Melatonin protects liver from intestine ischemia reperfusion injury in rats

AIM: To investigate the protective effect of melatonin on liver after intestinal ischemia-reperfusion injury in rats. METHODS: One hundred and fifty male Wistar rats, weighing 190-210 g, aged 7 wk, were randomly divided into melatonin exposure group, alcohol solvent control group and normal saline control group. Rats in the melatonin exposure group received intraperitoneal (IP) melatonin (20 mg/kg) 30 min before intestinal ischemia-reperfusion (IR), rats in the alcohol solvent control group received the same concentration and volume of alcohol, and rats in the normal saline control group received the same volume of normal saline. Serum samples were collected from each group 0.5, 1, 6, 12, and 24 h after intestinal IR. Levels of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured with an auto-biochemical analyzer. Serum TNF-α was tested by enzyme-linked immunosorbent assay (ELISA). Malondialdehyde (MDA) in liver was detected by colorimetric assay. Pathological changes in liver and immunohistochemical straining of ICAM-1 were observed under an optical microscope. RESULTS: The levels of ALT measured at various time points after intestinal IR in the melatonin exposure group were significantly lower than those in the other two control groups (P < 0.05). The serum AST levels 12 and 24 h after intestinal IR and the ICAM-1 levels (%) 6, 12 and 24 h after intestinal IR in the melatonin exposure group were also significantly lower than those in the other two control groups (P < 0.05). CONCLUSION: Exotic melatonin can inhibit the activity of ALT, AST and TNF-α, decrease the accumulation of MDA, and depress the expression of ICAM-1 in liver after intestinal IR injury, thus improving the liver function.

Reconfigurable manufacturing systems： Principles, design, and future trends

Reconfigurable manufacturing systems （RMSs）, which possess the advantages of both dedicated serial lines and flexible manufacturing systems, were introduced in the mid-1990s to address the challenges initiated by globalization. The principal goal of an RMS is to enhance the responsiveness of manufacturing systems to unforeseen changes in product demand. RMSs are cost- effective because they boost productivity, and increase the lifetime of the manufacturing system. Because of the many streams in which a product may be produced on an RMS, maintaining product precision in an RMS is a challenge. But the experience with RMS in the last 20 years indicates that product quality can be definitely maintained by inserting in-line inspection stations. In this paper, we formulate the design and operational principles for RMSs, and provide a state-of-the-art review of the design and operations methodologies of RMSs according to these principles. Finally, we propose future research directions, and deliberate on how recent intelligent manufacturing technologies may advance the design and operations of RMSs.

Astaxanthine attenuates cisplatin ototoxicity in vitro and protects against cisplatin-induced hearing loss in vivo

Astaxanthine(AST) has important biological activities including antioxidant and antiinflammatory effects that could alleviate neurological and heart diseases, but its role in the prevention of cisplatin-induced hearing loss(CIHL) is not yet well understood. In our study, a steady interaction between AST and the E3 ligase adapter Kelch-like ECH-associated protein 1, a predominant repressor of nuclear factor erythroid 2-related factor 2(NRF2), was performed and tested via computer molecular docking and dynamics. AST protected against cisplatin-induced ototoxicity via NRF2 mediated pathwayusing quantitative PCR and Western blotting. The levels of reactive oxygen species(ROS) and mitochondrial membrane potential revealed that AST reduced ROS overexpression and mitochondrial dysfunction.Moreover, AST exerted anti-apoptosis effects in mouse cochlear explants using immunofluorescence staining and HEI-OC1 cell lines using quantitative PCR and Western blotting. Finally, AST combined with poloxamer was injected into the middle ear through the tympanum, and the protection against CIHL was evaluated using the acoustic brain stem test and immunofluorescent staining in adult mice. Our results suggest that AST reduced ROS overexpression, mitochondrial dysfunction, and apoptosis via NRF2-mediated pathway in cisplatin-exposed HEI-OC1 cell lines and mouse cochlear explants, finally promoting cell survival. Our study demonstrates that AST is a candidate therapeutic agent for CIHL.

Melatonin ameliorates tau-related pathology via the miR-504-3p and CDK5 axis in Alzheimer’s disease

Background:Intracellular accumulation of the microtubule-associated protein tau and its hyperphosphorylated forms is a key neuropathological feature of Alzheimer’s disease(AD).Melatonin has been shown to prevent tau hyperphosphorylation in cellular and animal models.However,the molecular mechanisms by which melatonin attenuates tau hyperphosphorylation and tau-related pathologies are not fully understood.Methods:Immunofluorescence,immunoblotting analysis and thioflavin-S staining were employed to examine the effects of early and late treatment of melatonin on tau-related pathology in hTau mice,in which nonmutated human tau is overexpressed on a mouse tau knockout background.High-throughput microRNA(miRNA)sequencing,quantitative RT-PCR,luciferase reporter assay and immunoblotting analysis were performed to determine the molecular mechanism.Results:We found that both early and late treatment of melatonin efficiently decreased the phosphorylation of soluble and insoluble tau at sites related to AD.Moreover,melatonin significantly reduced the number of neurofibrillary tangles(NFTs)and attenuated neuronal loss in the cortex and hippocampus.Furthermore,using miRNA microarray analysis,we found that miR-504-3p expression was upregulated by melatonin in the hTau mice.The administration of miR-504-3p mimics dramatically decreased tau phosphorylation by targeting p39,an activator of the well-known tau kinase cyclin-dependent kinase 5(CDK5).Compared with miR-504-3p mimics alone,co-treatment with miR-504-3p mimics and p39 failed to reduce tau hyperphosphorylation.Conclusions:Our results suggest for the first time that melatonin alleviates tau-related pathologies through upregulation of miR-504-3p expression by targeting the p39/CDK5 axis and provide novel insights into AD treatment strategies.

FSIP1 enhances the therapeutic sensitivity to CDK4/6 inhibitors in triple-negative breast cancer patients by activating the Nanog pathway

CDK4/6 inhibitors are routinely recommended agents for the treatment of advanced HR+HER2-breast cancer.However,their therapeutic effectiveness in triple-negative breast cancer(TNBC)remains controversial.Here,we observed that the expression level of fibrous sheath interacting protein 1(FSIP1)could predict the treatment response of TNBC to CDK4/6 inhibitors.High FSIP1 expression level was related to a poor prognosis in TNBC,which was associated with the ability of FSIP1 to promote tumor cell proliferation.FSIP1 downregulation led to slowed tumor growth and reduced lung metastasis in TNBC.FSIP1knockout caused cell cycle arrest at the G0/G1 phase and reduced treatment sensitivity to CDK4/6 inhibitors by inactivating the Nanog/CCND1/CDK4/6 pathway.FSIP1 could form a complex with Nanog,protecting it from ubiquitination and degradation,which may facilitate the rapid cell cycle transition from G0/G1 to S phase and exhibit enhanced sensitivity to CDK4/6 inhibitors.Our findings suggest that TNBC patients with high FSIP1 expression levels may be suitable candidates for CDK4/6 inhibitor treatment.

TMSOTf-catalyzed intramolecular seleno-arylation of tethered alkenes:A novel method for the solid-phase synthesis of dihydrocoumarins and coumarins

拴住的链烯的催化 TMSOTf 的 intramolecular seleno-arylation 作为硒来源用支持聚苯乙烯的 succinimidyl 硒化物被执行。这催化进程为拥有 seleno 功能的 dihydrocoumarins 的 regioselective 合成提供一个有效方法，由硒连接器的无踪迹的劈开列在后面在好收益和纯净提供 dihydrocoumarins 和香豆素。