Benefits and Risks of Antihyperlipidemic Medication in Adults with Different Low-Density Lipoprotein Cholesterol Based on the Number Needed to Treat.

PURPOSE: The objective of this investigation is to examine the benefits and potential risks of these drugs in individuals by varying baseline low-density lipoprotein cholesterol (LDL-C) values, utilizing the concept of the number needed to treat (NNT). METHODS: We extensively searched electronic databases, such as PubMed, EMBASE, Cochrane, and Web of Science, up to 6 August 2023. Baseline LDL-C values were stratified into four categories: < 100, 100-129, 130-159, and ≥ 160 mg/dL. Risk ratios (RRs) and NNT values were computed. RESULTS: This analysis incorporated data from 46 randomized controlled trials (RCTs), encompassing a total of 237,870 participants. The meta-regression analysis demonstrated an incremental diminishing risk of major adverse cardiovascular events (MACE) with increasing baseline LDL-C values. Statins exhibited a significant reduction in MACE [number needed to treat to benefit (NNTB) 31, 95% confidence interval (CI) 25-37], but this effect was observed only in individuals with baseline LDL-C values of 100 mg/dL or higher. Ezetimibe and PCSK9 inhibitors also were effective in reducing MACE (NNTB 18, 95% CI 11-41, and NNTB 18, 95% CI 16-24). Notably, the safety outcomes of statins and ezetimibe did not reach statistical significance, while the incidence of injection-site reactions with PCSK9 inhibitors was statistically significant [number needed to treat to harm (NNTH) 41, 95% CI 80-26]. CONCLUSION: Statins, ezetimibe, and PCSK9 inhibitors demonstrated a substantial capacity to reduce MACE, particularly among individuals whose baseline LDL-C values were relatively higher. The NNT visually demonstrates the gradient between baseline LDL-C and cardiovascular disease (CVD) risk. SYSTEMATIC REVIEW REGISTRATION: Registration: PROSPERO identifier number: CRD42023458630.

A Free Amino Acid Diet Alleviates Colorectal Tumorigenesis through Modulating Gut Microbiota and Metabolites.

Colorectal cancer (CRC), a major global health concern, may be influenced by dietary protein digestibility impacting gut microbiota and metabolites, which is crucial for cancer therapy effectiveness. This study explored the effects of a casein protein diet (CTL) versus a free amino acid (FAA)-based diet on CRC progression, gut microbiota, and metabolites using carcinogen-induced (AOM/DSS) and spontaneous genetically induced (ApcMin/+ mice) CRC mouse models. Comprehensive approaches including 16s rRNA gene sequencing, transcriptomics, metabolomics, and immunohistochemistry were utilized. We found that the FAA significantly attenuated CRC progression, evidenced by reduced colonic shortening and histopathological alterations compared to the CTL diet. Notably, the FAA enriched beneficial gut bacteria like Akkermansia and Bacteroides and reversed CRC-associated dysbiosis. Metabolomic analysis highlighted an increase in ornithine cycle metabolites and specific fatty acids, such as Docosapentaenoic acid (DPA), in FAA-fed mice. Transcriptomic analysis revealed that FAA up-regulated Egl-9 family hypoxia inducible factor 3 (Egln 3) and downregulated several cancer-associated pathways including Hippo, mTOR, and Wnt signaling. Additionally, DPA was found to significantly induce EGLN 3 expression in CRC cell lines. These results suggest that FAA modulate gut microbial composition, enhance protective metabolites, improve gut barrier functions, and inhibit carcinogenic pathways.

Prognostic value of secretory autophagosomes in patients with acute respiratory distress syndrome.

BACKGROUND: Growing evidence supports that extracellular vesicles (EVs) in blood plasma and other body fluids may function as biomarkers for disease. We previously found that secretory autophagosomes (SAPs), a kind of EV, could exacerbate lung injury in mice. However, the clinical value of SAPs in acute respiratory distress syndrome (ARDS), the most severe form of lung injury, remains unknown. Our study investigated the prognostic value of secretory autophagosomes in ARDS. METHODS: ARDS patients (n = 46) and controls (n = 8) were included in a prospective monocentric study. Bronchoalveolar lavage fluid (BALF) samples were collected from ARDS patients on the first day (Day 1) or the third day (Day 3) of enrollment and were collected from controls on Day 1. Gradient centrifugation was performed to isolate EVs. The size and concentration of EVs were characterized by nanoparticle tracking analysis (NTA). SAPs in EVs were characterized by flow cytometry, transmission electron microscopy, and western blot analysis, and the proportion of SAPs in EVs (PSV) was measured by flow cytometry. The association of SAPs with 28-day mortality was assessed. RESULTS: On Days 1 and 3, the proportion of SAPs (SAPs%) in BALF was higher in patients with ARDS than in controls. On Day 3, the SAPs% was significantly higher in nonsurvivors than in survivors. In particular, a high SAPs% was associated with poor overall survival in ARDS patients. Furthermore, the combination of SAPs% and SOFA obtained a higher predictive value of ARDS outcome than PSV or SOFA alone. CONCLUSION: SAPs% in BALF is elevated in patients with ARDS and is associated with the risk of death in ARDS, suggesting that SAPs% may be a novel prognostic biomarker in ARDS.

[Overview of systematic reviews of Chinese herbal injections for sepsis].

In this study, an overview of systematic reviews/Meta-analysis(SR/MA) of Chinese herbal injections for sepsis was performed to provide references for clinical practice and promote the quality improvement of clinical evidence. Eight Chinese and English databases such as CNKI, Medline, and EMbase were electronically searched for SR/MA of Chinese herbal injections for sepsis from database inception to June 2022. AMSTAR 2, PRISMA 2020, and GRADE system, combined with Recommendations for Clinical Evidence Grading on Traditional Chinese Medicine Based on Evidence Body, were applied to evaluate the methodological quality, reporting quality, and evidence quality of the included articles. Twenty-seven articles of SR/MA were included, containing four Chinese herbal injections(Xuebijing Injection, Shenfu Injection, Shenmai Injection, and Shengmai Injection). AMSTAR 2 checklist showed that the methodological quality of the SR/MA ranged from moderate to very low. Item 2(prior study design) was the critical item with poor scores, and the non-critical items with poor scores were items 3(explain the selection of the study designs), items 10(report on the sources of funding), and items 16(conflicts of interest stated). In terms of PRISMA 2020, items in eight topics with complete reporting of missing>50%, including search strategy, certainty assessment, results of syntheses, certainty of evidence, registration and protocol, support, competing interests, availability of data, code and other materials. The included SR/MA involved 30 outcome indicators. Evidence quality of mortality, APACHE Ⅱ, and safety, the top three outcome indicators, was evaluated, and all of them were graded as the medium level. The lack of random allocation sequence, allocation concealment mechanism, blinding, and trial sample size was the main reason for the reduction of the evidence level. The available evidence shows that Chinese herbal injections can serve as an effective and safe adjunctive treatment for sepsis, which can reduce mortality, inhibit inflammation, improve coagulation function, and regulate immune function, tissue perfusion, and oxygenation in patients with sepsis. However, the quality of SR/MA was suboptimal, and more high-quality SR/MA is needed to provide evidence to support the efficacy and safety of Chinese herbal injections in the treatment of sepsis.

Association of leisure activity changes and reversion from mild cognitive impairment to normal cognitive function among older adults: A prospective cohort study.

Background: Older adults with mild cognitive impairment (MCI) have the possibility of reverting to normal cognitive function. Leisure activity engagement (LAE) plays a critical role in the progress of the cognitive function. A better understanding of the dynamic relationship between LAE and MCI reversion would inform the implementation of preclinical dementia interventions. This study aimed to investigate the association between change patterns of LAE and MCI reversion among older adults using the Chinese Longitudinal Healthy Longevity Survey (CLHLS) database. Study design: Longitudinal population-based study. Methods: Older adults with MCI at the baseline were enrolled in this study. Information about cognitive function, overall, cognitively stimulating, physically active/demanding, and socially engaged LAE was collected at baseline and follow-up. Adjusted hazard ratios (HRs) for reversion and 95% confidence intervals (CIs) were calculated by Cox hazard models with time as the underlying time metric. We also assessed potential effect modifications by creating a cross-product of the stratifying variable with LAE change patterns in the fully adjusted model. Results: The restricted cubic spline showed that the association between LAE change scores and MCI reversion rate was statistically significant and nonlinear (p<0.01). Taking participants in the low-low group as a reference, participants in the low-medium, low-high, medium-medium, medium-high, high-medium, and high-high groups had increased possibilities of MCI reversion with HRs (95% CI) of 2.19 (1.57-3.06), 2.97 (2.13-4.13), 0.87 (0.64-1.19), 2.28 (1.71-3.03), 2.78 (2.10-3.69), 1.93 (1.43-2.59), and 2.74 (2.09-3.60), respectively. Further stratified models showed that the impact of LAE change patterns on MCI reversion varied in different ages (nonagenarian, octogenarian, and younger elderly) and gender. Conclusions: Participants who maintained the highest LAE had the greatest possibility of MCI reversion. Meanwhile, a higher level of LAE maintenance was associated with the increased possibility of MCI reversion. These results provide a practical message to older adults about how dynamic changes in LAE are associated with improved cognitive function.

Effect of alirocumab and evolocumab on all-cause mortality and major cardiovascular events: A meta-analysis focusing on the number needed to treat.

Aims: The efficacy of anti-proprotein convertase subtilisin/Kexin type 9 (PCSK9) monoclonal antibodies in patients with atherosclerotic cardiovascular disease (ASCVD) remains unclear. Therefore, this study aims to assess the effect of PCSK9 inhibitors (alirocumab and evolocumab) on ASCVD patients considering the number needed to treat (NNT). Methods: We reviewed randomized controlled trials (RCTs) which compared the effects of alirocumab or evolocumab and placebo or standards of care. All articles were published in English up to May 2022. Using random effect models, we estimated risk ratios (RRs), NNT, and 95% confidence intervals (CI). Results: We incorporated 12 RCTs with 53 486 patients total, of which 27 674 received PCSK9 inhibitors and 25 812 received placebos. The mean follow-up duration was 1.56 years. The effect of PCSK9 inhibitors on major adverse cardiovascular events (MACE) was statistically significant, and the corresponding mean NNT was 36. Alirocumab reduced the risk of MACE, stroke, and coronary revascularization; the corresponding mean NNT were 37, 319, and 107, respectively. Evolocumab positively affected MACE, myocardial infarction, stroke, and coronary revascularization; the corresponding mean NNT were 32, 78, 267, and 65, respectively. The effects of alirocumab or evolocumab on all-cause mortality and cardiovascular mortality were not statistically significant. Conclusion: This study suggests that preventing one patient from MACE needed to treat 36 patients with ASCVD with PCSK9 inhibitors for 1.56 years. Both alirocumab and evolocumab reduced MACE, stroke, and coronary revascularization. Evolocumab had a positive effect on myocardial infarction, but no effects were noted for alirocumab. In addition, alirocumab may not be as effective as evolocumab. NNT visualizes the magnitude of efficacy to assist in clinical decisions. Systematic review registration: [https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=344908], identifier [CRD42022344908].

Telephone-Based Behavioral Activation for Improving Sleep Quality in Family Caregivers of People With Dementia: A Pilot Randomized Controlled Trial.

Sleep disturbances are common among family caregivers of people with dementia (PWD). Although behavioral activation (BA) shows the potential to improve sleep quality, to date, evidence for this treatment's feasibility and efficacy for family caregivers of PWD is limited. Therefore, this study pilot tested an evidence-based BA protocol for improving sleep quality in Chinese family caregivers of PWD. The BA intervention involved eight weekly individual telephone-based sessions designed to teach caregivers specific BA techniques. Sleep quality and depression were measured using the Chinese versions of the Pittsburgh Sleep Quality Index (PSQI) and Center for Epidemiologic Studies Depression (CES-D) Scale, respectively. This study also measured leisure activity, positive aspect of caregiving, caregiving burden, health status, and relationship satisfaction. All participants were asked to complete the assessments on paper at baseline and immediately after the intervention. After completing the pilot randomized controlled trial, semistructured interviews were conducted to explore participants' experiences participating in the BA intervention. A total of 71 family caregivers of PWD (35 in the intervention group and 36 in the control group) were recruited. The majority of participants were female (n = 53, 74.65%), and their mean age was 54.07 years (SD = 10.95). Compared with controls, caregivers in the intervention group displayed significantly greater improvement in sleep quality, as well as perceptions of positive aspects of caregiving and reduction of depression. Most participants were very satisfied with the intervention. These findings suggest that individual telephone-based BA interventions are feasible, acceptable, and effective in improving sleep quality and psychological health in family caregivers of PWD. These results contribute to the literature by providing evidence for developing effective, accessible, and sustainable BA interventions for family caregivers of PWD.

Skeletal Muscle Change During Neoadjuvant Therapy and Its Impact on Prognosis in Patients With Gastrointestinal Cancers: A Systematic Review and Meta-Analysis.

Background: Gastrointestinal cancers are the most common malignant tumors worldwide. As the improvement of survival by surgical resection alone for cancers is close to the bottleneck, recent neoadjuvant therapy has been emphasized and applied in the treatment. Despite the advantage on improving the prognosis, some studies have reported neoadjuvant therapy could reduce skeletal muscle and therefore affect postoperative outcomes. However, the conclusions are still controversial. Methods: PubMed, CINAHL, Embase, and Cochrane Library were searched from inception to September 2, 2021. The inclusion criteria were observational studies, published in English, of individuals aged ≥18 years who underwent neoadjuvant therapy with gastrointestinal cancers and were assessed skeletal muscle mass before and after neoadjuvant therapy, with sufficient data on skeletal muscle change or the association with clinical outcomes. Meta-analysis was conducted by using the STATA 12.0 package when more than two studies reported the same outcome. Results: A total of 268 articles were identified, and 19 studies (1,954 patients) were included in the review. The fixed effects model showed that the risk of sarcopenia increased 22% after receiving neoadjuvant therapy (HR=1.22, 95% CI 1.14, 1.31, Z=4.286, P<0.001). In the random effects model, neoadjuvant therapy was associated with skeletal muscle loss, with a standardized mean difference of -0.20 (95% CI -0.31, -0.09, Z=3.49, P<0.001) and a significant heterogeneity (I2 = 62.2%, P<0.001). Multiple meta regression indicated that population, neoadjuvant therapy type, and measuring tool were the potential sources of heterogeneity. The funnel plot revealed that there was no high publication bias in these studies (Begg's test, P=0.544) and the sensitivity analysis showed stable results when separately excluding studies. For the postoperative outcomes, the results revealed that muscle loss during neoadjuvant therapy was significantly related to overall survival (HR=2,08, 95% CI =1.47, 2.95, Z=4.12, P<0.001, I2 = 0.0%), but not related to disease-free survival and other short-term outcomes. Conclusions: This systematic review and meta-analysis revealed that skeletal muscle decreased significantly during neoadjuvant therapy in patients with gastrointestinal cancers and skeletal muscle loss was strongly associated with worse overall survival. More high-quality studies are needed to update and valid these conclusions in a more specific or stratified way. Systematic Review Registration: [https://www.crd.york.ac.uk/PROSPERO/], identifier PROSPERO (CRD42021292118).

[Analysis of material preparation, anti-bacterial activity of Porphyromonas gingivalis and cell bioassays of TiO2-PEEK-CRGDS].

PURPOSE: To modify polyetheretherketone(PEEK) composite material with nanometer titanium dioxide (TiO2) and CRGDS peptide to prepare TiO2-PEEK-CRGDS, and evaluate its anti- activity of Porphyromonas gingivalis and effect on cell activity. METHODS: TiO2-PEEK was prepared by plasma immersion ion implantation(PⅢ), then immersed into gelatin solution of pentapeptides of CRGDS, and freeze-dried. The same diameter and thickness of PEEK was set as control. Scanning electron microscope (SEM) was used to observe the three-dimensional topography and roughness on the surface of the specimen, colony count was calculated to evaluate the survival of Porphyromonas gingivalis, living/dead cell count was used to detect the activity of human gingival fibroblasts(HGFs), CCK-8 assay was used to detect the proliferation ability of HGFs. The quantitative data was indicated as and analyzed by using GraphPad Prism 7.0 software package. RESULTS: The antibacterial rates of PEEK, TiO2-PEEK and TiO2-PEEK-CRGDS were 40.3%, 57.2% and 60.3%, respectively. At 12 days, the ability of TiO2-PEEK-CRGDS to promote the growth of human gingival fibroblasts was significantly different from that of the TiO2-PEEK and PEEK group(P＜0.05). CONCLUSIONS: The optimized TiO2-PEEK-CRGDS has better hydrophilicity than pure titanium and PEEK, and can significantly promote the proliferation of gingival fibroblasts.

"Am I entitled to take a break in caregiving?": Perceptions of leisure activities of family caregivers of loved ones with dementia in China.

Leisure activities are essential for family caregivers of loved ones with dementia living in the community, yet these caregivers tend not to engage in them, especially in China, wherein it may have a negative impact on their physical and psychological health. To date, limited knowledge exists regarding underlying reasons that deter these family caregivers from doing leisure activities. This study aims to explore perceptions of family caregivers of people living with dementia and their engagement in leisure activities. A qualitative descriptive research design was used with semi-structured, face-to-face, individual in-depth interviews. The data were collected in Shijiazhuang, China between October and November 2019. Content analysis was used to develop categories. Results of 20 family caregivers (5 men and 15 women, mean age = 55.6±12.7) reported their perceptions under four main categories: (i) "the condition of leisure life," (ii) "needs for leisure activities," (iii) "reasons for the reluctance to do leisure activities," and (iv) "motivations supporting the implementation of leisure activities." In addition to the heavy caregiving workload and lack of support, traditional Chinese beliefs including filial commitment and "fatalistic voluntarism" were the reasons that prevented Chinese family caregivers of people living with dementia from doing leisure activities. However, engaging their loved ones in leisure activities, like doing exercise together, could motivate family caregivers themselves to participate in leisure activities. These findings encourage healthcare professionals to consider the influence of culture on family caregivers' engagement in leisure activities which is one of the ways to reduce stress. Family caregivers may benefit from the leisure activities by learning how to better cope with and balance caregiving tasks with their leisure pursuits in the community.

Antrodia camphorata-Derived Antrodin C Inhibits Liver Fibrosis by Blocking TGF-Beta and PDGF Signaling Pathways.

Hepatic stellate cells (HSCs) play an essential role in the development of liver fibrosis. Antrodia camphorata (A. camphorata) is a medicinal fungus with hepatoprotective effect. This study investigated whether Antrodin C, an A. camphorata-fermented metabolite, could exert a protective role on liver fibrosis both in vitro and in vivo. The anti-fibrotic effect of Antrodin C was investigated in CFSC-8B cell (hepatic stellate cell) stimulated by transforming growth factor-ß1 (TGF-ß1) or platelet-derived growth factor-BB (PDGF-BB) in vitro and in CCl4 induced liver fibrosis in mice. Antrodin C (50 µM) inhibited TGF-ß1 or PDGF-BB stimulated CFSC-8B cell activation, migration and extracellular matrix (ECM) accumulation (all p < 0.05). Antrodin C (3, 6 mg/kg/d) oral administration reduced the degree of liver fibrosis induced by CCl4 in mice. Antrodin C down-regulated the expression of α-smooth muscle actin (α-SMA) and collagen I in fibrotic livers. Furthermore, Antrodin C ameliorated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevation in serum (all p < 0.05). Mechanistically, Antrodin C executes its anti-fibrotic activity through negatively modulate TGF-ß1 downstream SMAD Family Member 2 (Smad2), AKT Serine/Threonine Kinase 1 (AKT), extracellular signal-regulated kinase (ERK), and P38 MAP Kinase (P38), as well as PDGF-BB downstream AKT and ERK signaling pathways. Antrodin C ameliorates the activation, migration, ECM production in HSCs and CCl4-induced liver fibrosis in mice, suggesting that Antrodin C could serve as a protective molecule against liver fibrosis.

Salidroside Promotes Sensitization to Doxorubicin in Human Cancer Cells by Affecting the PI3K/Akt/HIF Signal Pathway and Inhibiting the Expression of Tumor-Resistance-Related Proteins.

Salidroside (Sal), the major active constituent of Rhodiola rosea L., is considered as a potential pro-drug with various activities; however, its role in tumor therapy is not clear. Here, we demonstrated in vitro and in vivo that Sal enhanced the inhibitory activity of doxorubicin (DOX) in drug-resistant cancer cell lines. Our results showed that combination drug treatment (Sal and DOX) significantly decreased cell proliferation, migration, and motility. Besides biological validation, a luciferase-labeled animal tumor xenograft model and bioluminescence imaging (BLI) were applied for assessing the tumor progression. Sal combined with DOX inhibited the growth of HeLa-ADR-luc cells in vivo and downregulated the DOX-induced high expression of MDR1. Also, Sal downregulated the Bcl-2, MMP-2, MMP-9, PI3K, and AKT and upregulated BAX proteins. Sal demonstrated high safety and cardiac protection activity. We discovered that Sal enhances DOX sensitivity through the regulation of PI3K/Akt/HIF-1α and DOX-induced resistance pathways. Our results suggest that Sal could be a novel chemosensitization agent for the treatment of multi-drug-resistance tumors.

Comparison of five sarcopenia screening tools in preoperative patients with gastric cancer using the diagnostic criteria of the European Working Group on Sarcopenia in Older People 2.

OBJECTIVES: The aim of this study was to compare the performance of five sarcopenia screening tools in preoperative patients with gastric cancer, including strength, assistance with walking, rise from a chair, climb stairs, and falls; strength, assistance with walking, rise from a chair, climb stairs, falls, and calf circumference (SARC-CalF); Ishii score chart; short version of the mini sarcopenia risk assessment; and full version of the mini sarcopenia risk assessment. METHODS: We conducted a cross-sectional study of consecutive patients undergoing a gastrectomy between May 2020 and October 2020. Sarcopenia was diagnosed per the diagnostic criteria proposed by the European Working Group on Sarcopenia in Older People 2 (EWGSOP2). Data on the five sarcopenia screening tools, patient characteristics, nutrition risk screening 2002, and diagnostic indicators of sarcopenia were collected preoperatively, and pathological characteristics of the tumor were collected postoperatively. Based on the EWGSOP2 criteria, the clinical validity of the sarcopenia tools was measured using sensitivity, specificity, and predictive value. A receiver operator characteristic curve and area under curve were applied to compare the overall screening accuracy, and a Youden index was calculated to determine the optimal cutoff value of each tool. RESULTS: We included 260 participants age 62.38 ± 11.21 y. Based on the EWGSOP2 criteria, the prevalence of sarcopenia and severe sarcopenia were 8.46% and 4.62%, respectively. Moreover, the prevalence of sarcopenia risk ranged from 3.46% to 73.85% based on the five screening tools. Of these tools, SARC-CalF had the largest area under the curve (0.896) with moderate-to-high sensitivity (86.36%) and high specificity (92.86%). For SARC-CalF, the cutoff value of 10 reached the highest Youden index, and the corresponding sensitivity and specificity were 81.82% and 93.44%, respectively. CONCLUSION: Among the above five screening tools, SARC-CalF appeared to be the optimal choice to screen sarcopenia in preoperative patients with gastric cancer.

Effect of leisure activities on cognitive aging in older adults: A systematic review and meta-analysis.

Abnormal cognitive aging in older adults is a growing public health problem. Previous studies showed inconsistent results pertaining to the effects of leisure activities on cognitive function in older adults. We conducted a systematic review and meta-analysis of published observational longitudinal studies to examine and synthesize the effects of leisure activities on cognitive function in older adults. MEDLINE, PubMed, EMBASE, PsycINFO (Ovid), CINAHL (EBSCO), and Web of Science databases were searched from January 2012 to January 2022. Relative risks (RRs) with 95% confidence intervals (CIs) were pooled using random-effects meta-analysis. Most studies found that leisure activities had a positive effect on cognitive function in older adults. The pooled RR for the effect of leisure activity on cognitive function was 0.77 (95% CI: 0.72-0.81, p < 0.01). The effects of leisure activities on cognitive function varied by different cognitive statuses in older adults, with RRs ranging from 0.55 (95% CI: 0.37-0.83) to 1.07 (95% CI: 0.95-1.22). Meta-regression analysis showed that compared with studies with percentage of female ≥50%, studies with female participant percentage <50% had significantly increased RR (p = 0.01). Moreover, studies conducted in European and American countries had significantly lower RR (p = 0.019), compared with those conducted in Asian countries. Our study revealed different effects of various types of leisure activities on different cognitive statuses in older adults. To make innovative recommendations for promoting cognitive function in older adults, more detailed observational longitudinal studies investigating the effects of different types of leisure activities on different cognitive statuses in older adults are needed.

A strategy to discover lead chemome from traditional Chinese medicines based on natural chromatogram-effect correlation (NCEC) and natural structure-effect correlation (NSEC): Mahonia bealei and Mahonia fortunei as a case study.

Lead compound is an important concept for modern drug discovery. In this study, a new concept of lead chemome and an efficient strategy to discover lead chemome were proposed. Compared with the concept of lead compound, lead chemome can provide not only the starting point for drug development, but also the direction for structure optimization. Two traditional Chinese medicines of Mahonia bealei and Mahonia fortunei were used as examples to illustrate the strategy. Based on natural chromatogram-effect correlation (NCEC), berberine, palmatine and jatrorrhizine were discovered as acetylcholinesterase (AchE) inhibitors. Taking the three compounds as template molecules, a lead chemome consisting of 10 structurally related natural compounds were generated through natural structure-effect correlation (NSEC). In the lead chemome, the IC50 values of jatrorrhizine, berberine, coptisine, palmatine and epiberberine are at nanomolar level, which are comparable to a widely used drug of galantamine. Pharmacophore modeling shows that the positive ionizable group and aromatic rings are important substructures for AchE inhibition. Molecular docking further shows that pi-cation interaction and pi-pi stacking are critical for compounds to maintain nanomolar IC50 values. The structure-activity information is helpful for drug design and structure optimization. This work also expanded the traditional understanding of "stem is the medicinal part of Mahonia bealei and Mahonia fortunei". Actually, all parts except the leaf of Mahonia bealei exhibited potent AchE-inhibitory activity. This study provides not only a strategy to discover lead chemome for modern drug development, but also a reference for the application of different parts of medicinal plants.

The association among apathy, leisure activity participation, and severity of dementia in nursing home residents with Alzheimer's disease: A cross-sectional study.

The purpose of this study was to examine 1) the relationship between apathy and leisure activity participation in nursing home residents with Alzheimer disease (AD) and 2) the moderator effect of the severity of dementia on this relationship. Data were collected from 290 residents with AD using the Apathy Evaluation Scale-informant version (AES-I), Leisure Activities Questionnaire (LAQ), and Clinical Dementia Rating scale (CDR). The multiple linear regression model showed that leisure activity participation (ß=-0.452, p<0.001) was negatively associated with apathy, while the severity of dementia (ß=0.515, p<0.001) was positively associated with apathy. The severity of dementia moderated the effect of leisure activity participation on apathy (ß=-0.108, p=0.015). The results indicate that the effects of leisure activity participation on apathy diminish with the aggravation of AD. The severity of dementia should be considered when designing and delivering leisure activity interventions to manage apathy in nursing home residents with AD.

miR-5000-3p confers oxaliplatin resistance by targeting ubiquitin-specific peptidase 49 in colorectal cancer.

Colorectal cancer (CRC) is the most common form of gastrointestinal malignancies. A growing number of reports focusing on oxaliplatin (OXA) resistance in CRC treatment have revealed that drug resistance is an urgent issue in clinical applications, especially for finding effective therapeutic targets. Recently, microRNAs (miRNAs) are reported to play a critical role in tumor progressions and multi-drug resistance. The main aim of this study is to establish whether miR-5000-3p is an oncogene that is resistant to OXA and further confirm its underlying regulatory role in CRC. The OXA-associated gene expression dataset in CRC cells was downloaded from Gene Expression Omnibus (GEO) database. Statistical software R was used for significance analysis of differentially expressed genes (DEGs) between OXA-resistant (OR)-CRC cells and CRC cells, and results indicated ubiquitin-specific peptidase 49 (USP49) was upregulated in OR-CRC cells. Luciferase reporter assay showed that USP49 was verified to act as a downstream target gene of miR-5000-3p. From the results of TCGA database, miR-5000-3p expression was upregulated and USP49 was downregulated in patients with CRC. The function of miR-5000-3p was detected using MTT assay, wound healing, Transwell, and flow cytometry assays. Moreover, through in vitro and in vivo experiments, miR-5000-3p expression was confirmed to be upregulated in CRC cells or OR-CRC cells comparing to normal cell lines. Molecular mechanism assays revealed that USP49 binds to the miR-5000-3p promoter to increase the expression of miR-5000-3p, resulting in cancer cells sensitized to OXA. To sum up, these results suggest that miR-5000-3p may be a novel biomarker involved in drug-resistance progression of CRC. Moreover, the drug-resistance mechanism of miR-5000-3p/USP49 axis provides new treatment strategies for CRC in clinical trials.

Risk factors and the utility of three different kinds of prediction models for postoperative fatigue after gastrointestinal tumor surgery.

BACKGROUND: Postoperative fatigue (POF) is a common complication after gastrointestinal tumor surgery, and it also brings negative effect on prognosis and life quality. However, there are no prediction models for POF, and studies of risk factors are not comprehensive. Therefore, the aim of this study is to investigate the risk factors and pick out the best prediction model for POF and to validate it. METHODS: A prospective study was conducted for patients undergoing elective gastrointestinal tumor surgery. Physiological, psychological, and socioeconomic factors were collected. Logistic regression, back-propagation artificial neural networks (BP-ANNs), and classification and regression tree (CART) were constructed and compared. RESULTS: A total of 598 patients consisting of 463 derivation sample and 135 validation sample were included. The incidence of POF in derivation sample, validation sample, and total were 58.3%, 57.0%, and 58.7%, respectively. Logistic regression results showed age, higher degree of education, lower personal monthly income, advanced cancer, hypoproteinemia, preoperative anxiety or depression, and limited social support were risk factors for POF. Receiver operating characteristic curve (ROC) and performance indices were used to test three models. BP-ANN was the best by the comparison of models, and its strong predictive performance was also validated. CONCLUSIONS: More attention should be paid on specific patients after gastrointestinal tumor surgery. BP-ANN is a powerful mathematical tool that could predict POF exactly. It may be used as a noninvasive screening tool to guide clinicians for early identification of high-risk patients and grading interventions.

The relative risk of developing type 2 diabetes among individuals with prediabetes compared with individuals with normoglycaemia: Meta-analysis and meta-regression.

AIMS: To assess the overall relative risk of diabetes in individuals with prediabetes based on updated diagnostic criteria, as compared with individuals with normoglycaemia; and to identify the study characteristics associated with the heterogeneity between studies. DESIGN: Meta-analysis, meta-regression. DATA SOURCES: PubMed, CINAHL, British Nursing Index. Search time frame: December 1998-December 2018. REVIEW METHODS: The pooled relative risk of developing diabetes among individuals with prediabetes compared with those with normoglycaemia was calculated under a random effects model. Studies reported the natural progression from prediabetes to diabetes were included in this review. Sources of study heterogeneity were examined by a meta-regression. RESULTS: Fifty-nine eligible studies were systematically identified. The pooled relative risk for diabetes among individuals with prediabetes as compared with normoglycaemia was 5.88 (95% CI: 5.02-6.89). The annualized incidence rate (per 1,000 person-year) for diabetes among individuals with prediabetes defined by different criteria varied from 2.20-212.15, with high heterogeneity between studies (I2  = 96.64%, Q test: p < .001). In the multivariable meta-regression analysis, Asian population significantly increased RR compare to Caucasians. Besides, people with 'elevated glycated haemoglobin A1c or impaired fasting glucose' had highest relative risk compare to people with other types of prediabetes. CONCLUSION: Individuals with prediabetes had higher risk of developing diabetes than those with normoglycaemia. Races and diagnostic criteria of prediabetes were associated with the magnitude of the estimated risk. IMPACT: Prediabetes is a precursor of diabetes. To screen people with prediabetes as early as possible, practitioners could consider haemoglobin A1c test as an alternative to fasting plasma glucose test. Nurses should educate people especially Asians with prediabetes for the prevention of progression to diabetes.

Targeting Follistatin like 1 ameliorates liver fibrosis induced by carbon tetrachloride through TGF-ß1-miR29a in mice.

BACKGROUND: Hepatic fibrosis is a pathological response of the liver to a variety of chronic stimuli. Hepatic stellate cells (HSCs) are the major source of myofibroblasts in the liver. Follistatin like 1 (Fstl1) is a secreted glycoprotein induced by transforming growth factor-ß1 (TGF-ß1). However, the precise functions and regulation mechanisms of Fstl1 in liver fibrogenesis remains unclear. METHODS: Hepatic stellate cell (HSC) line LX-2 stimulated by TGF-ß1, primary culture of mouse HSCs and a model of liver fibrosis induced by CCl4 in mice was used to assess the effect of Fstl1 in vitro and in vivo. RESULTS: Here, we found that Fstl1 was significantly up regulated in human and mouse fibrotic livers, as well as activated HSCs. Haplodeficiency of Fstl1 or blockage of Fstl1 with a neutralizing antibody 22B6 attenuated CCl4-induced liver fibrosis in vivo. Fstl1 modulates TGF-ß1 classic Samd2 and non-classic JNK signaling pathways. Knockdown of Fstl1 in HSCs significantly ameliorated cell activation, cell migration, chemokines C-C Motif Chemokine Ligand 2 (CCL2) and C-X-C Motif Chemokine Ligand 8 (CXCL8) secretion and extracellular matrix (ECM) production, and also modulated microRNA-29a (miR29a) expression. Furthermore, we identified that Fstl1 was a target gene of miR29a. And TGF-ß1 induction of Fstl1 expression was partially through down regulation of miR29a in HSCs. CONCLUSIONS: Our data suggests TGF-ß1-miR29a-Fstl1 regulatory circuit plays a key role in regulation the HSC activation and ECM production, and targeting Fstl1 may be a strategy for the treatment of liver fibrosis. Video Abstract.