasma irisin levels was observed in db/db mice compared to db/+ controls. Moreover, echocardiography revealed that db/db mice exhibited normal cardiac systolic function and impaired diastolic function. Adverse structural remodeling, including cardiomyocyte apoptosis, myocardial fibrosis, and cardiac hypertrophy were observed in the hearts of db/db mice. Sixteen-week-old db/db mice were intramyocardially injected with adenovirus encoding FNDC5 or treated with recombinant human irisin via a peritoneal implant osmotic pump for 4 weeks. Both overexpression of myocardial FNDC5 and exogenous irisin administration attenuated diastolic dysfunction and cardiac structural remodeling in db/db mice. Results from in vitro studies revealed that FNDC5/irisin protein expression was decreased in high glucose (HG)/high fat (HF)-treated cardiomyocytes. Increased levels of inducible nitric oxide synthase (iNOS), NADPH oxidase 2 (NOX2), 3-nitrotyrosine (3-NT), reactive oxygen species (ROS), and peroxynitrite (ONOO-) in HG/HF-treated H9C2 cells provided evidence of oxidative/nitrosative stress, which was alleviated by treatment with FNDC5/irisin. Moreover, the mitochondria membrane potential (ΔΨm) was decreased and cytochrome C was released from mitochondria with increased levels of cleaved caspase-3 in HG/HF-treated H9C2 cells, indicating the presence of mitochondria-dependent apoptosis, which was partially reversed by FNDC5/irisin treatment. Mechanistic studies showed that activation of integrin αVß5-AKT signaling and attenuation of oxidative/nitrosative stress were responsible for the cardioprotective effects of FNDC5/irisin. Therefore, FNDC5/irisin mediates cardioprotection in DCM by inhibiting myocardial apoptosis, myocardial fibrosis, and cardiac hypertrophy. These findings implicate that FNDC5/irisin as a potential therapeutic intervention for DCM, especially in type 2 diabetes mellitus (T2DM).

Damage to the blood­brain barrier and activation of neuroinflammation by focal cerebral ischemia under hyperglycemic condition.

Hyperglycemia aggravates brain damage caused by cerebral ischemia/reperfusion (I/R) and increases the permeability of the blood­brain barrier (BBB). However, there are relatively few studies on morphological changes of the BBB. The present study aimed to investigate the effect of hyperglycemia on BBB morphological changes following cerebral I/R injury. Streptozotocin­induced hyperglycemic and citrate­buffered saline­injected normoglycemic rats were subjected to 30 min middle cerebral artery occlusion. Neurological deficits were evaluated. Brain infarct volume was assessed by 2,3,5­triphenyltetrazolium chloride staining and BBB integrity was evaluated by Evans blue and IgG extravasation following 24 h reperfusion. Changes in tight junctions (TJ) and basement membrane (BM) proteins (claudin, occludin and zonula occludens­1) were examined using immunohistochemistry and western blotting. Astrocytes, microglial cells and neutrophils were labeled with specific antibodies for immunohistochemistry after 1, 3 and 7 days of reperfusion. Hyperglycemia increased extravasations of Evan's blue and IgG and aggravated damage to TJ and BM proteins following I/R injury. Furthermore, hyperglycemia suppressed astrocyte activation and damaged astrocytic endfeet surrounding cerebral blood vessels following I/R. Hyperglycemia inhibited microglia activation and proliferation and increased neutrophil infiltration in the brain. It was concluded that hyperglycemia­induced BBB leakage following I/R might be caused by damage to TJ and BM proteins and astrocytic endfeet. Furthermore, suppression of microglial cells and increased neutrophil infiltration to the brain may contribute to the detrimental effects of pre­ischemic hyperglycemia on the outcome of cerebral ischemic stroke.

Effect of hyperglycemia on microglial polarization after cerebral ischemia-reperfusion injury in rats.

Hyperglycemia has been shown to aggravate ischemic brain damage, in which the inflammatory reaction induced by hyperglycemia is involved in the worsening of cerebral ischemia-reperfusion injury. However, the role of microglial polarization in hyperglycemia-aggravating cerebral ischemia-reperfusion injury remains unknown. The present study investigated whether diabetic hyperglycemia inhibited or activated microglia, as well as microglial subtypes 1 and 2. Rats were used to establish the diabetic hyperglycemia and middle cerebral artery occlusion (MCAO) model. The markers CD11b, CD16, CD32, CD86, CD206, and Arg1 were used to show M1 or M2 microglia. The results revealed increased neurological deficits, infarct volume, and neural apoptosis in rats with hyperglycemia subjected to MCAO for 30 min and reperfused at 1, 3, and 7 days compared with the normoglycemic rats. Microglia and astrocyte activation and proliferation were inhibited in hyperglycemic rats. Furthermore, M1 microglia polarization was promoted, while that of M2 microglia was inhibited in hyperglycemic rats. These findings suggested that the polarization of M1 and M2 microglia is activated and inhibited, respectively, in hyperglycemic rats and may be involved in the aggravated brain damage caused by ischemia-reperfusion in diabetic hyperglycemia.

Region-specific changes in aquaporin 4 induced by hyperglycemia underlie the differences in cell swelling in the cortex and striatum after cerebral ischemia-reperfusion.

Brain edema is a major cause of death in patients who suffer an ischemic stroke. Diabetes has been shown to aggravate brain edema after cerebral ischemia-reperfusion, but few studies have focused on the heterogeneity of this response across different brain regions. Aquaporin 4 plays an important role in the formation and regression of brain edema. Here, we report that hyperglycemia mainly affects the continuity of aquaporin 4 distribution around blood vessels in the cortical penumbra after ischemia-reperfusion; however, in the striatal penumbra, in addition to affecting the continuity of distribution, it also substantially affects the fluorescence intensity and the polarity distribution in astrocytes. Accordingly, hyperglycemia induces a more significant increase in the number of swelling cells in the striatal penumbra than in the cortical penumbra. These results can improve our understanding of the mechanism underlying the effects of diabetes in cerebral ischemic injury and provide a theoretical foundation for identification of appropriate therapeutic modalities.

Recent Applications of Benzimidazole as a Privileged Scaffold in Drug Discovery.

Benzimidazole is an aromatic bicyclic heterocycle that is regarded as a valuable privileged scaffold in medicinal chemistry. Many marketed drugs and natural products containing benzimidazole scaffolds exert great influence in fighting various diseases, such as hypertension, peptic ulcers, parasitic infections, and cancer. In this review, we introduce the pharmacological applications of some marketed drugs and lead compounds with a focus on anticancer agents, reporting the corresponding data to show the biological activities at their targets. The publications in this review encompass those from 2014 to 2019.