Human placenta-derived mesenchymal stem cells ameliorate diabetic kidney disease by modulating the T helper 17 cell/ regulatory T-cell balance through the programmed death 1 / programmed death-ligand 1 pathway.

AIM: To investigate the therapeutic effects and immunomodulatory mechanisms of human placenta-derived mesenchymal stem cells (PMSCs) in diabetic kidney disease (DKD). METHODS: Streptozotocin-induced DKD rats were administered an equivalent volume of saline or PMSCs (1 × 106 in 2 mL phosphate-buffered saline per rat) for 3 weeks. Eight weeks after treatment, we examined the biochemical parameters in the blood and urine, the ratio of T helper 17 cells (Th17) and regulatory T cells (Treg) in the blood, cytokine levels in the kidney and blood, and renal histopathological changes. In addition, we performed PMSC tracing and renal transcriptomic analyses using RNA-sequencing. Finally, we determined whether PMSCs modulated the Th17/Treg balance by upregulating programmed death 1 (PD-1) in vitro. RESULTS: The PMSCs significantly improved renal function, which was assessed by serum creatinine levels, urea nitrogen, cystatin C levels, urinary albumin-creatinine ratio, and the kidney index. Further, PMSCs alleviated pathological changes, including tubular vacuolar degeneration, mesangial matrix expansion, and glomerular filtration barrier injury. In the DKD rats in our study, PMSCs were mainly recruited to immune organs, rather than to the kidney or pancreas. PMSCs markedly promoted the Th17/Treg balance and reduced the levels of pro-inflammatory cytokines (interleukin [IL]-17A and IL-1ß) in the kidney and blood of DKD rats. In vitro experiments showed that PMSCs significantly reduced the proportion of Th17 cells and increased the proportion of Treg cells by upregulating PD-1 in a cell-cell contact manner and downregulating programmed death-ligand 1 (PD-L1) expression in PMSCs, which reversed the Th17/Treg balance. CONCLUSION: We found that PMSCs improved renal function and pathological damage in DKD rats and modulated Th17/Treg balance through the PD-1/PD-L1 pathway. These findings provide a novel mechanism and basis for the clinical use of PMSCs in the treatment of DKD.

Association between previous consumption of sugar-sweetened beverages and diabetes remission in patients with newly diagnosed type 2 diabetic ketoacidosis.

This study examined the potential correlation between the immoderate intake of sugar-sweetened beverages (SSBs) and the subsequent rate of diabetes remission (DR). 206 individuals who met the eligibility criteria between January 2019 and June 2022 were recruited. Inquiries were conducted to gather information on the participants' beverage consumption before the onset. Subsequently, the participants were separated into the diabetes remission group (DR group) and nondiabetes remission group (NDR group) depending on whether they met the diagnostic criteria for diabetes remission. Baseline clinical elements within the two groups were juxtaposed, and factors influencing diabetes remission were identified through logistic regression analyses. The cutoff values of each critical factor were determined based on the receiver operating characteristic curve. One hundred and nine patients reported a history of SSB consumption, while the remaining 58 reported no such history. After 1 year, 40 patients achieved remission from diabetes. Compared with the NDR group, a higher SSBs ratio, body mass index (BMI), and blood creatinine (BCr) was observed in the DR group after adjusting for confounders, SSBs (odds ratio [OR] = 3.503; 95% confidence interval [CI] = 1.334-9.202; p = 0.011) and BCr (OR = 1.038; 95% CI = 1.003-1.079; p = 0.042) emerged as independent predictors of DR. The composite index of SSBs and BCr efficaciously predicted DR (area under the ROC curve [AUC] = 0.810, p < 0.001). SSBs and BCr were independent risk factors for DR. The amalgamation of these markers could more accurately predict DR.

Rapid initiation of cell cycle reentry processes protects neurons from amyloid-ß toxicity.

Neurons are postmitotic cells. Reactivation of the cell cycle by neurons has been reported in Alzheimer's disease (AD) brains and models. This gave rise to the hypothesis that reentering the cell cycle renders neurons vulnerable and thus contributes to AD pathogenesis. Here, we use the fluorescent ubiquitination-based cell cycle indicator (FUCCI) technology to monitor the cell cycle in live neurons. We found transient, self-limited cell cycle reentry activity in naive neurons, suggesting that their postmitotic state is a dynamic process. Furthermore, we observed a diverse response to oligomeric amyloid-ß (oAß) challenge; neurons without cell cycle reentry activity would undergo cell death without activating the FUCCI reporter, while neurons undergoing cell cycle reentry activity at the time of the oAß challenge could maintain and increase FUCCI reporter signal and evade cell death. Accordingly, we observed marked neuronal FUCCI positivity in the brains of human mutant Aß precursor protein transgenic (APP23) mice together with increased neuronal expression of the endogenous cell cycle control protein geminin in the brains of 3-mo-old APP23 mice and human AD brains. Taken together, our data challenge the current view on cell cycle in neurons and AD, suggesting that pathways active during early cell cycle reentry in neurons protect from Aß toxicity.

Comparative efficacy of exercise modalities for general risk factors, renal function, and physical function in non-dialysis chronic kidney disease patients: a systematic review and network meta-analysis.

BACKGROUND: Exercise therapy can effectively manage chronic kidney disease (CKD) risk factors and improve renal function and physical fitness, but the challenge lies in choosing the right exercise type tailored to patients' condition. METHODS: An electronic search of databases including PubMed, The Cochrane Library, EMBASE, Web of Science, VIP, WanFang, and CNKI was performed. The random effects model was used. Mean difference was employed as the effect size for continuous variables, with 95% confidence interval (CI) provided. RESULTS: A total of 36 RCTs were included in this study. Compared to conventional therapy (CT), the combination of three exercise therapies with CT resulted in notable benefits in enhancing six minutes walk test (6MWT) capacity, 24-h urinary protein quantity (24hUTP), systolic blood pressure (SBP), diastolic blood pressure (DBP). Resistance exercise therapy (RT) + CT were more effective than CT to reduce serum creatinine (Scr), body mass index (BMI), and hemoglobin A1c (HbA1c) and improve estimated glomerular filtration rate (eGFR). In terms of improving peak oxygen uptake (VO2 peak), only two exercise modalities were involved, aerobic exercise therapy (AT) and combined (Resistance-Aerobic) exercise therapy (CBT), both of which were more efficacious than CT. The efficacy ranking overall demonstrated clear benefits for RT in enhancing eGFR and 6MWT, decreasing Scr, BMI, SBP, DBP, and HbA1c, while AT was more suitable for boosting VO2 peak, and CBT had greater potential for reducing 24hUTP. CONSLUSIONS: Exercise therapy combined with CT offers significant advantages over CT in many cases, but no single exercise modality is universally effective for all indicators.

Supramolecular deep eutectic solvents: Current advances and critical evaluation of cyclodextrins from solute to solvent in emerging functional food.

The acceptance of nonconventional solvents as viable substitutes for traditional organic solvents has been widely recognized in order to comply with food-safety and sustainability regulations. Cyclodextrins (CDs), derived from starch, are cyclic oligosaccharides with the ability to form inclusion complexes with a variety of functional substances as the result of their distinctive structure, which enables them to effectively encapsulate bioactive compounds, rendering them highly sought after for use in food applications. In the implementing plan to achieve carbon-neutral emissions by 2050, the novel generation of supramolecular deep eutectic solvents (SUPRADES) has garnered increased attention and interest. The approach of utilizing SUPRADES as emerging solvents was just beginning to be applied to food studies. This review summarizes a revision of the current advances and critical evaluation of cyclodextrin-based SUPRADES (CD-based SUPRADES) as promising solvents for the enhancement of the extraction efficiency, solubilization and stability of bioactive compounds, adsorption and separation of food components, packaging materials, and modification of biopolymers. To meet the sustainable processing needs of the food industry, the emerging categories of CD-based SUPRADES need to be further fabricated. Herein, our review will sort out the potential application of CD-based SUPRADES in the food industry, aiming to provide a better understanding of CD-based SUPRADES within the viewpoint of food science. Formulation intricacies and scalability issues in real functional foods using CD-based SUPRADES as media need more efforts.

Phosphoproteome analysis of cerebrospinal fluid extracellular vesicles in primary central nervous system lymphoma.

Primary central nervous system lymphoma (PCNSL) is a rare but highly aggressive extra-nodal non-Hodgkin's lymphoma, mostly of the diffuse large B-cell lymphoma (DLBCL) type. The present invasive diagnosis and poor prognosis of PCNSL propose an urgent need to develop molecular markers for early detection, real-time monitoring and treatment evaluation. Cerebrospinal fluid (CSF)-derived extracellular vesicles (EVs) are promising biomarker carriers for liquid biopsy of CNS diseases and brain tumors; however, research remains challenging due to the low concentration of EVs in the limited available volume of CSF from each individual patient and the low efficiency of existing methods for EV enrichment. Here, we introduce functionalized magnetic beads called EVTRAP (extracellular vesicles total recovery and purification) for rapid and efficient EV isolation from CSF. By coupling with high-performance mass spectrometry, over 19 000 peptides representing 1841 proteins were identified from just 30 µL of CSF. Furthermore, up to 3000 phosphopeptides representing over 1000 phosphoproteins were identified from about 2 mL of CSF. Finally, we analyzed the EV phosphoproteomics of CSF samples from PCNSL patients and non-PCNSL controls. Among them, multiple phosphoproteins related to PCNSL, including SPP1, MARCKS, NPM1 and VIM, were shown to be up-regulated in the PCNSL group. These results demonstrated the feasibility of the EVTRAP-based analytical strategy in CSF EV phosphoproteomic analysis of PCNSL molecular markers.

Risk factors for the development of postpartum depression in individuals who screened positive for antenatal depression.

BACKGROUND: Women with antenatal depression often have a higher risk of developing postpartum depression (PPD) after delivery. A number of factors associated with the PDD in those previously reporting antenatal depression have been suggested, but further research is needed. This study aimed to investigate factors associated with developing subsequent postnatal depression in women who had screened positive for antenatal depression. METHODS: This study was carried out in Hangzhou women's Hospital. 578 women who experienced antenatal depression from this cohort were enrolled in this study. The sociodemographic and clinical characteristics of the participants were collected and tabulated against the incidence of postnatal depression. Binary logistic regression was used to estimate the effects of the principal underlying variables. The Chinese-version Edinburgh Postnatal Depression Scale (EPDS) was used to screen for PPD. Antenatal screening for depression was conducted at 28-34 weeks during pregnancy and postpartum depressive symptoms were assessed at 6 weeks after childbirth in the women. Path Analysis of Structural Equation Model (SEM) was employed to explore the direct, indirect, and total effects of risk factors of PPD. RESULTS: 57.6% (n = 333) of the participants subsequently developed PPD in our study. The results of the logistic analysis indicated that ages ≤ 35 years old (OR = 1.852; 95%CI: 1.002-3.423), non-one-child families (OR = 1.518; 95%CI: 1.047-2.200), and rare care from partner during pregnancy (OR = 2.801; 95%CI: 1.038-7.562), the antenatal EPDS score (OR = 1.128; 95%CI: 1.052-1.209), pyrexia during pregnancy (OR = 2.43; 95%CI: 1.358-4.345), fairly good (OR = 1.836; 95%CI: 1.009-3.340), fairly bad (OR = 3.919; 95%CI:2.072-7.414) and very bad postpartum sleep quality (OR = 9.18; 95%CI: 2.335-36.241) were associated with increased risk of PPD (compared to very good postpartum sleep quality). In path analysis model, antenatal EPDS score (standardized total ß = 0.173) and pyrexia during pregnancy (standardized total ß = 0.132) had both direct and indirect effects (the impact on outcome variables needs to be determined through other variables) on PPD. Sleep quality after delivery (standardized ß = 0.226) and one-child family (standardized ß = 0.088) had direct effects only on PPD. CONCLUSION: The results from our study indicated that more than 50% of the women who experienced antepartum depression would subsequently develop PPD. Depressive symptoms and pyrexia during pregnancy increase PPD scores, and these effects were in part mediated via poor sleep quality during the postpartum period.

LncRNA-WAKMAR2 regulates expression of CLDN1 to affect skin barrier through recruiting c-Fos.

BACKGROUND: Chronic actinic dermatitis (CAD) is an immune-mediated photo-allergic skin disease. In the clinic, the treatment of this disease is hampered by the lack of proper understanding of the skin barrier dysfunction mechanism. OBJECTIVE: To illuminate the mechanism of skin barrier dysfunction in CAD. METHODS: Transcriptome sequencing and protein profiling were used to detect skin barrier injury-related genes. RNA pull down, a promoter-reporter gene assay, and chromatin isolation by RNA purification-sequencing were used to elucidate the effect of WAKMAR2 in skin barrier functionality. RESULTS: Transcriptome sequencing from patient's tissues showed a significantly decreased expression of WAKMAR2. Down-regulation of WAKMAR2 destroyed the keratinocyte barrier. Moreover, WAKMAR2 can directly bind to the c-Fos protein. This novel long non-coding RNA (LncRNA)-protein complexes were targeted to the CLDN1 promotor. Overexpression of WAKMAR2 enhanced the promoter activity of CLDN1, while the addition of AP-1 inhibitor could reverse this phenomenon. Furthermore, our in vivo results suggested that expression of WAKMAR2 was required for the repair of skin damage in mice induced by ultraviolet irradiation. CONCLUSIONS: We identified a crucial LncRNA (WAKMAR2) for the protection of the skin barrier in vitro and in vivo. Mechanically, it can specifically interact with c-Fos protein for the regulation of CLDN1, a finding which could be applied for CAD treatment.

Placental Mesenchymal Stem Cells Alleviate Podocyte Injury in Diabetic Kidney Disease by Modulating Mitophagy via the SIRT1-PGC-1alpha-TFAM Pathway.

The use of mesenchymal stem cells (MSCs) has become a new strategy for treating diabetic kidney disease (DKD). However, the role of placenta derived mesenchymal stem cells (P-MSCs) in DKD remains unclear. This study aims to investigate the therapeutic application and molecular mechanism of P-MSCs on DKD from the perspective of podocyte injury and PINK1/Parkin-mediated mitophagy at the animal, cellular, and molecular levels. Western blotting, reverse transcription polymerase chain reaction, immunofluorescence, and immunohistochemistry were used to detect the expression of podocyte injury-related markers and mitophagy-related markers, SIRT1, PGC-1α, and TFAM. Knockdown, overexpression, and rescue experiments were performed to verify the underlying mechanism of P-MSCs in DKD. Mitochondrial function was detected by flow cytometry. The structure of autophagosomes and mitochondria were observed by electron microscopy. Furthermore, we constructed a streptozotocin-induced DKD rat model and injected P-MSCs into DKD rats. Results showed that as compared with the control group, exposing podocytes to high-glucose conditions aggravated podocyte injury, represented by a decreased expression of Podocin along with increased expression of Desmin, and inhibited PINK1/Parkin-mediated mitophagy, manifested as a decreased expression of Beclin1, the LC3II/LC3I ratio, Parkin, and PINK1 associated with an increased expression of P62. Importantly, these indicators were reversed by P-MSCs. In addition, P-MSCs protected the structure and function of autophagosomes and mitochondria. P-MSCs increased mitochondrial membrane potential and ATP content and decreased the accumulation of reactive oxygen species. Mechanistically, P-MSCs alleviated podocyte injury and mitophagy inhibition by enhancing the expression of the SIRT1-PGC-1α-TFAM pathway. Finally, we injected P-MSCs into streptozotocin-induced DKD rats. The results revealed that the application of P-MSCs largely reversed the markers related to podocyte injury and mitophagy and significantly increased the expression of SIRT1, PGC-1α, and TFAM compared with the DKD group. In conclusion, P-MSCs ameliorated podocyte injury and PINK1/Parkin-mediated mitophagy inhibition in DKD by activating the SIRT1-PGC-1α-TFAM pathway.

The serial mediation effect of prospective imagery vividness and anxiety symptoms on the relationship between perceived stress and depressive symptoms among Chinese vocational college students during the COVID-19 pandemic.

The mental health of vocational college students has been neglected during the COVID-19 pandemic. Prospective imagery may play a role in the relationships among stress, anxiety and depression. This study aimed to survey the mental health of Chinese vocational college students and explore the mediation effect of prospective imagery vividness and anxiety symptoms on the relationship between perceived stress and depressive symptoms. A total of 2, 381 vocational college students (Mage = 18.38 years, range: 16-21, SD = 0.92) provided self-report data on perceived stress, anxiety and depressive symptoms and prospective imagery vividness. Two potential serial mediation models were postulated regarding the roles of prospective imagery vividness and anxiety symptoms in the relationship between perceived stress and depressive symptoms. The prevalence rates of stress, anxiety and depressive symptoms were 55.7%, 33.2% and 53.5%, respectively, among vocational college students. Perceived stress was associated with decreased vividness of positive prospective imagery and increased vividness of negative prospective imagery and anxiety symptoms, leading to increased depressive symptoms. Additionally, prospective imagery vividness and anxiety symptoms had a serial mediation effect on the relationship between perceived stress and depressive symptoms. The results demonstrated that impoverished vividness of positive prospective imagery is not only a central feature of depression but also associated with anxiety. Interventions targeting prospective imagery vividness may alleviate anxiety and depressive symptoms among Chinese vocational college students and should be implemented as soon as possible during the COVID-19 pandemic.

Loss of LAMP5 interneurons drives neuronal network dysfunction in Alzheimer's disease.

In Alzheimer's disease (AD), where amyloid-ß (Aß) and tau deposits in the brain, hyperexcitation of neuronal networks is an underlying disease mechanism, but its cause remains unclear. Here, we used the Collaborative Cross (CC) forward genetics mouse platform to identify modifier genes of neuronal hyperexcitation. We found LAMP5 as a novel regulator of hyperexcitation in mice, critical for the survival of distinct interneuron populations. Interestingly, synaptic LAMP5 was lost in AD brains and LAMP5 interneurons degenerated in different AD mouse models. Genetic reduction of LAMP5 augmented functional deficits and neuronal network hypersynchronicity in both Aß- and tau-driven AD mouse models. To this end, our work defines the first specific function of LAMP5 interneurons in neuronal network hyperexcitation in AD and dementia with tau pathology.

Syntaxins 6 and 8 facilitate tau into secretory pathways.

Tau pathology initiates in defined brain regions and is known to spread along neuronal connections as symptoms progress in Alzheimer's disease (AD) and other tauopathies. This spread requires the release of tau from donor cells, but the underlying molecular mechanisms remained unknown. Here, we established the interactome of the C-terminal tail region of tau and identified syntaxin 8 (STX8) as a mediator of tau release from cells. Similarly, we showed the syntaxin 6 (STX6), part of the same SNARE family as STX8 also facilitated tau release. STX6 was previously genetically linked to progressive supranuclear palsy (PSP), a tauopathy. Finally, we demonstrated that the transmembrane domain of STX6 is required and sufficient to mediate tau secretion. The differential role of STX6 and STX8 in alternative secretory pathways suggests the association of tau with different secretory processes. Taken together, both syntaxins, STX6 and STX8, may contribute to AD and PSP pathogenesis by mediating release of tau from cells and facilitating pathology spreading.

DrugCombDB: a comprehensive database of drug combinations toward the discovery of combinatorial therapy.

Drug combinations have demonstrated high efficacy and low adverse side effects compared to single drug administration in cancer therapies and thus have drawn intensive attention from researchers and pharmaceutical enterprises. Due to the rapid development of high-throughput screening (HTS), the number of drug combination datasets available has increased tremendously in recent years. Therefore, there is an urgent need for a comprehensive database that is crucial to both experimental and computational screening of synergistic drug combinations. In this paper, we present DrugCombDB, a comprehensive database devoted to the curation of drug combinations from various data sources: (i) HTS assays of drug combinations; (ii) manual curations from the literature; and (iii) FDA Orange Book and external databases. Specifically, DrugCombDB includes 448 555 drug combinations derived from HTS assays, covering 2887 unique drugs and 124 human cancer cell lines. In particular, DrugCombDB has more than 6000 000 quantitative dose responses from which we computed multiple synergy scores to determine the overall synergistic or antagonistic effects of drug combinations. In addition to the combinations extracted from existing databases, we manually curated 457 drug combinations from thousands of PubMed publications. To benefit the further experimental validation and development of computational models, multiple datasets that are ready to train prediction models for classification and regression analysis were constructed and other significant related data were gathered. A website with a user-friendly graphical visualization has been developed for users to access the wealth of data and download prebuilt datasets. Our database is available at http://drugcombdb.denglab.org/.

Insight into disinfection byproduct formation potential of aged biochar and its effects during chlorination.

Biochar can achieve multiple benefits including solid waste management, polluted water remediation, carbon sequestration, and emission reduction. However, various environmental factors (such as temperature variations and dry-wet alternation) and microbial activity may lead to the fragmentation, dissolution, and oxidation of biochar. These accelerate the dissolution of biochar-derived dissolved organic matter (DOM) and then influence disinfection byproducts formation potential (DBPFP) throughout the water treatment process. In this paper, biochars from six biomass feedstocks with five aging processes were prepared, and the DBPFP of biochar and its derived DOM were first studied systematically. Different aging processes might increase the DBPFP of biochar by increasing DOM content and changing the fraction distribution of DOM derived from biochar. Especially, the DBPFP of biochar increased apparently with the chemical aging process. Coexisting with the environmental concentration of humic acid, even aged biochar showed the potential to reduce DBPFP and integrated toxic risk value of the mixed system. In this study, the DBPFP of biochar-derived DOM during the disinfection process is confirmed, and the results can give information to the selection of biomass feedstocks of biochar and its service life in the water treatment process.

[Association between the diet balance index-based dietary quality and cognitive function among Zhejiang population aged 40 years and older].

OBJECTIVE: To evaluation the dietary quality of Zhejiang population aged 40 years and older using the Dietary Balance Index(DBI) and to analyze the association between dietary quality and cognitive function. METHODS: The dietary information was collected with the help of questionnaire survey, a 3-day dietary recall and household condiment weighing method from Zhejiang participants of the 2018 wave of the China Health and Nutrition Survey aged 40 years and older, and the food and energy intakes were calculated. The cognitive function was assessed by the Mini Mental Status Examination. Dietary quality was evaluated using the DBI method. A multivariate Logistic regression model was used to examine the association between dietary quality and the risk of cognitive impairment. RESULTS: Among 640 participants aged 40 years and older, 14.2% had cognitive impairment. Univariate analysis showed that those with cognitive impairment had higher cereal(P=0.001), particularly, higher rice and products intake(P<0.001), as well as higher egg intake(P=0.008) than those with normal cognitive function; while the intake of soybean and its product(P=0.025) was lower. Those with cognitive impairment had higher DBI score of cereal(P=0.006) and high bound score(HBS)(P=0.028)than those with normal cognitive function. After adjustment for possible confounding factors, Logistic regression showed that moderated and severe over-consumption was positively associated with cognitive impairment(OR=2.486, 95% CI 1.130-5.470, P=0.024). CONCLUSION: Over-consumption may increase the risk of cognitive impairment among aged Zhejiang population, and should be used to prevent or reduce cognitive decline by improving the quality of the diet through a reasonable dietary mix.

CD36 as a Molecular Target of Functional DNA Aptamer NAFLD01 Selected against NAFLD Cells.

The aim of this study was to identify the target of nonalcoholic fatty liver disease (NAFLD) cell-specific aptamer NAFLD01 and investigate its effect on lipid metabolism in vitro. A distinct membrane protein of NAFLD cells pulled down by NAFLD01 was analyzed by mass spectrometry to determine target candidates, and affinity of NAFLD01 to target-protein-silent NAFLD cells was detected to validate it. Knockdown of CD36 abolished the binding of NAFLD01, and its binding affinity was associated with membrane-bound CD36. NAFLD01 affinity for NAFLD cells was proportional to the CD36 expression level. Moreover, compared to random sequences, NAFLD01 showed better recognition for both mouse and human tissue sections of NAFLD. Importantly, NAFLD01 could ameliorate liver fat deposition through interaction with CD36 in vitro. Therefore, aptamer NAFLD01 could act as an effective and safe targeted drug for NAFLD. NAFLD01 is the first reported CD36-specific aptamer. This aptamer can improve hepatocyte steatosis via specifically binding to CD36. This study provides a molecular tool to investigate the mechanism of CD36 in NAFLD.

Cyclometalated Ru(II) ß-carboline complexes induce cell cycle arrest and apoptosis in human HeLa cervical cancer cells via suppressing ERK and Akt signaling.

Two new cyclometalated Ru(II)-ß-carboline complexes, [Ru(dmb)2(Cl-Ph-ßC)](PF6) (dmb = 4,4'-dimethyl-2,2'-bipyridine; Cl-Ph-ßC = Cl-phenyl-9H-pyrido[3,4-b]indole; RußC-3) and [Ru(bpy)2(Cl-Ph-ßC)](PF6) (bpy = 2,2'-bipyridine; RußC-4) were synthesized and characterized. The Ru(II) complexes display high cytotoxicity against HeLa cells, the stabilized human cervical cancer cell, with IC50 values of 3.2 ± 0.4 µM (RußC-3) and 4.1 ± 0.6 µM (RußC-4), which were considerably lower than that of non-cyclometalated Ru(II)-ß-carboline complex [Ru(bpy)2(1-Py-ßC)] (PF6)2 (61.2 ± 3.9 µM) by 19- and 15-folds, respectively. The mechanism studies indicated that both Ru(II) complexes could significantly inhibit HeLa cell migration and invasion, and effectively induce G0/G1 cell cycle arrest. The new Ru(II) complexes could also trigger apoptosis through activating caspase-3 and poly (ADP-ribose) polymerase (PARP), increasing the Bax/Bcl-2 ratio, enhancing reactive oxygen species (ROS) generation, decreasing mitochondrial membrane potential (MMP), and inducing cytochrome c release from mitochondria. Further research revealed that RußC-3 could deactivate the ERK/Akt signaling pathway thus inhibiting HeLa cell invasion and migration, and inducing apoptosis. In addition, RußC-3-induced apoptosis in HeLa cells was closely associated with the increase of intracellular ROS levels, which may act as upstream factors to regulate ERK and Akt pathways. More importantly, RußC-3 exhibited low toxicity on both normal BEAS-2B cells in vitro and zebrafish embryos in vivo. Consequently, the developed Ru(II) complexes have great potential on developing novel low-toxic anticancer drugs.

Effects of topical insulin on wound healing: a meta-analysis of animal and clinical studies.

Various researches have reported that the application of topical insulin improves wound healing. Considering the lack of a quantitative comprehensive research on this matter, we conducted a meta-analysis of clinical research and experimental animal studies. Prospective and randomized controlled trials of PubMed, Embase, and Cochrane Library were conducted using appropriate search strategies to compare the effectiveness of topical application of saline and insulin on wounds. The standardized mean difference was calculated as follows: wound healing time, wound healing rate, wound area, and the percentage of wound contraction. Each study used the Cochrane risk-of-bias tool and RevMan 5.3 software to create aggregated assessments and forest plots. The quality of evidence was evaluated in accordance with the methods of the Grading of Recommendations, Assessment, Development and Evaluation working group. Four clinical and nine animal studies eligible for inclusion were included in the meta-analysis. The assessments for clinical studies were as follows: wound healing time, -2.48 [-3.44, -1.51] and wound healing rate, 22.23 [18.17, 26.28]. Meanwhile, for animal studies, the following assessments were noted: wound healing time, -1.27 [-1.75, -0.79]; wound contraction rate, 15.91 [13.88, 17.95]; and wound area, -19.3 [-21.16, -17.44]. For the measurement of the following results, only one animal study was performed, pericyte recruitment of microvessels. Based on the analysis, it can be preliminarily judged that application of topical insulin can aid wound healing.

Glass Fiber-Supported Hybrid Monolithic Spin Tip for Enrichment of Phosphopeptides from Urinary Extracellular Vesicles.

Extracellular vesicles (EVs) are attracting increasing interest with their intriguing role in intercellular communications. Protein phosphorylation in EVs is of great importance for understanding intercellular signaling processes. However, the study of EV phosphoproteomics is impeded by their relatively low amount in limited clinical sample volumes, and it is necessary to have a sensitive and efficient enrichment method for EV phosphopeptides. Herein, a novel Ti(IV)-functionalized and glass fiber-supported hybrid monolithic spin tip, termed PhosTip, was prepared for enriching phosphopeptides from urinary EVs. Glass fiber as the stationary phase positions the hybrid monolith in a standard pipet tip and prevents the monolith from distortion during experiments. The preparation procedure for the new PhosTip is simple and time-saving. The hybrid monolithic PhosTip provides excellent enrichment efficiency of low-abundance phosphopeptides from cell digests and urinary EVs with minimum contamination and sample loss. Using the PhosTip, we demonstrate that 5373 and 336 unique phosphopeptides were identified from 100 and 1 µg of cell lysates, while 3919 and 217 unique phosphopeptides were successfully identified from 10 and 1 mL of urinary samples, respectively. The PhosTip was finally applied to enrich phosphopeptides in urine EVs from prostate cancer patients and healthy controls and quantify 118 up-regulated proteins with phosphosites in prostate cancer samples. These results demonstrated that the PhosTip could be a simple and convenient tool for enriching phosphopeptides from clinical samples and for broader applications in biomarker discovery.

Comparison of the Effects of Different Food-Grade Emulsifiers on the Properties and Stability of a Casein-Maltodextrin-Soybean Oil Compound Emulsion.

The improvement of food-grade emulsifiers in the properties and stability of complex emulsion has attracted much interest. In this study, the effects of six food-grade emulsifiers with a hydrophilic-lipophilic balance (HLB) range of 3.4-8.0 on a casein-maltodextrin-soybean oil compound emulsion were investigated by centrifugal precipitation rate (CPR), emulsifying activity index (EAI), microrheological properties, zeta potential, average particle size, and Turbiscan stability index (TSI). The optimal amounts of added succinylated monoglyceride (SMG) and polyglycerol fatty acid ester were 0.0025% and 0.1% (w/w), respectively, while that of the other four emulsifiers was 0.2% (w/w), according to the CPR. Thereinto, the SMG-stabilized emulsion exhibited the highest emulsifying activity and the lowest viscosity value and possessed the highest stability over 14 days of storage, which was indicated by the lowest TSI value and the smallest change in delta backscattering signal, relative to those of the other groups. Moreover, the emulsion stabilized by SMG displayed better emulsion stability than the control under a range of pH (6.0-8.0) and calcium ion concentrations (0-10 mM), which was attributed to the increased zeta potential value and the decreased average particle size of droplets with the addition of SMG. The present study provides a basic understanding for SMG improving the properties and stability of the complex emulsion.