Activatable unsaturated liposomes increase lipid peroxide of cell membrane and inhibit tumor growth.

The cancer chemodynamic therapy based on the Fenton reaction has been attracting more and more attention. However, the performance of the Fenton reaction is restricted by the unsuitable physiological pH value and inadequate H2O2 content in the tumor microenvironment (TME). In this study, we proposed a novel method of inducing lipid peroxide (LPO) of the cancer cell membrane, whose performance is not limited by the pH value and H2O2 in the TME. The activatable LPO-inducing liposomes were constructed by encapsulating Fe3+-containing compound ferric ammonium citrate (FC) in the unsaturated soybean phospholipids (SPC). It was found that the FC could be reduced by the overexpressed glutathione (GSH) in the TME and produce iron redox couple. The Fe3+/Fe2+ mediated the peroxidation of the unsaturated SPC and induced the LPO in the cancer cells. Finally, LPO accumulation led to cancer cell death and tumor growth inhibition. Furthermore, the activatable liposomes did not damage healthy tissues because of the low GSH content in normal tissues and the GSH-triggered activation of the nanocarrier. Together, our findings revealed that FC-SPC-lipo displayed excellent anti-tumor performance and its therapeutic effects are less influenced by the TME, compared with the traditional ferroptosis.

Exploration of the mechanism of NORAD activation of TGF-ß1/Smad3 through miR-136-5p and promotion of tacrolimus-induced renal fibrosis.

BACKGROUND: Tacrolimus is a potent immunosuppressant, but has various side effects, with nephrotoxicity being the most common. Renal fibrosis is an important process of tacrolimus nephrotoxicity. Therefore, it is important to identify the factors that contribute to renal fibrosis after tacrolimus nephrotoxicity, and control its development. METHODS: The present study aims to determine whether tacrolimus may speed up the course of renal fibrosis by upregulating noncoding RNA activated by DNA damage (NORAD) to compete with miR-136-5p, and activating the TGF-ß1/Smad3 pathway. Furthermore, in vivo rat models and in vitro cell models were established. Then, the expression levels of NORAD and miR-136-5p were determined by RT-qPCR, while the expression of the TGF-ß1/Smad3 pathway was determined by western blot and RT-qPCR. In order to investigate the interaction between NORAD and miR-136-5p, as well as miR-136-5p and SYK, two luciferase reporters were employed. The renal fibrosis of mice was observed using Masson and PAS staining. The expression of inflammatory factors IL-1, IL-6, MCP-1 and TNF-α was detected by ELISA. RESULTS: In the in vitro experiments, NORAD was upregulated, while miR-136-5p was downregulated after tacrolimus induction. The expression of the TGF-ß1/Smad3 pathway correspondingly changed after the induction by tacrolimus. In the in vivo experiments, the expression of NORAD and miR-136-5p, and the trend for renal fibrosis were consistent with the results in the in vitro experiments. Furthermore, the inflammatory factors correspondingly changed with the severity of renal fibrosis. Moreover, the expression trend of the TGF-ß1/Smad3 pathway in tacrolimus-induced rats was consistent with that in the in vitro experiments. CONCLUSION: Through in vitro and in vivo experiments, the present study was able to successfully prove that tacrolimus upregulates NORAD to compete with miR-136-5p, resulting in a decrease in miR-136-5p expression, which in turn activates the TGF-ß1/smad3 pathway, and finally induces the aggravation of renal fibrosis.

Bone marrow mesenchymal stem cells repress renal transplant immune rejection by facilitating the APRIL phosphorylation to induce regulation B cell production.

Bone marrow mesenchymal stem cells (BMSCs) exert pivotal roles in suppressing immune rejection in organ transplantation. However, the function of BMSCs on immune rejection in renal transplantation remains unclear. This study aimed to evaluate the effect and underlying mechanism of BMSCs on immune rejection in renal transplantation. Following the establishment of the renal allograft mouse model, the isolated primary BMSCs were injected intravenously into the recipient mice. Enzyme-linked immunosorbent assay, flow cytometry, hematoxylin-eosin staining, and Western blot assays were conducted to investigate BMSCs' function in vivo and in vitro. Mechanistically, the underlying mechanism of BMSCs on immune rejection in renal transplantation was investigated in in vivo and in vitro models. Functionally, BMSCs alleviated the immune rejection in renal transplantation mice and facilitated B cell activation and the production of IL-10+ regulatory B cells (Bregs). Furthermore, the results of mechanism studies revealed that BMSCs induced the production of IL-10+ Bregs by facilitating a proliferation-inducing ligand (APRIL) phosphorylation to enhance immunosuppression and repressed renal transplant rejection by promoting APRIL phosphorylation to induce IL-10+ Bregs. BMSCs prevent renal transplant rejection by facilitating APRIL phosphorylation to induce IL-10+ Bregs.

Efficacy and Safety of MRI and CT Guided VX2 Hepatic Para-vascular Tumor Model in Rabbits.

OBJECTIVE: To compare the efficacy and safety of 1.5 T MRI and CT-guided VX2 hepatic para-vascular tumor model in rabbits. MATERIALS AND METHODS: Sixty New Zealand white rabbits were randomly and equally divided into MRI-guided group (n=30) and CT-guided group (n=30). Rabbit VX2 tumor fragments were implanted beside the rabbit hepatic great vessels under MRI and CT guidance in the MRI and CT group to evaluate the success rate of tumor model establishment, puncture needle display and tip peripheral vascular situation, operation time and safety. RESULTS: In the MRI-guided group, 29 rabbits (29/30, 96.7%) had a successful establishment of liver tumor model, and 1 rabbit had needle metastasis. In the CT-guided group, 24 rabbits (24/30, 80%) had a successful establishment of liver tumor model, while 2 rabbits had needle metastasis, 3 rabbits had metastases in other parts of the liver, and 1 had an unknown cause of death. The differences in tumor model establishment success rate between the two groups were statistically significant (χ2 = 4.043, P < 0.05). The fold number of artifacts at T1WI was 7.26±0.38 for the 20 G coaxial puncture needle in the MRI-guided group and 2.51±0.57 for the 20 G coaxial puncture needle in the CT-guided group, and the difference was statistically significant (t=36.76, P < 0.001), but star-shaped hypodense artifacts would appear around the needle tip. The operation time was longer in the MRI-guided group than in the CT-guided group (13.32±2.45 minutes in the MRI-guided group vs. 8.42±1.46 minutes in the CTguided group; t=9.252, P < 0.001). A small number of ascites occurred in 2 patients (2/30, 6.67%) in the CT-guided group; no serious complications such as liver abscess, jaundice or diaphragmatic perforation were observed in both groups. CONCLUSION: Compared with CT, MRI-guided hepatic para-vascular tumor implantation in rabbits might be a more effective modeling method. Although the needle tip pseudopacity of the puncture needle is large and the operation time is long, the incidence of complications is low.

Mendelian randomization study of causal link from gut microbiota to colorectal cancer.

Recent studies have shown the relevance of gut microbiota in the occurrence and development of colorectal cancer (CRC), but the causal relationship remains unclear in the human population. The present study aims to assess the causal relationship from the gut microbiota to CRC and to identify specific causal microbe taxa via genome-wide association study (GWAS) summary statistics based two-sample Mendelian randomization (MR) analyses. Microbiome GWAS (MGWAS) in the TwinsUK 1,126 twin pairs was used as discovery exposure sample, and MGWAS in 1,812 northern German participants was used as replication exposure sample. GWAS of CRC in 387,156 participants from the UK Biobank (UKB) was used as the outcome sample. Bacteria were grouped into taxa features at both family and genus levels. In the discovery sample, a total of 30 bacteria features including 15 families and 15 genera were analyzed. Five features, including 2 families (Verrucomicrobiaceae and Enterobacteriaceae) and 3 genera (Akkermansia, Blautia, and Ruminococcus), were nominally significant. In the replication sample, the genus Blautia (discovery beta=-0.01, P = 0.04) was successfully replicated (replication beta=-0.18, P = 0.01) with consistent effect direction. Our findings identified genus Blautia that was causally associated with CRC, thus offering novel insights into the microbiota-mediated CRC development mechanism.

Progress on the role and mechanism of MT1-MMP in tumor metastasis.

The matrix metallopeptidase family (matrix metallopeptidase, MMPs) is a class of zinc-dependent endopeptidases that can degrade most extracellular matrices. MT1-MMP (membrane type 1 metalloprotease) is an important metallopeptidase, which is located on plasma membrane and highly expressed in most tumors. MT1-MMP promotes cancer metastasis through affecting the extracellular matrix remodeling, angiogenesis, lipid metabolism, and inflammation. However, the mechanisms of MT1-MMP in different tumors have not been fully elucidated. In this review, we summarize the latest progress and the metastasis-promoting regulatory mechanisms of MT1-MMP in different tumors, which will provide references for its in-depth research and application in the field of cancer biology.

Mendelian randomization analysis identified causal Association of Childhood Obesity with adult major depressive disorder.

BACKGROUND: Childhood obesity is associated with adult major depressive disorder (MDD), but their causality is not clear. METHODS: We performed a two-sample Mendelian randomization (MR) analysis to explore the causality of childhood body mass index (BMI) and childhood obesity on MDD, followed by a multivariable MR (MVMR) analysis to investigate the potential role of adult BMI in mediating such effect. We accessed genome-wide association summary statistics of childhood BMI, childhood obesity, adult BMI and adult MDD from the Early Growth Genetics consortium (nBMI  = 47 541, nobesity  = 24 160), the Genetic Investigation of Anthropometric Traits consortium (nadult_BMI  = âˆ¼700 000) and the Psychiatric Genomics consortium (nMDD  = 500 199), respectively. The MR-PRESSO test was performed to remove SNPs with potential pleiotropic effect. The MR analysis was performed by inverse-variance weighted test. Further sensitivity analyses, including the MR-Egger intercept test and leave-one-out analysis, were performed to evaluate the reliability of the results. RESULTS: Our study found that childhood obesity might increase the odds of developing MDD in adults (OR = 1.03, 95% CI: 1.01-1.06, p = 2.6 × 10-3 ). Children with higher BMI were more likely to develop MDD in adulthood, with an OR of 1.12 per standard deviation score (SDS) increase in BMI (95% CI: 1.07-1.17, p = 4.4 × 10-7 ). Sensitivity analyses verified the reliability of the causality between childhood BMI/obesity and MDD. Further MVMR results revealed that the impact of childhood BMI on MDD risk was predominantly mediated by adult BMI. CONCLUSION: Our findings provided evidence of a causal relationship between childhood BMI/obesity and adult MDD, thus providing new insights into the prevention of MDD.

Neutrophil-to-Lymphocyte Ratio Predicts in-Hospital Mortality in Intracerebral Hemorrhage.

OBJECTIVES: The neutrophil-to-lymphocyte ratio is gaining popularity as a low-cost biomarker of inflammation and outcome prediction. Intracerebral hemorrhage has high mortality and disability, which strongly influences societal development. This study aimed to research whether the neutrophil-to-lymphocyte ratio can predict hospital mortality in patients with severe intracerebral hemorrhage. MATERIALS AND METHODS: It was a retrospective analysis of prospectively collected data. The survival analysis and proportional hazards models analyzed clinical data from the Medical Information Mart for Intensive Care III database of patients with intracerebral hemorrhage. RESULTS: The records of 1,000 patients were included in our study. Two hundred forty-seven individuals died in the hospital, while 753 survived to discharge. According to data analysis, the neutrophil-to-lymphocyte ratio of the death group (11.21±7.81) significantly exceeded the survival group (7.94±6.04). The univariate Cox regression revealed that the neutrophil-to-lymphocyte ratio is a potential predictor of in-hospital mortality (HR:1.044; 95% CI:1.029-1.059; p <0.001). Furthermore, the proportional hazards model demonstrated that the risk of in-hospital death increased 2.34-fold for each increase in neutrophil-to-lymphocyte ratio when other factors were held constant. Following the ROC analysis, the Kaplan-Meier based on the proportional hazards model showed that patients with a neutrophil-to-lymphocyte ratio >7.68 on the first day of hospitalization had a higher risk of death. CONCLUSIONS: In patients with severe intracerebral hemorrhage, the neutrophil-to-lymphocyte ratio is a potential predictor of in-hospital mortality.

Response of different benthic biotic indices to eutrophication and sediment heavy metal pollution, in fujian coastal water, East China sea.

The types and intensity of anthropogenic pressure in the same sea area may differ spatially and may change as time passes, but response of benthic biotic indices to different pressure is different, which makes it unreasonable to use the same benthic biotic indices in a large sea area. We provided a new way of thinking as to selecting benthic biotic indices according to pressure type. The study took six bays under eutrophication and sediment heavy metal pollution to different levels in Fujian coastal water, East China sea, as examples, analysed the response of five benthic biotic indices, namely AZTI marine biotic index (AMBI), multivariate AMBI (M-AMBI), Shannon-Wiener diversity index (H'), benthic opportunistic polychaetes amphipods (BOPA) and benthic polychaetes amphipods (BPA), to eutrophication factors and sediment heavy metal pollution factors firstly. The result indicated that AMBI well responded to dissolved inorganic nitrogen (DIN) and dissolved inorganic phosphorus (DIP); M-AMBI responded soundly in the range of DIN >0.131 mg L-1 and DIP >0.022 mg L-1 and responded universally to heavy metals; H' responded to only Hg and Cd; BOPA has response to eutrophication condition of DIN >0.242 mg L-1; BPA had response to DIN, Cu and As. Then, suitable indices were selected based on the four pressure scenarios in the study area. AMBI was selected in no pressure scenario; M-AMBI was chosen under only eutrophication pressure and under dual pressure; H' was preferred in only heavy metal pressure scenario (mainly Hg pollution). At last, the density plot of the distribution of the selected indices in the evaluation grades under different pressure scenarios proved the proposal of selecting benthic biotic indices according to pressure types feasible. This study can offer some new insights into rapidly choosing indices to evaluate the coastal benthic ecological quality status.

Pharmacological Perturbation of Mechanical Contractility Enables Robust Transdifferentiation of Human Fibroblasts into Neurons.

Direct cell reprogramming, also called transdifferentiation, is valuable for cell fate studies and regenerative medicine. Current approaches to transdifferentiation are usually achieved by directly targeting the nuclear functions, such as manipulating the lineage-specific transcriptional factors, microRNAs, and epigenetic modifications. Here, a robust method to convert fibroblasts to neurons through targeting the cytoskeleton followed by exposure to lineage-specification surroundings is reported. Treatment of human foreskin fibroblasts with a single molecule inhibitor of the actomyosin contraction, can disrupt the cytoskeleton, promote cell softening and nuclear export of YAP/TAZ, and induce a neuron-like state. These neuron-like cells can be further converted into mature neurons, while single-cell RNA-seq shows the homogeneity of these cells during the induction process. Finally, transcriptomic analysis shows that cytoskeletal disruption collapses the original lineage expression profile and evokes an intermediate state. These findings shed a light on the underestimated role of the cytoskeleton in maintaining cell identity and provide a paradigm for lineage conversion through the regulation of mechanical properties.

Yixin Ningshen Tablet Alleviates Comorbidity of Myocardial Infarction and Depression by Enhancing Myocardial Energy Metabolism and Increasing Availability of Monoamine Neurotransmitter.

OBJECTIVE: To investigate the therapeutic effect of Yixin Ningshen Tablet (YXNS) on comorbidity of myocardial infarction (MI) and depression in rats and explore the underlying mechanism. METHODS: The Sprague-Dawley rats were randomly divided into 5 groups with 7 rats in each group according to their weights, including control, model, fluoxetine (FLXT, 10 mg/kg), low-dose YXNS (LYXNS, 100 mg/kg), and high-dose YXNS (HYXNS, 300 mg/kg) groups. All rats were pretreated with corresponding drugs for 12 weeks. The rat model of MI and depression was constructed by ligation of left anterior descending coronary artery and chronic mild stress stimulation. The echocardiography, sucrose preference test, open field test, and forced swim test were performed. Myocardial infarction (MI) area and myocardial apoptosis was also detected. Serum levels of interleukin (IL)-6, IL-1ß, tumor necrosis factor-α (TNF-α), 5-hydroxytryptamine (5-HT), adrenocorticotrophic hormone (ACTH), corticosterone (CORT), and norepinephrine (NE) were determined by enzyme linked immunosorbent assay. The proteins of adenosine 5'-monophosphate -activated protein kinase (AMPK), p-AMPK, peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), and nuclear respiratory factor 1 (NRF1) in heart were detected by Western blot analysis. The expression levels of TNF-α, IL-6, indoleamine 2,3-dioxygenase (IDO1), kynurenine 3-monooxygenase (KMO), and kynureninase (KYNU) in hippocampus were detected by real-time quantitative polymerase chain reaction. RESULTS: Compared with the model group, the cardiac function of rats treated with YXNS improved significantly (P<0.01). Meanwhile, YXNS effectively reduced MI size and cardiomyocytes apoptosis of rats (P<0.01 or P<0.05), promoted AMPK phosphorylation, and increased PGC-1α protein expression (P<0.01 or P<0.05). HYXNS significantly increased locomotor activity of rats, decreased the levels of TNF-α, IL-6 and IL-1ß, and increased the serum levels of 5-HT, NE, ACTH, and CORT (all P<0.05). Moreover, HYXNS decreased the mRNA expressions of IDO1, KMO and KYNU (P<0.05). CONCLUSIONS: YXNS can relieve MI by enhancing myocardial energy metabolism. Meanwhile, YXNS can alleviate depression by resisting inflammation and increasing availability of monoamine neurotransmitters. It may be used as a potential drug to treat comorbidity of MI and depression.

Dysprosium(III) Metal-Organic Framework Demonstrating Ratiometric Luminescent Detection of pH, Magnetism, and Proton Conduction.

A multifunctional metal-organic framework, (Hdmbpy)[Dy(H2dobdc)2(H2O)]·3H2O (Dy-MOF, H4dobdc = 2,5-dihydroxyterephthalic acid, dmbpy = 4,4'-dimethyl-2,2'-bipyridine), was synthesized and structurally characterized. The metal center DyIII is connected by four carboxyl groups to form the [Dy2(CO2)4] binuclear nodes, which are further interconnected by eight separate H2dobdc2- ligands to form a three-dimensional (3D) framework including hydrophilic triangular channels and abundant hydrogen-bonding networks. Dy-MOF has good stability in aqueous solution as well as in harsh acidic or alkaline solutions (pH range: 2.0-12.0). Furthermore, the luminescence signal of Dy-MOF undergoes a visualized color change as the acidity of the solution alters, which is the typical behavior of pH ratiometric probe. At a 100% relative humidity, Dy-MOF exhibits a high proton conductivity σ (1.70 × 10-4 S cm-1 at 303 K; 1.20 × 10-3 S cm-1 at 343 K) based on the proton hopping mechanism, which can be classified as a superionic conductor with σ exceeding 10-4 S cm-1. Additionally, the ferromagnetic interaction and magnetic relaxation behavior are simultaneously achieved in Dy-MOF. Herein, the combination of luminescence sensing, magnetism, and proton conduction in a single-phase 3D MOF may offer great potential applications in smart multitasking devices.

Mendelian Randomization Analysis Reveals Causal Effects of Plasma Proteome on Body Composition Traits.

CONTEXT: Observational studies have demonstrated associations between plasma proteins and obesity, but evidence of causal relationship remains to be studied. OBJECTIVE: We aimed to evaluate the causal relationship between plasma proteins and body composition. METHODS: We conducted a 2-sample Mendelian randomization (MR) analysis based on the genome-wide association study (GWAS) summary statistics of 23 body composition traits and 2656 plasma proteins. We then performed hierarchical cluster analysis to evaluate the structure and pattern of the identified causal associations, and we performed gene ontology enrichment analysis to explore the functional relevance of the identified proteins. RESULTS: We identified 430 putatively causal effects of 96 plasma proteins on 22 body composition traits (except obesity status) with strong MR evidence (P < 2.53 × 10 - 6, at a Bonferroni-corrected threshold). The top 3 causal associations are follistatin (FST) on trunk fat-free mass (Beta = -0.63, SE = 0.04, P = 2.00 × 10-63), insulin-like growth factor-binding protein 1 (IGFBP1) on trunk fat-free mass (Beta = -0.54, SE = 0.03, P = 1.79 × 10-57) and r-spondin-3 (RSPO3) on WHR (waist circumference/hip circumference) (Beta = 0.01, SE = 4.47 × 10-4, P = 5.45 × 10-60), respectively. Further clustering analysis and pathway analysis demonstrated that the pattern of causal effect to fat mass and fat-free mass may be different. CONCLUSION: Our findings may provide evidence for causal relationships from plasma proteins to various body composition traits and provide basis for further targeted functional studies.

Donor BMSC-derived small extracellular vesicles relieve acute rejection post-renal allograft through transmitting Loc108349490 to dendritic cells.

Bone marrow-derived mesenchymal stem cell (BMSC)-derived small extracellular vesicles (sEVs) are potent candidates for the suppression of acute rejection post-renal allograft and have been reported to halt dendritic cells (DCs) maturation. However, whether BMSC-derived sEVs mitigate acute rejection post-renal allograft by targeting DCs is still unclear. In this study, donor BMSC-derived sEVs (sEVs) relieved the inflammatory response and suppressed mature DCs (mDCs) location in kidney grafts, and increased regulatory T (Treg) cell population in the spleens of the rats that underwent kidney allograft. In lipopolysaccharide (LPS)-stimulated immature DCs (imDCs), sEVs suppressed the maturation and migration of DCs and inactivated toll-like receptor 4 (TLR4) signaling. Compared with LPS-treated imDCs, imDCs treated with LPS+sEVs promoted CD4+ T cells differentiated toward Treg cells. Subsequently, we found that Loc108349490, a long non-coding RNA (lncRNA) abundant in sEVs, mediated the inhibitory effect of sEVs on DC maturation and migration by promoting TLR4 ubiquitination. In rats that underwent an allograft, Loc108349490 deficiency weakened the therapeutic effect of sEVs on acute rejection. The present study firstly found that sEVs alleviated acute rejection post-renal allograft by transferring lncRNA to DCs and screened out the functional lncRNA loaded in sEVs was Loc108349490.

Risk factors and predictive model of adrenocortical insufficiency in patients with traumatic brain injury.

BACKGROUND: Neuroendocrine dysfunction after traumatic brain injury (TBI) has received increased attention due to its impact on the recovery of neural function. The purpose of this study is to investigate the incidence and risk factors of adrenocortical insufficiency (AI) after TBI to reveal independent predictors and build a prediction model of AI after TBI. METHODS: Enrolled patients were grouped into the AI and non-AI groups. Fourteen preset impact factors were recorded. Patients were regrouped according to each impact factor as a categorical variable. Univariate and multiple logistic regression analyses were performed to screen the related independent risk factors of AI after TBI and develop the predictive model. RESULTS: A total of 108 patients were recruited, of whom 34 (31.5%) patients had AI. Nine factors (age, Glasgow Coma Scale [GCS] score on admission, mean arterial pressure [MAP], urinary volume, serum sodium level, cerebral hernia, frontal lobe contusion, diffuse axonal injury [DAI], and skull base fracture) were probably related to AI after TBI. Three factors (urinary volume [X 4], serum sodium level [X 5], and DAI [X 8]) were independent variables, based on which a prediction model was developed (logit P= -3.552+2.583X 4+2.235X 5+2.269X 8). CONCLUSIONS: The incidence of AI after TBI is high. Factors such as age, GCS score, MAP, urinary volume, serum sodium level, cerebral hernia, frontal lobe contusion, DAI, and skull base fracture are probably related to AI after TBI. Urinary volume, serum sodium level, and DAI are the independent predictors of AI after TBI.

Joint Genome-Wide Association Analyses Identified 49 Novel Loci For Age at Natural Menopause.

BACKGROUND: Age at natural menopause (ANM) is an important index for women's health. Either early or late ANM is associated with a series of adverse outcomes later in life. Despite being an inheritable trait, its genetic determinant has not yet been fully understood. METHODS: Aiming to better characterize the genetic architecture of ANM, we conducted genome-wide association study (GWAS) meta-analyses in European-specific as well as trans-ancestry samples by using GWAS summary statistics from the following 3 large studies: the Reproductive Genetics Consortium (ReproGen; N = 69 626), the UK Biobank cohort (UKBB; N = 111 593) and the BioBank Japan Project (BBJ; N = 43 861), followed by a series of bioinformatical assessments and functional annotations. RESULTS: By integrating the summary statistics from the 3 GWAS of up to 225 200 participants, this largest meta-analysis identified 49 novel loci and 3 secondary signals that were associated with ANM at the genome-wide significance level (P < 5 × 10-8). No population specificity or heterogeneity was observed at most of the associated loci. Functional annotations prioritized 90 candidate genes at the newly identified loci. Among the 26 traits that were genetically correlated with ANM, hormone replacement therapy (HRT) exerted a causal relationship, implying a causal pattern by which HRT was determined by ANM. CONCLUSION: Our findings improved our understanding of the etiology of female menopause, as well as shed light on potential new therapies for abnormal menopause.

The Antibacterial Effects of Supermolecular Nano-Carriers by Combination of Silver and Photodynamic Therapy.

The over-use of antibiotics has promoted multidrug resistance and decreased the efficacy of antibiotic therapy. Thus, it is still in great need to develop efficient treatment strategies to combat the bacteria infection. The antimicrobial photodynamic therapy (aPDT) and silver nanoparticles have been emerged as effective antibacterial methods. However, the silver therapy may induce serious damages to human cells at high concentrations and, the bare silver nanoparticles may rapidly aggregate, which would reduce the antibacterial efficacy. The encapsulation of sliver by nano-carrier is a promising way to avoid its aggregation and facilitates the co-delivery of drugs for combination therapy, which does not require high concentration of sliver to exert antibacterial efficacy. This work constructed a self-assembled supermolecular nano-carrier consisting of the photosensitizers (PSs), the anti-inflammatory agent and silver. The synthesized supermolecular nano-carrier produced reactive oxygen species (ROS) under the exposure of 620-nm laser. It exhibited satisfying biocompatibility in L02 cells. And, this nano-carrier showed excellent antibacterial efficacy in Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) as indicated by bacterial growth and colony formation. Its antibacterial performance is further validated by the bacteria morphology through the scanning electron microscope (SEM), showing severely damaged structures of bacteria. To summary, the supermolecular nano-carrier TCPP-MTX-Ag-NP combining the therapeutic effects of ROS and silver may serve as a novel strategy of treatment for bacterial infection.

Total glucosides of Paeony restores intestinal barrier function through inhibiting Lyn/Snail signaling pathway in colitis mice.

BACKGROUND: Inflammatory bowel disease (IBD) is an autoimmune disease. The pathogenesis of IBD is complicated and intestinal mucosal barrier damage is considered as the trigger factor for the initiation and recurrence of IBD. Total Glucosides of Paeony (TGP) has shown good inhibitory effects on immune-inflammation in clinic studies. However, its effect and mechanism on IBD are largely unknown. PURPOSE: The purpose of this study is to evaluate the effect and mechanism of TGP on IBD. STUDY DESIGN: DSS-induced colitis mouse model was used. TGP was given by gavage. Caco-2 cells were stimulated by outer membrane vesicles (OMV) to establish an in vitro model. METHODS: C57BL/6 mice were divided into normal control group, model group, mesalazine group, paeoniflorin (PA) group, high-dose group of TGP, and low-dose group of TGP. The model was induced with 2.5% DSS for 7 days, and TGP was intragastrically administered for 10 days. The therapeutic effect of TGP was evaluated by symptoms, histochemical analysis, RT-qPCR and ELISA. The mechanism was explored by intestinal permeability, Western blot and immunofluorescence in vivo and in vitro. RESULTS: Our results showed that TGP could significantly improve the symptoms and pathological changes, with reduced levels of TNF-α, IL-17A, IL-23 and IFN-γ in the colon tissues and serum under a dose-dependent manner. TGP also reduced the intestinal permeability and restored the protein expression of tight junction and adherens junction proteins of intestinal epithelial cells in vivo and in vitro. Furthermore, TGP could inhibit the expression of p-Lyn and Snail and prevent Snail nuclear localization, thereby maintaining tight and adherens junctions. CONCLUSION: TGP effectively improves the symptoms of DSS-induced colitis in mice, protects the intestinal epithelial barrier by inhibiting the Lyn/Snail signaling pathway, and maybe a promise therapeutic agent for IBD treatment.

Doxorubicin-loaded hydrogen peroxide self-providing copper nanodots for combination of chemotherapy and acid-induced chemodynamic therapy against breast cancer.

In recent years, chemodynamic therapy (CDT) has gained increasing interest in cancer treatment. In contrast to photodynamic therapy and sonodynamic therapy, extrinsic excitations such as laser or ultrasound are not required in CDT. As a result, the CDT performance is not limited by the penetration depth of the external irritation. However, CDT relies heavily on hydrogen peroxide (H2O2) in the tumour microenvironment (TME). Insufficient H2O2 in the TME limits the CDT performance, and the most reported methods to produce H2O2 in the TME are dependent on oxygen supply, which is restricted by the hypoxic TME. In this study, H2O2 self-providing copper nanodots were proposed, and the drug doxorubicin (DOX) was successfully loaded to construct DOX-nanodots. Our results showed that the nanodots produced H2O2 in the weakly acidic TME due to the peroxo group and further generated the most active hydroxyl radical (OH) through the Fenton-like reaction. This process was pH-dependent and did not occur in a neutral environment. In addition to OH, the nanodots also produced singlet oxygen (1O2) and superoxide anions (O2-) in the cancer cells. The copper nanodots performed promising CDT against breast cancer in vitro and in vivo, with enhanced cell apoptosis and decreased cell proliferation. The combination of chemotherapy and CDT using DOX-nanodots further improved the therapeutic effects. The treatments showed good biocompatibility with no obvious toxicity in major tissues, possibly due to the specific OH generation in the weakly acidic TME. In summary, the H2O2 self-providing copper nanodots in combination with DOX showed promising cancer-curing effects due to the oxygen-independent and tumour-specific production of reactive oxygen species and the cooperation of chemotherapy.

Poor consistency between reflux symptom index and laryngopharyngeal pH monitoring in laryngopharyngeal reflux diagnosis in Chinese population.

BACKGROUND: It is unknown whether the reflux symptom index (RSI) can replace pH monitoring as a diagnostic tool for laryngopharyngeal reflux (LPR) in Chinese people. The relationships between reflux parameters and LPR symptoms also require further research. METHODS: A total of 216 Chinese patients underwent laryngopharyngeal pH monitoring and filled out an RSI questionnaire. Laryngopharyngeal pH monitoring indicated a diagnosis of LPR for patients with 7 or more episodes of reflux or a reflex area index (RAI) of 6.3 or more. The RSI questionnaire indicated a diagnosis of LPR for patients with RSI scores of 14 or higher. RESULTS: Of the 216 patients, 85 were diagnosed with LPR as assessed by the RSI, and 72 were diagnosed with LPR through laryngopharyngeal pH monitoring. The Cohen's kappa coefficient comparing LPR diagnosis consistency between RSI score and laryngopharyngeal pH monitoring was 0.133 (P=0.007). This indicated the two diagnostic methods were consistent to a low degree; the total consistency rate was only 59.7% (129/216). The sensitivity of the RSI was 48.6% (35/72), and its specificity was 82.5% (94/114). For convenience, we named the nine symptom groups in the RSI sequentially as P1-P9. P1, P2, P3, P5, P6, and P7 were all correlated with at least one reflux parameter (P<0.05), but P4, P8, and P9 were not correlated with any reflux parameters (P>0.05). A total of 72 patients were diagnosed using pH monitoring, the gold standard for LPR diagnosis. The most common symptoms of LPR were found to be P9, P3, P8, P7, and P2 in these patients. The symptoms that most seriously affected patients were P9, P8, P3, P7, and P2. CONCLUSIONS: The consistency in diagnosis of LPR between the RSI and laryngopharyngeal pH monitoring was poor, meaning the RSI is not a suitable LPR initial screening tool and cannot replace pH monitoring. Additionally, reflux symptoms P4, P8, and P9 were not correlated with any reflux parameters. The most prevalent LPR symptom was P9, followed by P3, P8, P7, and P2. The most severe symptom was also P9, followed by P8, P3, P7, and P2.