Effects of paroxetine hydrochloride combined with idebenone on inflammatory factors and antioxidant molecules in treatment of depression after ischemic stroke.

Objectives: To evaluate the effects of paroxetine hydrochloride combined with idebenone on inflammatory factors and antioxidant molecules in the treatment of depression after ischemic stroke. Methods: Randomized controlled trial was adopted on 80 patients with depression after ischemic stroke were randomly divided into two groups, with 40 patients in each group at Xingtai Sanli Health Quannan Clinic from March 17, 2019 to December 20, 2021. Both groups were given basic treatment. On this basis, the control group was treated with paroxetine hydrochloride, while the study group was treated with paroxetine hydrochloride combined with idebenone. The clinical efficacy was evaluated using the Hamilton Rating Scale for Depression (HRSD) before and after treatment. Additionally, the difference in HRSD score after treatment and the improvement in inflammatory factors and antioxidant molecules were compared and analyzed between the two groups. Results: After treatment, the HRSD score of the study group was significantly improved compared with that of the control group (p= 0.00). The effective rate was 82.5% in the study group, which was significantly higher than 62.5% in the control group (p= 0.04). After treatment, TNF-a, CRP and IL-6 in the study group were significantly lower than those in the control group (p= 0.00). Serum SOD, TAC and CAT levels in the study group were significantly higher than those in the control group after treatment (SOD and TAC, p= 0.00; CAT, p= 0.01). The incidence of adverse reactions was 37.5% in the study group and 25% in the control group. Although the incidence of adverse reactions in the study group was higher than that in the control group, the difference was not statistically significant (p= 0.23). Conclusion: Paroxetine hydrochloride combined with idebenone in the treatment of depression after ischemic stroke can significantly improve HRSD score, enhance clinical efficacy, reduce the levels of inflammatory factors, and increase the levels of antioxidant factors, without a significant increase in adverse reactions. Therefore, it is a safe and effective treatment method.

Cinnamaldehyde prevents intergenerational effect of paternal depression in mice via regulating GR/miR-190b/BDNF pathway.

Paternal stress exposure-induced high corticosterone (CORT) levels may contribute to depression in offspring. Clinical studies disclose the association of depressive symptoms in fathers with their adolescent offspring. However, there is limited information regarding the intervention for intergenerational inheritance of depression. In this study we evaluated the intervention of cinnamaldehyde, a major constituent of Chinese herb cinnamon bark, for intergenerational inheritance of depression in CORT- and CMS-induced mouse models of depression. Depressive-like behaviors were induced in male mice by injection of CORT (20 mg·kg-1·d-1, sc) for 6 weeks or by chronic mild stress (CMS) for 6 weeks. We showed that co-administration of cinnamaldehyde (10, 20, or 40 mg·kg-1·d-1, ig) for 6 weeks in F0 males prevented the depressive-like phenotypes of F1 male offspring. In addition, co-administration of cinnamaldehyde (20 mg·kg-1·d-1, ig) for 4 weeks significantly ameliorated depressive-like behaviors of chronic variable stress (CVS)-stimulated F1 offspring born to CMS mice. Notably, cinnamaldehyde had no reproductive toxicity, while positive drug fluoxetine showed remarkable reproductive toxicity. We revealed that CMS and CORT significantly reduced testis glucocorticoid receptor (GR) expression, and increased testis and sperm miR-190b expression in F0 depressive-like models. Moreover, pre-miR-190b expression was upregulated in testis of F0 males. The amount of GR on miR-190b promoter regions was decreased in testis of CORT-stimulated F0 males. Cinnamaldehyde administration reversed CORT-induced GR reduction in testis, miR-190b upregulation in testis and sperm, pre-miR-190b upregulation in testis, and the amount of GR on miR-190b promoter regions of F0 males. In miR-190b-transfected Neuro 2a (N2a) cells, we demonstrated that miR-190b might directly bind to the 3'-UTR of brain-derived neurotrophic factor (BDNF). In the hippocampus of F1 males of CORT- or CMS-induced depressive-like models, increased miR-190b expression was accompanied by reduced BDNF and GR, which were ameliorated by cinnamaldehyde. In conclusion, cinnamaldehyde is a potential intervening agent for intergenerational inheritance of depression, probably by regulating GR/miR-190b/BDNF pathway.

Characterization of a Protease Hyper-Productive Mutant of Bacillus pumilus by Comparative Genomic and Transcriptomic Analysis.

Bacillus pumilus BA06 has great potential for the production of alkaline proteases. To improve the protease yield, classical mutagenesis to combine the physical and chemical mutagens was performed to obtain a protease hyper-productive mutant SCU11. The full genome sequences of BA06 and SCU11 strains were assembled through DNA sequencing using the PacBio sequencing platform. By comparative genomics analysis, 147 SNPs and 15 InDels were found between these two genomes, which lead to alternation of coding sequence in 15 genes. Noticeable, the gene (kinA) encoding sporulation kinase A is interrupted by introducing a stop codon in its coding region in BA06. Interestedly, this gene is reversely corrected in SCU11. Furthermore, comparative transcriptome analysis revealed that kinA and two positive regulatory genes (DegU and Spo0A) were upregulated in transcription in SCU11. In terms of the transcriptional data, upregulation of a phosphorylation cascade starting with KinA may enhance Spo0A phosphorylation, and thus activate expression of the gene aprE (encoding major extracellular protease) through repression of AbrB (a repressor of aprE) and activation of SinI, an antagonist of SinR (a repressor of aprE). In addition, the other genes involved in various metabolic pathways, especially of membrane transport and sporulation, were altered in transcription between these two strains. Conclusively, our transcriptome data suggested that upregulation degU and spo0A, as well as kinA, may at least partially contribute to the high production of alkaline protease in SCU11.

Thermo- and pH-responsive, Lipid-coated, Mesoporous Silica Nanoparticle-based Dual Drug Delivery System To Improve the Antitumor Effect of Hydrophobic Drugs.

Evodiamine (EVO) and Berberine (BBR), from Euodiae Fructus and Coptidis rhizoma, have been used as an herbal medicine pair in traditional Chinese medicine to exert synergistic antitumor effects against various types of tumor cells. However, their clinical use is limited by their poor solubility and adverse toxic side effects. Mesoporous silica nanoparticles (MSNs) possess excellent properties such as a readily functionalized surface, prominent biocompatibility, and huge specific surface area for loading with hydrophobic and hydrophilic drug. On this basis, a novel temperature- and pH-responsive dual drug delivery platform has been developed, in which lipid-coated MSN@p(NIPAM- co-MA) codelivers EVO and BBR. The results indicate that the nanocarrier improves the efficacy and biocompatibility of the drug pair and maintain desirable drug profiles at the low pH and higher temperature of the tumor microenvironment. The dual drug-loaded MSNs showed excellent synergistic therapy effects in vitro (cytotoxicity, cell migration and invasion, angiogenesis) and in vivo (growth of tumor grafts in mice). Meanwhile, the dual drug-loaded nanoparticles showed lower systemic toxicity than either drug alone, the free drug combination, or Taxol. These results suggest that the temperature- and pH-sensitive lipid-coated MSNs are a promising novel carrier for both hydrophobic and hydrophilic drugs.

Study on mitigating membrane fouling based on precursor and flocculant Alb matching in EC/O-UF system.

One of the effective ways to remove halogenated disinfection by-products (DBPs) from drinking water is the application of ultrafiltration technology. However, membrane fouling is an important factor affecting the service life and treatment effect. In this study, the electrocoagulation/oxidation-ultrafiltration (EC/O-UF) process was used to remove the precursor substance that produced DBPs, i.e. dissolved organic matters (DOMs). Operating parameters were optimized from the matching of different flocculant morphology to low concentration DOM. The degree of membrane fouling was characterized by analyzing DOMs concentration and membrane flux. The results showed that the optimal conditions for the production of Alb were: current density 10 A/m2, hydraulic retention time 10 min, and initial pH 5.0-7.0. Under these conditions, the production of flocculant Alb could reach 58-61%, 94-97% DOMs were removed by EC/O-UF.

Fabrication of a Homogeneous, Integrated, and Compact Film of Organic-Inorganic Hybrid Ni(en)3Ag2I4 with Near-Infrared Absorbance and Semiconducting Features.

The organic-inorganic hybrid crystal Ni(en)3Ag2I4 (where en represents 1,2-ethylenediamine) crystallizes in hexagonal space group P63, in which the AgI4(3-) tetrahedra connect into a diamondlike inorganic framework via sharing of the vertex and the Ni(en)3(2+) octahedra fill in the pores of the framework. UV-vis-near-IR (NIR) spectroscopy disclosed that this hybrid shows intense NIR absorbance centered at ca. 870 nm, and the variable-temperature conductivity measurement revealed that the hybrid is a semiconductor with Ea = 0.46 eV. The electronic band structure of Ni(en)3Ag2I4 was calculated using the density functional theory method, indicating that the NIR absorbance arises from d-d transition within the Ni(2+) cation of Ni(en)3(2+). The homogeneous, compact, and transparent crystalline film of Ni(en)3Ag2I4 was fabricated via a secondary seed growth strategy, which has promising application in NIR devices.

Enhancement of the synthesis of n-3 PUFAs in fat-1 transgenic mice inhibits mTORC1 signalling and delays surgically induced osteoarthritis in comparison with wild-type mice.

BACKGROUND: An exogenous supplement of n-3 polyunsaturated fatty acids (PUFAs) has been reported to prevent osteoarthritis (OA) through undefined mechanisms. OBJECTIVE: This study investigated the effect of alterations in the composition of endogenous PUFAs on OA, and associations of PUFAs with mammalian target of rapamycin complex 1 (mTORC1) signalling, a critical autophagy pathway in fat-1 transgenic (TG) mice. METHODS: fat-1 TG and wild-type mice were used to create an OA model by resecting the medial meniscus. The composition of the endogenous PUFAs in mouse tissues was analysed by gas chromatography, and the incidence of OA was evaluated by micro-computed tomography (micro-CT), scanning electron microscopy and histological methods. Additionally, primary chondrocytes were isolated and cultured. The effect of exogenous and endogenous PUFAs on mTORC1 activity and autophagy in chondrocytes was assessed. RESULTS: The composition of endogenous PUFAs of TG mice was optimised both by increased n-3 PUFAs and decreased n-6 PUFAs, which significantly alleviated the articular cartilage destruction and osteophytosis in the OA model (p<0.01), decreased protein expression of matrix metalloproteinase-13 (MMP-13) and ADAMTS-5 (a disintegrin and metalloproteinase with thrombospondin motifs) in the articular cartilage (p<0.01) and reduced chondrocyte number and loss of cartilage extracellular matrix. Both exogenous and endogenous n-3 PUFAs downregulated mTORC1 activity and promoted autophagy in articular chondrocytes. Conversely, mTORC1 pathway activation suppressed autophagy in articular chondrocytes. CONCLUSIONS: Enhancement of the synthesis of endogenous n-3 PUFAs from n-6 PUFAs can delay the incidence of OA, probably through inhibition of mTORC1, promotion of autophagy and cell survival in cartilage chondrocytes. Future investigation into the role of the endogenous n-6/n-3 PUFAs composition in OA prevention and treatment is warranted.

Establishing a disc degeneration model using computed tomography-guided percutaneous puncture technique in the rabbit.

BACKGROUND: Various animal models have been developed to investigate the complex mechanisms leading to intervertebral disc disorders and to evaluate the different therapeutic options. The needle puncture technique is commonly used to induce intervertebral degeneration in animal models. The present study aimed to establish a rabbit model of intervertebral disc degeneration using a simple, minimally invasive procedure. METHODS AND MATERIALS: The animal model was created in the rabbit using computed tomography-guided percutaneous puncture technology. An 18-gauge needle was used to induce a disc injury with a 5-mm puncture depth. Radiographic, histologic, and biochemical analyses and magnetic resonance imaging were performed to assess the consequent disc degeneration. RESULTS: Significant disc space narrowing was observed as early as 4 wk, and osteophytes were formed at 12 wk after puncture. The magnetic resonance imaging assessment demonstrated a progressive loss of T2-weighted signal intensity at the stabbed discs throughout the 12-wk period. The histologic analysis showed a progressive loss of the normal architecture from 4 wk to the end point. The biochemical assays suggested that the expression of proteoglycan decreased progressively with increasing time. CONCLUSIONS: A simple, but minimally invasive, intervertebral disc degeneration model was established successfully using computed tomography-guided percutaneous puncture technology in the rabbit. The puncture procedure can be performed with minimal damage and handling of the other structures, ensuring a uniform reproducible disc degeneration model.

Vitreous metabolomic signatures of pathological myopia with complications.

BACKGROUND: Pathological myopia (PM) is closely associated with blinding ocular morbidities. Identifying biomarkers can provide clues on pathogeneses. This study aimed to identify metabolic biomarkers and underlying mechanisms in the vitreous humour (VH) of PM patients with complications. METHODS: VH samples were collected from 39 PM patients with rhegmatogenous retinal detachment (RRD) (n = 23) or macular hole (MH)/myopic retinoschisis (MRS) (n = 16) and 23 controls (MH with axial length < 26 mm) who underwent surgical treatment. VH metabolomic profiles were investigated using ultra-performance liquid chromatography‒mass spectrometry. The area under the receiver operating characteristic curve (AUC) was computed to identify potential biomarkers for PM diagnosis. RESULTS: Bioinformatics analysis identified nineteen and four metabolites altered in positive and negative modes, respectively, and these metabolites were involved in tryptophan metabolism. Receiver operating characteristic analysis showed that seventeen metabolites (AUC > 0.6) in the positive mode and uric acid in the negative mode represent potential biomarkers for PM with complications (AUC = 0.894). Pairwise and pathway analyses among the RRD-PM, MH/MRS-PM and control groups showed that tryptophan metabolism and uric acid were closely correlated with PM. Altered metabolites and pathways in our study were characterized by increased oxidative stress and altered energy metabolism. These results contribute to a better understanding of myopia progression with or without related complications. CONCLUSIONS: Our study provides metabolomic signatures and related immunopathological features in the VH of PM patients, revealing new insight into the prevention and treatment of PM and related complications.

Morphological and functional changes in the macular area in diabetic macular edema after a single intravitreal injection of aflibercept.

AIM: To evaluate the changes in macular morphology and function after a single intravitreal injection of aflibercept in diabetic macular edema (DME) using optical coherence tomography angiography (OCTA) and MP-3 microperimetry. METHODS: Twenty-eight patients (42 eyes) diagnosed with DME were treated with intravitreal injection of aflibercept. The changes in best corrected visual acuity (BCVA), central retinal thickness (CRT), foveal avascular zone (FAZ) area, vessel density of superficial retinal capillary plexus (SVD), vessel density of deep retinal capillary plexus (DVD), mean light sensitivity (MLS), 2° fixation rate (P1), 4° fixation rate (P2), and other indicators 1mo after treatment were compared; of these, BCVA was converted into logarithm of the minimum angle of resolution (logMAR), and the correlation among the factors was analyzed. RESULTS: After treatment, logMAR BCVA was 0.47±0.24, which was significantly better than that before treatment (0.63±0.28, P<0.001). The CRT was 359.21±107.87 µm after treatment, which was significantly lower than before treatment (474.10±138.20 µm, P<0.001). The FAZ area, SVD, and DVD were not significantly changed after treatment compared with the baseline. MLS was 22.16±4.20 dB after treatment, which was significantly higher than before treatment (19.63±4.23 dB, P<0.001). P2 significantly increased after treatment than before treatment (P=0.007). P1 had no significant change after treatment than before treatment (P=0.086). CONCLUSION: A single intravitreal injection of aflibercept effectively reduces macular edema and improves retinal sensitivity, fixation stability, and visual acuity, possibly without causing significant changes in the retinal vascular condition in a short time.

[Retracted] Isopsoralen­mediated suppression of bone marrow adiposity and attenuation of the adipogenic commitment of bone marrow­derived mesenchymal stem cells.

Following the publication of the above article, an interested reader drew to the authors' attention that Figs. 1C and 2 in the paper appeared to contain instances of duplicated data. The authors were able to consult their original data files, and realized that these figures had indeed been assembled incorrectly. Moreover, they identified further errors with a number of the other figures in their published formats (specifically, Figs. 3, 4, 6 and 7), and requested that a corrigendum be published to take account of all the errors that were made during the compilation of these figures. The Editor of International Journal of Molecular Medicine has considered the authors' request to publish a corrigendum, but has declined this request on account of the large number of errors that have been identified, and subsequently determined that this article should be retracted from the Journal on the basis of an overall lack of confidence in the presented data. Upon receiving this decision from the Editor, the authors were in agreement that the article should be retracted. The Editor apologizes to the readership of the Journal for any inconvenience caused. [International Journal of Molecular Medicine 39: 527­538, 2017; DOI: 10.3892/ijmm.2017.2880].

[Ten-year Trend Analysis of Eutrophication Status and the Related Causes in Lake Hongze].

In order to propose pertinent suggestions regarding eutrophication control for Lake Hongze, we used monthly monitoring data from 2011 to 2020 to elucidate the spatiotemporal changing characteristics of eutrophic status and the relevant driving factors. As the main river entering Lake Hongze, River Huaihe experienced an increase in permanganate index and a decrease in TN in the last 10 years. Meanwhile, Secchi depth, TP, and permanganate index increased, whereas TN and Chl-a concentration decreased significantly in Lake Hongze. As a result, the eutrophic status TLI index of Lake Hongze declined over the past 10 years. The change trend of TLI in Lake Hongze differed spatially. As the main water passage of River Huaihe, the algal biomass was lower in the eastern region than that in the other two lake regions, regardless of the relatively high nutrient concentration, due to the short water retention time. Furthermore, the water quality of River Huaihe improved; thus, the TLI index decreased significantly in the eastern lake region. The northern region had a high coverage of aquatic vegetation, which not only reduced the concentration of water nutrients but also provided a habitat for zooplankton and fish, effectively inhibiting algal growth. Thus, the TLI index was lowest among the three lake areas and showed a downward trend over the last 10 years. In the western region, the algal biomass was the highest due to the intensification of phosphorus release from sediment in summer. Thus, the TLI index was the highest and had not improved in the past 10 years. There were also significant seasonal differences in the TLI of Lake Hongze, which was highest in summer, due to the relatively high algal biomass. Moreover, the algal biomass in summer was mainly affected by the concentration of nitrate. According to the spatiotemporal distribution characteristics of eutrophic status and the impacting factors in Lake Hongze, corresponding measures for eutrophication control should be taken for different seasons and lake areas.

Decreased serum CXCL12/SDF-1 concentrations may reflect disease severity of non-traumatic osteonecrosis of femoral head.

OBJECTIVE: The current study was performed to investigate the potential association of serum CXCL12 with disease severity in non-traumatic ONFH. METHODS: This study enrolled 182 patients with non-traumatic ONFH and 182 age- and gender-matched healthy controls. The CXCL12 levels in serum were measured by enzyme-linked immunosorbent assay. Meanwhile, serum levels of procollagen type I (PINP) and Interleukin-33(IL-33) were also detected. The radiographic severity was determined by FICAT grade. Clinical severity was evaluated by visual analogue scale (VAS), Harris Hip Score (HHS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Among the non-traumatic ONFH, 90 patients ONFH received total hip arthroplasty, the localization and expression of the CXCL12 protein and mRNA were detected by immunohistochemistry, Western blot analysis, RT-PCR and in necrotic area and adjacent non-necrotic area from lesioned femoral neck from ONFH patients and healthy femoral head from femoral neck fracture patients. Receiver operating characteristic (ROC) curve analysis was carried out to confirm the diagnostic value serum CXCL12, PINP and IL-33 with regard to the FICAT grade. RESULTS: Serum CXCL12 levels were significantly lower in non-traumatic ONFH patients compared with healthy controls. CXCL12 mRNA and protein expressions were both significantly decreased in necrotic area in comparison with non-necrotic area and healthy femoral head. Serum CXCL12 concentrations were drastically reduced in patients with FICAT stage 4 compared with stage 3, and CXCL12 concentrations in patients with stage 3 were markedly lower than stage 2. Serum CXCL12 levels were negatively related to FICAT grading. In addition, Serum CXCL12 concentrations were also negatively related to VAS, WOMAC scores and positively correlated with HHS scores. Meanwhile, serum CXCL12 levels were positively correlated with serum PINP and negatively correlated with IL-33 levels. ROC curve analysis implicated that decrease CXCL12 in serum may act as a favorable marker for FICAT grade. CONCLUSIONS: Decreased serum CXCL12 concentrations may reflect disease severity of non-traumatic ONFH.

Polydatin enhances glomerular podocyte autophagy homeostasis by improving Nrf2-dependent antioxidant capacity in fructose-fed rats.

High fructose is considered a causative factor for oxidative stress and autophagy imbalance that cause kidney pathogenesis. Antioxidant polydatin isolated from Polygonum cuspidatum has been reported to protect against kidney injury. In this study, polydatin was found to ameliorate fructose-induced podocyte injury. It activated mammalian target of rapamycin complex 1 (mTORC1) and suppressed autophagy in glomeruli of fructose-fed rats and in fructose-exposed conditionally immortalized human podocytes (HPCs). Polydatin also enhanced nuclear factor-E2-related factor 2 (Nrf2)-dependent antioxidant capacity to suppress fructose-induced autophagy activation in vivo and in vitro, with the attenuation of fructose-induced up-regulation of cellular light chain 3 (LC3) II/I protein levels. This effect was abolished by Raptor siRNA in fructose-exposed HPCs. These results demonstrated that polydatin ameliorated fructose-induced autophagy imbalance in an mTORC1-dependent manner via improving Nrf2-dependent antioxidant capacity during podocyte injury. In conclusion, polydatin with anti-oxidation activity suppressed autophagy to protect against fructose-induced podocyte injury.

[Effects of slow-release urea combined with common urea application layered in different soil depths on soil nitrogen, enzyme activity, and maize yield]. / ä¸åŒåœŸå±‚æ·±åº¦é æ–½ç¼“é‡Š/æ™®é€šå°¿ç´ å¯¹åœŸå£¤æ°®ç´ å’Œé ¶æ´»æ€§åŠçŽ‰ç±³äº§é‡çš„å½±å“.

We examined the effects of a combination of slow-release urea (PCU) and common urea (PU) applied at different soil depths (0-30 cm soil layer) on inorganic nitrogen content, enzyme activity, and crop yield during two years (2017-2018) in a field experiment. There were eight treatments: CK (without N fertilizer); PU1(common urea applied at 5-10 cm deep soil layer); PU2(common urea applied at 5-10 cm deep soil layer, 60% seed fertilizer + 40% topdressing); PU3(20% common urea at 5-10 cm soil depth, 30% common urea at 15-20 cm soil depth, 50% common urea at 25-30 cm soil depth); PCU1(20% total nitrogen application rate at 5-10 cm soil depth, 30% total nitrogen application rate at 15-20 cm soil depth, 50% total nitrogen application rate at 25-30 cm soil depth), the N fertilizer at 5-10 cm was common urea, but, at 15-20 and 25-30 cm, it was a combination of PCU and PU at ratios of 3:7 and 3:7; PCU2 was as PCU1 but the ratio of PCU and PU was 5:5 at 15-20 cm and 5:5 at 25-30 cm; in PCU3, the ratio of PCU and PU was 3:7 at 15-20 cm and 5:5 at 25-30 cm; in PCU4, the ratio of PCU and PU was 5:5 at 15-20 cm and 3:7 at 25-30 cm. The results showed that PU1 could meet nitrogen demand at the 0-10 cm layer in the early growth stage compared with CK. PU2 and PU3 could meet nitrogen demand for 10-30 cm soil layer in the early stage of maize development. The combined application of slow release urea and common urea could meet nitrogen demand for the whole growth period of maize. In the filling and maturing period, combined application of slow release and common urea significantly increased not only NO3--N, NH4+-N, and alkali-hydrolyzed nitrogen contents but also urease and protease activities in the 10-20 cm and 20-30 cm soil layers compared with PU1-PU3. Compared with PU3, maize yield increased by 2.3%-24.6% and 1.3%-16.5% in the PCU1-PCU4 treatments in 2017 and 2018, respectively. PCU4 had the highest yield, with 13899 and 12439 kg·hm-2, respectively. Therefore, the combined application of slow-release and common urea at different soil layers could meet nitrogen demand in the early growth stage of maize and increase the content of inorganic nitrogen and enzyme activities in the 10-30 cm soil layers in the later growth period, which promoted the growth and increased the yield of maize. Among all the treatments PCU4 treatment was the most effective.

Pterostilbene prevents hepatocyte epithelial-mesenchymal transition in fructose-induced liver fibrosis through suppressing miR-34a/Sirt1/p53 and TGF-ß1/Smads signalling.

BACKGROUND AND PURPOSE: Excessive fructose consumption is a risk factor for liver fibrosis. Pterostilbene protects against liver fibrosis. Here, we investigated the potential role and the mechanisms underlying the hepatocyte epithelial-mesenchymal transition (EMT) in fructose-induced liver fibrosis and protection by pterostilbene. EXPERIMENTAL APPROACH: Characteristic features of liver fibrosis in 10% fructose-fed rats and EMT in 5 mM fructose-exposed BRL-3A cells with or without pterostilbene and the change of miR-34a/Sirt1/p53 and transforming growth factor-ß1 (TGF-ß1)/Smads signalling were examined. MiR-34a inhibitor, miR-34a minic, or p53 siRNA were used to explore the role of miR-34a/Sirt1/p53 signalling in fructose-induced EMT and the action of pterostilbene. KEY RESULTS: Pterostilbene prevented fructose-induced liver injury with fibrosis in rats. Fructose caused hepatocyte undergoing EMT, gaining fibroblast-specific protein 1 and vimentin, and losing E-cadherin, effects attenuated by pterostilbene. Moreover, fructose induced miR-34a overexpression in hepatocytes with down-regulated Sirt1, increased p53 and ac-p53, and activated TGF-ß1/Smads signalling, whereas these disturbances were suppressed by miR-34a inhibitor. Additionally, miR-34a inhibitor and p53 siRNA prevented TGF-ß1-driven hepatocyte EMT under fructose exposure. Pterostilbene down-regulated miR-34a, up-regulated Sirt1, and suppressed p53 activation and TGF-ß1/Smads signalling in fructose-stimulated animals and cells but showed no additional effects with miR-34a inhibitor on miR-34a/Sirt1/p53 signalling in fructose-exposed hepatocytes. CONCLUSIONS AND IMPLICATIONS: These results strongly suggest that activation of miR-34a/Sirt1/p53 signalling is required for fructose-induced hepatocyte EMT mediated by TGF-ß1/Smads signalling, contributing to liver fibrosis in rats. Pterostilbene exhibits a protective effect against liver fibrosis at least partly through inhibiting miR-34a/Sirt1/p53 signalling activation.

Pterostilbene Attenuates Fructose-Induced Myocardial Fibrosis by Inhibiting ROS-Driven Pitx2c/miR-15b Pathway.

Excessive fructose consumption induces oxidative stress and myocardial fibrosis. Antioxidant compound pterostilbene has cardioprotective effect in experimental animals. This study is aimed at investigating how fructose drove fibrotic responses via oxidative stress in cardiomyocytes and explored the attenuation mechanisms of pterostilbene. We observed fructose-induced myocardial hypertrophy and fibrosis with ROS overproduction in rats. Paired-like homeodomain 2 (Pitx2c) increase, microRNA-15b (miR-15b) low expression, and p53 phosphorylation (p-p53) upregulation, as well as activation of transforming growth factor-ß1 (TGF-ß1)/drosophila mothers against DPP homolog (Smads) signaling and connective tissue growth factor (CTGF) induction, were also detected in fructose-fed rat hearts and fructose-exposed rat myocardial cell line H9c2 cells. The results from p53 siRNA or TGF-ß1 siRNA transfection showed that TGF-ß1-induced upregulation of CTGF expression and p-p53 activated TGF-ß1/Smads signaling in fructose-exposed H9c2 cells. Of note, Pitx2c negatively modulated miR-15b expression via binding to the upstream of the miR-15b genetic loci by chromatin immunoprecipitation and transfection analysis with pEX1-Pitx2c plasmid and Pitx2c siRNA, respectively. In H9c2 cells pretreated with ROS scavenger N-acetylcysteine, or transfected with miR-15b mimic and inhibitor, fructose-induced cardiac ROS overload could drive Pitx2c-mediated miR-15b low expression, then cause p-p53-activated TGF-ß1/Smads signaling and CTGF induction in myocardial fibrosis. We also found that pterostilbene significantly improved myocardial hypertrophy and fibrosis in fructose-fed rats and fructose-exposed H9c2 cells. Pterostilbene reduced cardiac ROS to block Pitx2c-mediated miR-15b low expression and p-p53-dependent TGF-ß1/Smads signaling activation and CTGF induction in high fructose-induced myocardial fibrosis. These results firstly demonstrated that the ROS-driven Pitx2c/miR-15b pathway was required for p-p53-dependent TGF-ß1/Smads signaling activation in fructose-induced myocardial fibrosis. Pterostilbene protected against high fructose-induced myocardial fibrosis through the inhibition of Pitx2c/miR-15b pathway to suppress p-p53-activated TGF-ß1/Smads signaling, warranting the consideration of Pitx2c/miR-15b pathway as a therapeutic target in myocardial fibrosis.

Pterostilbene alleviates fructose-induced renal fibrosis by suppressing TGF-ß1/TGF-ß type I receptor/Smads signaling in proximal tubular epithelial cells.

High dietary fructose is a key causative factor in the development of renal fibrosis. Pterostilbene has anti-fibrotic effect. Understanding the action mechanism of pterostilbene in fructose-induced renal fibrosis remains as a challenge. Here, fructose feeding was found to promote the progress of epithelial-to-mesenchymal transition (EMT) of proximal tubule epithelial cells (PTECs) and collagen deposition in renal cortex of rats with tubulointerstitial fibrosis. Simultaneously, it impaired insulin receptor (IR)/insulin receptor substrate-1 (IRS-1)/protein kinase B (Akt) pathway, and increased transforming growth factor-beta 1 (TGF-ß1) and TGF-ß type I receptor to enhance phosphorylation of drosophila mothers against decapentaplegic homolog 2 (Smad2) and Smad3, and Smad4 expression in rat kidney cortex. These changes were also observed in cultured PTECs HK-2 cells exposed to 5 mM fructose. The data from fructose-exposed HK-2 cells co-incubated with TGF-ß type I receptor inhibitor further demonstrated that the activation of TGF-ß1/TGF-ß type I receptor/Smads signaling promoted renal tubular EMT and collagen accumulation. Pterostilbene was found to ameliorate fructose-induced renal fibrosis in rats. Importantly, pterostilbene improved IR/IRS-1/Akt pathway impairment and suppressed TGF-ß1/TGF-ß type I receptor/Smads signaling activation in vivo and in vitro, being consistent with its reduction of EMT and collagen deposition. Upregulation of IR/Akt signaling by pterostilbene was also confirmed in Akt inhibitor (MK-2206 2HCl) or IR inhibitor (GSK1904529A)-treated HK-2 cells. Taken together, pterostilbene may be a promising therapeutic agent for the treatment of fructose-induced kidney fibrosis with insulin signaling impairment.

Air tamponade and without heavy liquid usage in pars plana vitrectomy for rhegmatogenous retinal detachment repair.

AIM: To report the results of rhegmatogenous retinal detachment (RRD) repair after pars plana vitrectomy (PPV) without operative use of heavy liquid, and utilizing air tamponade in selected cases. METHODS: RRD patients without severity of proliferative vitreoretinopathy C2 or more underwent PPV without operative use of heavy liquid, and utilizing air tamponade were consecutively enrolled. Alternative postoperative facedown position or lateral position was required for 3-5d. RESULTS: Totally 36 eyes of 36 patients (24 males, 66.7%) aged 53.8±10.9y underwent this modified surgery. The mean number of retinal break was 2.1±1.3. Most of the eyes (29, 80.6%) had retinal detachment involving more than one quadrant. Twenty-two (61.1%) eyes with cataract had combined phacoemulsification and intraocular lens implantation. The mean follow up time was 4.6±1.8mo. Two eyes with retinal redetachment underwent a second retinal repair surgery with silicone oil tamponade, yielding the primary reattachment rate to 94.4% (34/36). Six (16.7%) eyes had intraocular pressure higher than 25 mm Hg. The visual acuity (logMAR) improved from 0.98±0.74 preoperatively to 0.52±0.31 postoperatively (P<0.001). CONCLUSION: The success rate of this modified retinal repair surgery is comparable with traditional surgery. This technique can be considered for certain retinal detachment patients, since its apparent advantages included lower surgical complications, reduced surgery expenditure, shorter time for postoperative facedown position, and avoiding silicone oil removal surgery.