Exercise-primed extracellular vesicles improve cell-matrix adhesion and chondrocyte health.

Extracellular vesicles (EVs) have been suggested to transmit the health-promoting effects of exercise throughout the body. Yet, the mechanisms by which beneficial information is transmitted from extracellular vesicles to recipient cells are poorly understood, precluding a holistic understanding of how exercise promotes cellular and tissue health. In this study, using articular cartilage as a model, we introduced a network medicine paradigm to simulate how exercise facilitates communication between circulating EVs and chondrocytes, the cells resident in articular cartilage. Using the archived small RNA-seq data of EV before and after aerobic exercise, microRNA regulatory network analysis based on network propagation inferred that circulating EVs activated by aerobic exercise perturb chondrocyte-matrix interactions and downstream cellular aging processes. Building on the mechanistic framework identified through computational analyses, follow up experimental studies interrogated the direct influence of exercise on EV-mediated chondrocyte-matrix interactions. We found that pathogenic matrix signaling in chondrocytes was abrogated in the presence of exercise-primed EVs, restoring a more youthful phenotype, as determined by chondrocyte morphological profiling and evaluation of chondrogenicity. Epigenetic reprograming of the gene encoding the longevity protein, α-Klotho, mediated these effects. These studies provide mechanistic evidence that exercise transduces rejuvenation signals to circulating EVs, endowing EVs with the capacity to ameliorate cellular health even in the presence of an unfavorable microenvironmental signals.

Effectiveness of integrated care for older adults with depression and hypertension in rural China: A cluster randomized controlled trial.

BACKGROUND: Effectiveness of integrated care management for common, comorbid physical and mental disorders has been insufficiently examined in low- and middle-income countries (LMICs). We tested hypotheses that older adults treated in rural Chinese primary care clinics with integrated care management of comorbid depression and hypertension (HTN) would show greater improvements in depression symptom severity and HTN control than those who received usual care. METHODS AND FINDINGS: The study, registered with ClinicalTrials.gov as Identifier NCT01938963, was a cluster randomized controlled trial with 12-month follow-up conducted from January 1, 2014 through September 30, 2018, with analyses conducted in 2020 to 2021. Participants were residents of 218 rural villages located in 10 randomly selected townships of Zhejiang Province, China. Each village hosts 1 primary care clinic that serves all residents. Ten townships, each containing approximately 20 villages, were randomly selected to deliver either the Chinese Older Adult Collaborations in Health (COACH) intervention or enhanced care-as-usual (eCAU) to eligible village clinic patients. The COACH intervention consisted of algorithm-driven treatment of depression and HTN by village primary care doctors supported by village lay workers with telephone consultation from centrally located psychiatrists. Participants included clinic patients aged ≥60 years with a diagnosis of HTN and clinically significant depressive symptoms (Patient Health Questionnaire-9 [PHQ-9] score ≥10). Of 2,899 eligible village residents, 2,365 (82%) agreed to participate. They had a mean age of 74.5 years, 67% were women, 55% had no schooling, 59% were married, and 20% lived alone. Observers, older adult participants, and their primary care providers (PCPs) were blinded to study hypotheses but not to group assignment. Primary outcomes were change in depression symptom severity as measured by the Hamilton Depression Rating Scale (HDRS) total score and the proportion with controlled HTN, defined as systolic blood pressure (BP) <130 mm Hg or diastolic BP <80 for participants with diabetes mellitus, coronary heart disease, or renal disease, and systolic BP <140 or diastolic BP <90 for all others. Analyses were conducted using generalized linear mixed effect models with intention to treat. Sixty-seven of 1,133 participants assigned to eCAU and 85 of 1,232 COACH participants were lost to follow-up over 12 months. Thirty-six participants died of natural causes, 22 in the COACH arm and 14 receiving eCAU. Forty COACH participants discontinued antidepressant medication due to side effects. Compared with participants who received eCAU, COACH participants showed greater reduction in depressive symptoms (Cohen's d [±SD] = -1.43 [-1.71, -1.15]; p < 0.001) and greater likelihood of achieving HTN control (odds ratio [OR] [95% CI] = 18.24 [8.40, 39.63]; p < 0.001). Limitations of the study include the inability to mask research assessors and participants to which condition a village was assigned, and lack of information about participants' adherence to recommendations for lifestyle and medication management of HTN and depression. Generalizability of the model to other regions of China or other LMICs may be limited. CONCLUSIONS: The COACH model of integrated care management resulted in greater improvement in both depression symptom severity and HTN control among older adult residents of rural Chinese villages who had both conditions than did eCAU. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01938963 https://clinicaltrials.gov/ct2/show/NCT01938963.

[Influence of Different Types of Dewatering Agents on the Solidification Effect and Physical and Chemical Properties of Sediment].

In order to study the comprehensive effects of different types of dehydrating agents on the dewatering and solidification of dredged sediments, this study took the dredged sediments of Taihu Lake as the research object and selected microorganisms, polymeric iron aluminum salts, organic polymers, organic-inorganic composites, and aluminum salt microorganisms. These five types of composite dehydrating agents were used to conduct a three-month solidification test on the dredged sediment by means of geotechnical pipe bag solidification. The results of the study showed that the dehydration efficiency of organic polymers and organic-inorganic composite chemicals was better. After one month, the water content of sediment dropped to 61.78% and 63.26%, respectively, which then dropped to 40.56% and 32.16% after three months. Compared with that of the unsolidified sludge, the total nitrogen of the bottom sludge after solidification by the organic-inorganic composite agent was reduced by 74.82%, reaching 591 mg·kg-1, primarily due to the reduction in ammonia nitrogen. The solid sludge contained mainly aluminum-bound phosphorus, calcium-bound phosphorus, and iron-bound phosphorus. Among them, four groups (organic-inorganic composite) had the largest reduction in active phosphorus, with the lowest being 64.3 mg·kg-1. In addition, organic polymer agents had the best curing effect on heavy metals, the comprehensive ecological risk index of heavy metals was reduced by 51.3%, and the leaching toxicity concentration was far below the standard threshold. This study showed that organic polymers and organic-inorganic composite medicaments have a better effect on the dehydration and solidification of bottom sludge and thus have good application prospects.

Effect of different delivery modes on the short-term strength of the pelvic floor muscle in Chinese primipara.

BACKGROUND: To investigate the effect of different delivery modes and related obstetric factors on the short-term strength of the pelvic floor muscle after delivery in Chinese primipara. METHODS: A total of 4769 healthy Chinese primiparas at postpartum 6-8 weeks were interviewed. According to the difference of delivery mode, the selected primiparas were divided into 2 groups, including cesarean delivery group containing 2020 and vaginal delivery group containing 2749. All the vaginal deliveries were further divided into 3 groups, including episiotomy group containing 2279, perineal laceration group containing 398, and forceps assisted group containing72. The scales of their pelvic floor muscle (PFM) strengths were examined by specially trained personnel using digital palpation (Modified Oxford scale:0-5 grade). According to participants' willingness, if the PFM strength was weak (0 or 1 grade), at-home PFM training would be recommended and an electrical stimulation combined with biofeedback therapy would be conducted for them in hospital. Twelve weeks after delivery, the PFM strength would be measured again. For statistical analysis, t-test, one-way variance analysis, Chi-square analysis, Kruskal-Wallis test H, Mann-Whitney U test and Wilcoxon test were carried out. RESULTS: The PFM strength in cesarean delivery group was higher than in vaginal delivery group (p < 0.05). Among 3 vaginal delivery groups, the PFM strength in perineal laceration group was the highest (p < 0.05); however, there was no difference in PFM strength between episiotomy group and forceps assisted group (p>0.05). After accepting PFM training at home and therapy in hospital, 305 women showed increased PFM strength (p < 0.05). CONCLUSIONS: Vaginal delivery is an independent risk factor causing the damage of PFM, and episiotomy may cause injury of PFM. Through PFM training at home and therapy in hospital, those damage will resume as soon as possible in the short-time period after delivery.

The prevalence of depressive symptoms among older patients with hypertension in rural China.

OBJECTIVE: The comorbidity of depression and hypertension (HTN) is common and complicates the management of both conditions. This study investigated the prevalence of depressive symptoms among older patients with HTN in rural China and explored the relationship between the two conditions. METHODS: The baseline data of older patients diagnosed with HTN included in the depression/HTN in Chinese Older Adults-Collaborations for Health Study were used for the analysis. The Chinese Older Adults-Collaborations for Health Study was conducted in rural villages of Tonglu County, Zhejiang Province, China. In all, 10 389 older village residents had HTN (57.2% female, mean age 71.5 ± 8.1 years). Blood pressure was measured by using a calibrated manual sphygmomanometer and stethoscope. Depressive symptom was measured by using the Chinese version of the nine-item Patient Health Questionnaire. RESULTS: Among 10 389 patients with HTN, 12.8% had significant depressive symptoms (nine-item Patient Health Questionnaire ≥ 10). Rates of significant depressive symptoms were 5.3% and 32.8% among patients with controlled and uncontrolled HTN (systolic blood pressure ≥ 140 and/or diastolic blood pressure ≥ 90), respectively (χ2 = 8.701, p < 0.001). Logistic regression analysis indicated that those in older age group (≥70 years) and with uncontrolled HTN have higher rates of significant depressive symptoms than those who are younger (age 60 to <70) and with controlled HTN. CONCLUSION: Our findings show high rates of depressive symptoms among patients with HTN in rural China and higher rates of depressive symptoms among patients with uncontrolled HTN. These support the development and dissemination of integrative care approaches for older adults with HTN and depression in rural China. Copyright © 2016 John Wiley & Sons, Ltd.

The Effect of Lipid Emulsion on Pharmacokinetics of Bupivacaine in Rats: Long-Chain Triglyceride Versus Long- and Medium-Chain Triglyceride.

BACKGROUND: Lipid infusions have been proposed to treat local anesthetic-induced cardiac toxicity. This study compared the effects of long-chain triglyceride (LCT) emulsions with those of long- and medium-chain triglyceride (LCT/MCT) emulsions on the pharmacokinetics of bupivacaine in a rat model. METHODS: After administration of intravenous infusion of bupivacaine at 2 mg·kg·min for 5 minutes in Sprague-Dawley (SD) rats, either Intralipid 20%, an LCT emulsion (LCT group, n = 6), or Lipovenoes 20%, an LCT/MCT emulsion (LCT/MCT group, n = 6), was infused at 2mg·kg·min for 5 minutes. The concentrations of total plasma bupivacaine and bupivacaine that were not bound by lipid (lipid unbound) were measured by a liquid chromatography-tandem mass spectrometric method. A 2-compartmental analysis was performed to calculate the lipid-bound percentage of bupivacaine and its pharmacokinetics. RESULTS: In the LCT group, the clearance (15 ± 2 vs 10 ± 1 mL·min·kg, P = .003) was higher; the volume of distribution (0.57 ± 0.10 vs 0.36 ± 0.11 L·kg, P = .007) and K21 (0.0100 ± 0.0018 vs 0.0070 ± 0.0020 min, P = .021, P' = .032) were larger; and the area under the blood concentration-time curve 0 - t; (605 ± 82 vs 867 ± 110 mgL·min, P =.001) and the area under the blood concentration-time curve (0 - ∞) (697 ± 111 vs 991 ± 121 mgL·min, P =.001) were less, when compared with the LCT/MCT group. CONCLUSIONS: LCT emulsions are more effective than LCT/MCT emulsions in the metabolism of bupivacaine through demonstration of a superior pharmacokinetic profile.

[Effect of Modified Baizhu Powder on Gastrointestinal Functions in Mouse Models with Stomach-cold Functional Dyspepsia].

OBJECTIVE: To explore the effect of modified Baizhu (Rhizoma Atractylodis Macrocephalae) powder on the gastrointestinal function in mouse models with stomach-cold functional dyspepsia. Meanwhile,the mouse models were administered with Shihu (dendrobium), a traditional Chinese drug with cold nature and flavour, to explore the way via which it exert its effect on specific symptoms. Methods: Mouse models with stomach-cold functional dyspepsia were established by ice water and ice NaOH. The effects of modified Baizhu powder and dendrobium on mice were observed in terms of water intake, weight change,small intestine propulsion rate, intestinal absorption function, and effects on ghrelin and motilin. RESULTS: The modified Baizhu powder effectively increased food intake, water intake, body weight (P<0.05) and swimming time (P<0.01), increased the small intestine propulsion rate and serum D-xylose content (P<0.05), and up-regulated ghrelin (P<0.05). Also, it showed a trend to down-regulate the motilin, although the change was not statistically significant (P>0.05). In contrast,the use of Shihu aggravated symptoms in the mouse models. Conclusion: The changes in ghrelin and motilin levels may be the neuro-endocrine mechanisms via which the modified Baizhu powder and Shihu exert their effects on mouse models.

Targeting of multiple oncogenic signaling pathways by Hsp90 inhibitor alone or in combination with berberine for treatment of colorectal cancer.

There is a wide range of drugs and combinations under investigation and/or approved over the last decade to treat colorectal cancer (CRC), but the 5-year survival rate remains poor at stages II-IV. Therefore, new, more-efficient drugs still need to be developed that will hopefully be included in first-line therapy or overcome resistance when it appears, as part of second- or third-line treatments in the near future. In this study, we revealed that heat shock protein 90 (Hsp90) inhibitors have high therapeutic potential in CRC according to combinative analysis of NCBI's Gene Expression Omnibus (GEO) repository and chemical genomic database of Connectivity Map (CMap). We found that second generation Hsp90 inhibitor, NVP-AUY922, significantly downregulated the activities of a broad spectrum of kinases involved in regulating cell growth arrest and death of NVP-AUY922-sensitive CRC cells. To overcome NVP-AUY922-induced upregulation of survivin expression which causes drug insensitivity, we found that combining berberine (BBR), a herbal medicine with potency in inhibiting survivin expression, with NVP-AUY922 resulted in synergistic antiproliferative effects for NVP-AUY922-sensitive and -insensitive CRC cells. Furthermore, we demonstrated that treatment of NVP-AUY922-insensitive CRC cells with the combination of NVP-AUY922 and BBR caused cell growth arrest through inhibiting CDK4 expression and induction of microRNA-296-5p (miR-296-5p)-mediated suppression of Pin1-ß-catenin-cyclin D1 signaling pathway. Finally, we found that the expression level of Hsp90 in tumor tissues of CRC was positively correlated with CDK4 and Pin1 expression levels. Taken together, these results indicate that combination of NVP-AUY922 and BBR therapy can inhibit multiple oncogenic signaling pathways of CRC.

[Chemical constituents from Euphorbia lunulata].

The chemical constituents from Euphorbia lunulata was investigated in this paper. Fourteen compounds were isolated and purified by column chromatographies on silica gel and preparative HPLC. Their structures were identified by physiochemical properties and NMR data analysis as lupeol (1), euphol (2), cassipourol(3) , 24-methylenecycloartan-3beta-ol (4), 24-hydroperoxycycloart-25-en-3beta-ol (5), 25-hydroperoxycycloart-23-en-3beta-ol (6), betulin (7), uvaol (8), (23E) -25-methoxycycloart-23-en-3beta-ol (9), (23E) -cycloart-23,25-dien-3beta-ol (10), 24-methylenecycloartan-3beta, 28-diol (11), salicinolide (12), 2alpha, 3beta, 5alpha, 9alpha, 15beta-pentaacetoxy-11,12-epoxy-7beta, 8alpha-diisobutyryloxyjatropha-6 (17) -en-14-one (13) and 3beta, 5alpha, 15beta-triacetoxy-7beta-isobutyryloxy-9alpha-nicotinoyloxyjatropha-6 (17), 11(E)-dien-14-one (14). Among them, compounds 1-11 were isolated from E. lunulata for the first time.

A gene expression signature-based approach reveals the mechanisms of action of the Chinese herbal medicine berberine.

Berberine (BBR), a traditional Chinese herbal medicine, was shown to display anticancer activity. In this study, we attempted to provide a global view of the molecular pathways associated with its anticancer effect through a gene expression-based chemical approach. BBR-induced differentially expressed genes obtained from the Gene Expression Omnibus (GEO) at the National Center for Biotechnology Information (NCBI) were analyzed using the Connectivity Map (CMAP) database to compare similarities of gene expression profiles between BBR and CMAP compounds. Candidate compounds were further analyzed using the Search Tool for Interactions of Chemicals (STITCH) database to explore chemical-protein interactions. Results showed that BBR may inhibit protein synthesis, histone deacetylase (HDAC), or AKT/mammalian target of rapamycin (mTOR) pathways. Further analyses demonstrated that BBR inhibited global protein synthesis and basal AKT activity, and induced endoplasmic reticulum (ER) stress and autophagy, which was associated with activation of AMP-activated protein kinase (AMPK). However, BBR did not alter mTOR or HDAC activities. Interestingly, BBR induced the acetylation of α-tubulin, a substrate of HDAC6. In addition, the combination of BBR and SAHA, a pan-HDAC inhibitor, synergistically inhibited cell proliferation and induced cell cycle arrest. Our results provide novel insights into the mechanisms of action of BBR in cancer therapy.

Dendrimer-encapsulated copper as a novel oligonucleotides label for sensitive electrochemical stripping detection of DNA hybridization.

This paper describes the synthesis and characterization of a novel electrochemical label for sensitive electrochemical stripping detection of DNA hybridization based on dendrimer-encapsulated copper. The generation 4.5 (G 4.5) carboxyl-terminated poly(amidoamine) dendrimer with a trimesyl core was used as a template for synthesis of Cu²âº/dendrimer nanocomposites (Cu-DNCs). Ratios of Cu²âº/dendrimer were optimized in order to obtain stable nanocomposites with maximal copper loading in the interior of a polymeric shell. Cu-DNCs labeled DNA probe was employed for determining a target ssDNA immobilized on multi-walled carbon nanotubes-modified glassy carbon electrode (GCE) based on a specific hybridization reaction. The hybridization events were monitored by electrochemical detection of Cu anchored on the hybrids after the release in a diluted nitric acid by anodic stripping differential pulse voltammetry (ASDPV). The results showed that only a complementary sequence could form a dsDNA with the Cu-DNCs DNA probe and give an obvious electrochemical signal. The non-complementary sequence exhibited negligible signal change compared with the blank measurement (means: the electrode containing no target DNA incubating in hybridization buffer solution containing Cu-DNCs DNA probe for a certain time). The use of Cu encapsulated-dendrimer as tags and ASDPV for the detection of the released Cu ions could enhance the hybridization signal, and result in the increase of the sensitivity for the target DNA. Under the conditions employed here, the detection limit for measuring the full complementary sequence is down to pM level.

Light therapy for seasonal affective disorder in a clinical office setting.

OBJECTIVE: To determine predictors of response to light therapy (LT) for seasonal affective disorder, winter version, in a clinical office setting for patients with a spectrum of seasonality defined by the Seasonal Pattern Assessment Questionnaire (SPAQ). METHOD: A retrospective review was done of charts of 51 patients who had been treated with a 1-week light therapy intervention. Patient self-rated scales applied in a standard manner were used to measure clinical progress. The Beck Depression Inventory (BDI) with added atypical features was used as the primary outcome variable. Sleep patterns were analyzed and the effect of psychotropic medications on outcome was determined. Seven point scales were used to assess expected response and global response. The importance of having LT set up and available in an office setting was evaluated. Retrospective degree of disability was measured based on the SPAQ degree of problem. The severity of the depressive episode was determined based on BDI score at entry. RESULTS: Seasonality (how a patient's symptoms vary as a function of the season of the year), degree of disability based on the SPAQ, and severity of depressive episode at entry based on the BDI predicted response to LT. Greater severity at baseline based on BDI score predicted less chance of attaining full remission within 7 days of treatment compared with patients with lower severity scores at entry on the BDI. Sleep patterns relative to a fixed treatment time of 7 AM did not predict LT response. Light therapy was effective on its own, and the results were mixed as to whether adding LT to an existing antidepressant medication produced superior results. CONCLUSION: Degree of seasonality can be used as a predictor of response to LT and may be clinically useful when suggesting that patients consider a trial of LT.

[Studies on the chemical constituents of Pharbitis purpurea].

OBJECTIVE: To study the chemical constituents of Pharbitis purpurea. METHODS: The constituents were isolated by silica gel column chromatography, HPLC and recrystallization and their structures were elucidated on the basis of spectral analysis. RESULTS: Fourteen compounds were isolated and identified as daucosterol (1), umbelliferone (2), ursolic acid (3), N-p-hydroxy-cis-coumaroyltyramine (4), N-p-hydroxy-trans-coumaroyltyramine (5), N-cis-feruloyltyramine (6), N-trans-feruloyltyramine (7), (3R, 5R, 6S, 7E, 9S)-megastigman-5,6-epoxy-7-ene-3,9-diol (8), (6S,9R)-vomifoliol (9), (+)-syringaresinol (10), isovitexin (11), syringopicroside( 12), uricil (13), (6S,9R)-roseoside (14). CONCLUSION: Compounds 3, 8-2,14 are isolated from the genus for the first time.

Apigenin suppresses cancer cell growth through ERbeta.

Two flavonoids, genistein and apigenin, have been implicated as chemopreventive agents against prostate and breast cancers. However, the mechanisms behind their respective cancer-protective effects may vary significantly. The goal of this study was to determine whether the antiproliferative action of these flavonoids on prostate (DU-145) and breast (MDA-MB-231) cancer cells expressing only estrogen receptor (ER) beta is mediated by this ER subtype. It was found that both genistein and apigenin, although not 17beta-estradiol, exhibited antiproliferative effects and proapoptotic activities through caspase-3 activation in these two cell lines. In yeast transcription assays, both flavonoids displayed high specificity toward ERbeta transactivation, particularly at lower concentrations. However, in mammalian assay, apigenin was found to be more ERbeta-selective than genistein, which has equal potency in inducing transactivation through ERalpha and ERbeta. Small interfering RNA-mediated downregulation of ERbeta abrogated the antiproliferative effect of apigenin in both cancer cells but did not reverse that of genistein. Our data unveil, for the first time, that the anticancer action of apigenin is mediated, in part, by ERbeta. The differential use of ERalpha and ERbeta signaling for transaction between genistein and apigenin demonstrates the complexity of phytoestrogen action in the context of their anticancer properties.