Tea polyphenols alleviate TBBPA-induced inflammation, ferroptosis and apoptosis via TLR4/NF-κB pathway in carp gills.

The extensive application of Tetrabromobisphenol A (TBBPA) leads to the pollution of part of the water environment and brings great safety risks to aquatic animals. As a natural extract, tea polyphenols (TPs) have antioxidant and anti-inflammatory effects. Gills are one of the immune organs of fish and constitute the first line of defense of the immune system. However, it was unclear whether TPs could mitigate TBBPA-induced gills injury. Therefore, an animal model was established to investigate the effect of TPs on TBBPA-induced gills. The results indicated that TBBPA changed the coefficient and tissue morphology of carp gills. In addition, TBBPA induced oxidative stress and inflammation, leading to ferroptosis and apoptosis in carp gills. Dietary addition of TPs significantly improved the antioxidant capacity of carp, effectively inhibited the overexpression of TLR4/NF-κB and its mediated inflammatory response. Moreover, TPs restored iron metabolism, reduced the expression of pro-apoptotic factors thereby alleviating ferroptosis and apoptosis in carp gills. This study enriched the protective effect of TPs and provided a new way to improve the innate immunity of carp.

Polyethylene microplastics cause apoptosis via the MiR-132/CAPN axis and inflammation in carp ovarian.

Microplastics (MPs) are widely distributed pollutants in the environment and accumulate in the aquatic environment due to human activities. Carp, a common edible aquatic organism, has been found to accumulate MPs in body. MicroRNA (miRNAs) is a non-coding short RNA that regulates protein expression by binding to target genes in various physiological processes such as proliferation, differentiation and apoptosis. The ovary is a crucial role in carp reproduction. In this study, we established a model of carp exposed to polyethylene microplastics (PE-MPs) in the aquatic environment to investigate the specific mechanism of PE-MPs causing ovarian injury and the involvement of miR-132/calpain (CAPN) axis. H&E stained sections revealed that PE-PMs induced inflammation in ovarian tissues and impaired oocyte development. TUNEL analysis showed an increased rate of apoptosis in ovarian cells treated with PE-PMs. RT-PCR and Western Blot assays confirmed that exposure to PE-MPs significantly decreased miR-132 expression while increasing CAPN expression at both mRNA and protein levels. The concentration of calcium ions was significantly increased in tissues, leading to CAPN enzyme activity increase. The expression of mitochondrial damage-related genes (bax, AIF, cyt-c, caspase-7, caspase-9, and caspase-3) was higher while the expression of anti-apoptotic genes (bcl-2 and bcl-xl) was lower. Protein levels of bax, AIF, caspase-3, bcl-2 and bcl-xl changed accordingly with the genetic alterations. Additionally, we discovered that PE-MPs can activate the p65 factor through the TRAF6/NF-kB pathway resulting in elevated production of pro-inflammatory factors IL-6, IL-1ß and TNF-a which contribute to ovarian inflammation development. This study investigates the impact of PE-MPs on carp ovarian function and provides insights into miRNAs' role and their target genes.

The Discovery and Anti-Colorectal Cancer Activities of Cembranolides from the South China Sea Soft Coral Sinularia pendunculata.

A new cembranolide, namely, sinupendunculide A (1), along with eight known related compounds (2-9), was isolated from the South China Sea Soft coral Sinularia pendunculata. The structure of sinupendunculide A (1) was established by extensive spectroscopic analysis and X-ray diffraction experiments. In a bioassay, anti-colorectal cancer (CRC) activity was performed, and the results showed that several compounds exhibited cytotoxicity against RKO cells, and a preliminary structure-activity relationship was analysed. Meanwhile, the most effective compound 7 was proven to increase reactive oxygen species levels, which promoted cell apoptosis and inhibited cell proliferation.

A MATLAB GUI program for reservoir management to simultaneously optimise sediment release and power generation.

Sedimentation affects the normal function of reservoirs and is a decisive factor in the reservoir's service life. Flushing sediment during reservoir operation is an effective non-engineering measure to alleviate reservoir sedimentation; however, lowering water level to discharge more flow conflicts with hydropower generation. In this study, reservoir management software is developed to simultaneously optimise sediment discharge and hydropower generation with the reservoir discharge as the decision variables. The sediment transport rate is calculated by an integral of the vertical distribution of suspended load concentration and flow velocity instead of empirical formulas. The model is solved by the most widely used multi-objective optimisation algorithm NSGA-II, resulting in the optimal schedule corresponding to the maximal sediment discharge and hydropower generation, which can be displayed graphically in the software. The software was developed in MATLAB with a Graphical User Interface (GUI) and applied to a large reservoir and can be generalised to other reservoirs. The results show that within the recommended discharge variation of 5%, the sediment release can be increased by 2.07 × 106 t as a reduction of per 1010 kW h in annual power generation. Compared with the original scheme, sediment release can be increased most by 3.31% at the cost of 0.03% loss of power generation. Moreover, the dual objective in the flood season was optimised by 7.30% and 3.92%, respectively.

Myricetin Attenuated Diabetes-Associated Kidney Injuries and Dysfunction via Regulating Nuclear Factor (Erythroid Derived 2)-Like 2 and Nuclear Factor-κB Signaling.

Background/Aims: Previous studies have suggested that myricetin (Myr) could promote the expression and nuclear translocation of nuclear factor (erythroid-derived 2)-like (Nrf2). This study aimed to investigate whether Myr could attenuate diabetes-associated kidney injuries and dysfunction in wild-type (WT) and Nrf2 knockdown (Nrf2-KD) mice. Methods: Lentivirus-mediated Nrf2-KD and WT mice were used to establish type 1 diabetes mellitus (DM) by streptozotocin (STZ) injection. WT and Nrf2-KD mice were then randomly allocated into four groups: control (CON), Myr, STZ, and STZ + Myr. Myr (100 mg/kg/day) or vehicle was administered for 6 months. Kidneys were harvested and weighed at the end of the experiment. Hematoxylin and eosin staining and Masson's trichrome staining were used to assess the morphology and fibrosis of the kidneys, respectively. Urinary albumin-to-creatinine ratio was used to test renal function. Western blotting was performed to determine oxidative-stress- or inflammation-associated signaling pathways. Real-time polymerase chain reaction (RT-PCR) was performed to detect the expression of fibrosis or inflammatory cytokines at the message Ribonucleic Acid (mRNA) level. Results: In WT mice, Myr alleviated DM-induced renal dysfunction, fibrosis, and oxidative damage and enhanced the expression of Nrf2 and its downstream genes. After knockdown of Nrf2, Myr treatment partially but significantly mitigated DM-induced renal dysfunction and fibrosis, which might be associated with inhibition of the I-kappa-B (IκB)/nuclear factor-κB (NF-κB) (P65) signaling pathway. Conclusions: This study showed that Myr prevented DM-associated decreased expression of Nrf2 and inhibited IκB/NF-κB (P65) signaling pathway. Moreover, inhibition of IκB/NF-κB (P65) signaling pathway is independent of the regulation of Nrf2. Thus, Myr could be a potential treatment for preventing the development and progression of DM-associated kidney injuries and dysfunction.

Reciprocal Network between Cancer Stem-Like Cells and Macrophages Facilitates the Progression and Androgen Deprivation Therapy Resistance of Prostate Cancer.

Purpose: Cancer stem-like cells (CSC) contribute to the progression and androgen deprivation therapy (ADT) resistance of prostate cancer. As CSCs depend on their specific niche, including tumor-associated macrophages (TAM), elucidating the network between CSCs and TAMs may help to effectively inhibit the progression and ADT resistance of prostate cancer.Experimental Design: The underlying intracellular mechanism that sustains the stem-like characteristics of CSCs in prostate cancer was assessed via RNA sequencing, co-immunoprecipitation, chromatin immunoprecipitation, and other assays. A coculture system and cytokine antibody arrays were used to examine the interaction network between CSCs and TAMs. In addition, an orthotopic prostate cancer model was established to evaluate the in vivo effects of the combined targeting of CSCs and their interaction with TAMs on ADT resistance.Results: Autophagy-related gene 7 (ATG7) facilitated the transcription of OCT4 via ß-catenin, which binds to the OCT4 promoter, promoting CSC characteristics in prostate cancer, including self-renewal, tumor initiation, and drug resistance. In addition, CSCs remodeled their specific niche by educating monocytes/macrophages toward TAMs, and the CSC-educated TAMs reciprocally promoted the stem-like properties of CSCs, progression and ADT resistance of prostate cancer via IL6/STAT3. Furthermore, the combined targeting of CSCs and their interaction with TAMs by inhibiting ATG7/OCT4 and IL6 receptor effectively ameliorated ADT resistance in an orthotopic prostate cancer model.Conclusions: Targeting CSCs and their niche may prove to be a more powerful strategy than targeting CSCs alone, providing a rational approach to ameliorating ADT resistance in prostate cancer. Clin Cancer Res; 24(18); 4612-26. ©2018 AACR.

Blocking the Feedback Loop between Neuroendocrine Differentiation and Macrophages Improves the Therapeutic Effects of Enzalutamide (MDV3100) on Prostate Cancer.

Purpose: Androgen deprivation therapy (ADT), including enzalutamide, induces resistance in prostate cancer; ADT resistance is associated with neuroendocrine differentiation (NED) and tumor-associated macrophages (TAM). This study aimed to investigate the association between enzalutamide-induced NED and TAMs and its mechanism.Experimental Design: The association between enzalutamide-induced NED and TAMs was investigated by IHC using prostate cancer tissues, enzalutamide-resistant mouse xenografts, and a coculture system. The underlying mechanisms were assessed using in vitro cytokine antibody arrays, ELISAs, chromatin immunoprecipitation, and other methods. An orthotopic prostate cancer mouse model was established to evaluate the in vivo effects of combined IL6 receptor (IL6R) and high mobility group box 1 (HMGB1) inhibition on enzalutamide resistance.Results: High CD163 expression was observed in ADT-treated prostate cancer or castration-resistant prostate cancer (CRPC) tissues with high levels of neuron-specific enolase (NSE) and chromogranin A (CHGA) and in enzalutamide-resistant xenografts, indicating the crucial roles of NED and TAMs in enzalutamide resistance. Specifically, enzalutamide-induced HMGB1 expression facilitated TAM recruitment and polarization and drove NED via ß-catenin stabilization. HMGB1-activated TAMs secreted IL6 to augment enzalutamide-induced NED and directly promote HMGB1 transcription via STAT3. Finally, inhibition of the IL6/STAT3 pathway by tocilizumab combined with HMGB1 knockdown inhibited enzalutamide-induced resistance in an orthotopic prostate cancer mouse model.Conclusions: Enzalutamide elevates HMGB1 levels, which recruits and activates TAMs. Moreover, IL6 secreted by HMGB1-activated TAMs facilitates the enzalutamide-induced NED of prostate cancer, forming a positive feedback loop between NED in prostate cancer and TAMs. The combined inhibition of IL6R and HMGB1 may serve as a new treatment for enzalutamide resistance in patients with advanced or metastatic prostate cancer. Clin Cancer Res; 24(3); 708-23. ©2017 AACR.

Zinc finger protein X-linked promotes expansion of EpCAM+ cancer stem-like cells in hepatocellular carcinoma.

Zinc finger protein X-linked (ZFX) is frequently upregulated in multiple human malignancies and also plays a critical role in the maintenance of self-renewal in embryonic stem cells. However, the role of ZFX in liver cancer stem cells (CSCs) remains obscure. We observed that the elevated expression of both ZFX and epithelial cell adhesion molecule (EpCAM) was associated with aggressive clinicopathological features and indicated poor prognosis in patients with hepatocellular carcinoma (HCC). ZFX was commonly enriched in liver EpCAM+ CSCs. Knockdown of ZFX decreased the proportion of EpCAM+ CSCs in HCC cells and suppressed their expression of stemness-related genes, self-renewal capacity, chemoresistance, metastatic potential, and tumorigenicity. Conversely, upregulation of ZFX in CSCs rescued these inhibitory effects and enhanced stem-like properties. Mechanistically, depletion of ZFX reduced nuclear translocation and transactivation of ß-catenin, thereby inhibiting the self-renewal capacity of EpCAM+ CSCs. Moreover, knockdown of ß-catenin attenuated the self-renewal of EpCAM+ HCC cells stably expressing ZFX, further indicating that ß-catenin is required for ZFX-mediated expansion and maintenance of EpCAM+ CSCs. Taken together, our findings indicate that ZFX activates and maintains EpCAM+ liver CSCs by promoting nuclear translocation and transactivation of ß-catenin. Furthermore, combination of ZFX and EpCAM may serve as a significant indicator for prognosis of patients with HCC.

[Major domestication traits in Asian rice].

Rice (Oryza sativa L.) is an excellent model plant in elucidation of cereal domestication. Loss of seed shattering, weakened dormancy, and changes in plant architecture were thought to be three key events in the rice domestication and creating the high-yield, uniform-germinating, and densely-planting modern rice. Loss of shattering is considered to be the direct morphological evidence for identifying domesticated rice. Two major shattering QTLs, Sh4 and qSH1, have displayed different domestication histories. Weakened seed dormancy is essential for synchronous germination in agricultural production. Genes Sdr4, qSD7-1, and qSD12 impose a global and complementary adaptation strategies in controlling seed dormancy. The prostate growth habit of wild rice is an adaptation to disturbed habitats, while the erect growth habit of rice cultivars meet the needs of compact planting, and such a plant architecture is mainly controlled by PROG1. The outcrossing habit of wild rice promotes propagation of domestication genes among different populations, while the self-pollinating habit of cultivated rice facilitates fixation of domestication genes. Currently, the researches on rice domestication mainly focus on individual genes or multiple neutral markers, and much less attention has been paid to the evolution of network controlling domestication traits. With the progress in functional genomics research, the molecular mechanism of domestication traits is emerging. Rice domestication researches based on network will be more comprehensive and better reflect rice domestica-tion process. Here, we reviewed most progresses in molecular mechanisms of rice domestication traits, in order to provide the new insights for rice domestication and molecular breeding.

[Non-compaction cardiomyopathy in a 5-generation Chinese family].

OBJECTIVE: Familial left ventricular noncompaction(LVNC) is quite rare. We screened for the presence of LVNC and related clinical characteristics in a 5-generation Chinese family. METHODS: Comprehensive medical history was obtained from 40 members in a 5-generation Chinese family. Systemic clinical investigations including echocardiography (UCG), routine and ambulatory electrocardiogram (ECG), X-rays were performed in 33 family members. Cardiovascular magnetic resonance image (MRI) was carried out in 2 family members. RESULTS: Sudden cardiac death (including 1 occurred while following-up) was reported in 7 family members (17.5%, 7/40). LVNC was diagnosed in 10 out of the 33 family members (30.3%) and heart enlargement was evidenced in 3, heart failure in 2, complete left branch conductive block in 3, serious sick sinus syndrome (SSS) treated with permanent pacemaker implantation in 1 and paroxysmal supraventricular tachycardia treated with radiofrequency ablation procedure in 1 out of these 10 LVNC patients. Primary pedigree analysis revealed that offspring from female patients were at the highest risk to be affected by LVNC (15/18, 83.3%) while LVNC was absent in offspring of male LVNC patients (0/8). Moreover, clinical heart failure symptoms and arrhythmias were more severe in female LVNC patients than in male LVNC patients. CONCLUSION: Primary familial investigation reveals the matrilineal inheritance of familial LVNC in this 5-generation Chinese family, further investigations are warranted to explore the potential mutations in the mitochondrial genome responsible for LVNC in this family.

An integrated pericardial valved stent special for percutaneous tricuspid implantation: an animal feasibility study.

BACKGROUND: Various percutaneous valve replacement approaches have been reported in animals to replace the aortic and pulmonary valve. To broaden the indications of percutaneous approach to atrioventricular valves replacement, we developed a novel valved stent and evaluated the feasibility and safety of percutaneous implantation of the device in the tricuspid position. MATERIALS AND METHODS: A unidirectional semilunar valve of porcine pericardium was sutured to a valvular ring. Then the ring with pericardial valve was mounted on a double-edge nitinol stent to construct the tricuspid valved stent. Transcatheter tricuspid valved stent implantation was performed on 10 healthy sheep. These sheep were followed up shortly after procedure with echocardiography evaluation and 64-slice CT imaging examination during the periodical follow-up at 1 mo and at 6 mo post-implantation. Additionally, two sheep were sacrificed after the procedure for anatomic and histological evaluation one at 1 h and the other at 1 mo, respectively. RESULTS: Percutaneous valve implantation was successful in eight of 10 sheep. Two sheep died during the procedure due to migration of stent and fatal arrhythmia. The pressure of right heart did not significantly change after the procedure. Further echocardiography and imaging confirmed the stents were in desired position during the follow-up. The remaining six sheep with normal valvular and cardiac functionality survived for 6 mo after implantation. CONCLUSIONS: The tricuspid stent with a valvular ring and pericardial valve can be implanted in tricuspid annulus percutaneous. The double-edge stent could substitute the native tricuspid valve chronically.

Safety and bioactivity of intracoronary delivery of naked plasmid DNA encoding human atrial natriuretic factor.

AIM: To evaluate the safety and bioactivity of catheter-mediated intracoronary gene delivery of naked plasmid DNA encoding human atrial natriuretic factor (hANF). METHODS: hANF gene delivery was performed in 12 canines. For each canine, 4 mg of reconstructed naked plasmid DNA encoding hANF (pCR3*hANF, n=6) or pCR3 (n=6, control) in 2 mL normal saline was injected into left coronary artery via a coronary angiographic catheter. The expression of hANF mRNA in left ventricular myocardium, liver, lung, and kidney was identified by reverse transcription polymerase chain reaction and Southern blot analysis 40 d after gene delivery. Plasma ANF levels were determined by radioimmunoassay. RESULTS: The naked pCR3*hANF caused significant expression of hANF mRNA in ventricular myocardium (P <0.01). No hANF mRNA was detected in distal tissues, including liver, lung, and kidney (P >0.05). ANF levels were significantly higher in pCR3*hANF group than those in control group. CONCLUSION: These facts firstly demonstrate that intracoronary delivery of naked pCR3*hANF is probably a safe and feasible method for gene delivery by which hANF gene can be expressed in ventricular myocardium effectively.