Creatine–facilitated protection of stress caused by disrupted circadian rhythm

Disturbances in natural Circadian rhythm are well-known stress factors, affecting a range of metabolic pathways in the living body including the brain. Hence, discovery of natural compounds that could help to prevent and cure of adverse changes is very important. One of the recently discussed substances is creatine, that is believed to have anti-stressor properties. Recent paper describes the impact of intraperitoneally injected creatine (140 mg/kg) into rats with a disturbed natural circadian rhythm for an extended period of time (30 days). Markedly, creatine-treated animals show positive changes in open-field behavioral parameters, and an increase in certain antioxidant enzymes’ (SOD, catalase) activity in the hippocampus, whereas the concentration of nitric oxide, H₂O₂, and Ca²⁺ are approximated to the control value. Similar findings were also observed in case of Na⁺/K⁺- and Ca²⁺-ATPases. To sum up, the recent findings allow the conclusion that oxidative stress induced by long-term disturbances in natural circadian rhythm is accompanied and likely provoked by an increase in Ca²⁺-cytotoxicity, which is supposedly normalized by the creatine’s indirect action on the NMDA receptor. Therefore, impact on energy mediating pathways has a positive effect on stabilization of antioxidant and various metabolic systems and protecting hippocampal cells from stress.     

Diversification of plant agronomic traits by genome editing of brassinosteroid signaling family genes in rice

Brassinosteroids (BRs) regulate various agronomic traits such as plant height, leaf angle, and grain size in rice (Oryza sativa L.); thus, BR signaling components are promising targets for molecular rational design. However, genetic materials for BR-signaling genes or family members remain limited in rice. Here, by genome editing using clustered regularly interspaced short palindromic repeats (CRSPR)/Cas9 tools, we generated a panel of single, double, triple, or quadruple mutants within three BR signaling gene families, including GSK3/SHAGGY-LIKE KINASE1 (GSK1)–GSK4, BRASSINAZOLE-RESISTANT1 (OsBZR1)–OsBZR4, and protein phosphatases with kelch-like (PPKL)1–PPKL3, under the same background (Zhonghua11, japonica). The high-order mutants were produced by either simultaneously targeting multiple sites on different genes of one family (GSKs and PPKLs) or targeting the overlapping sequences of family members (OsBZRs). The mutants exhibited a diversity of plant height, leaf angle, and grain morphology. Comparison analysis of the phenotypes together with BR sensitivity tests suggested the existence of functional redundancy, differentiation, or dominancy among the members within each family. In addition, we generated a set of transgenic plants overexpressing GSK2, OsBZR1/2, and PPKL2, respectively, in wild-type or activated forms with fusion of different tags, and also verified the protein response to BR application. Collectively, these plants greatly enriched the diversity of important agronomic traits in rice. We propose that editing of BR-related family genes could be a feasible approach for screening of desired plants to meet different requirements. Release of these materials as well as the related information also provides valuable resources for further BR research and utilization.     

Low-Temperature Sodium-Ion Batteries: Challenges and Progress

As an ideal candidate for the next generation of large-scale energy storage devices, sodium-ion batteries (SIBs) have received great attention due to their low cost. However, the practical utility of SIBs faces constraints imposed by geographical and environmental factors, particularly in high-altitude and cold regions. In these areas, the low-temperature (LT) performance of SIBs presents a pressing technological challenge that requires significant breakthroughs. In LT environments, the electrochemical reaction kinetics of SIBs are sluggish, the electrode/electrolyte interface is unstable, and the diffusion of sodium ions in electrode materials is slow, leading to a decrease in battery performance. Therefore, the reasonable design of electrolyte and electrode materials is of great significance for optimizing the LT performance of SIBs. In this review, the research progress of LT SIBs electrolytes, cathode, and anode materials, as well as sodium metal batteries and solid-state electrolytes is systematically summarized in recent years, aiming to understand the design principles of LT SIBs, clarify the basic research and development of high-performance SIBs in practical applications, and promote the development of SIBs technology in the full temperature range.     

Piptadenin,a Novel 3,4‐Secooleanane Triterpene and Piptadenamide,a New Ceramide from the Stem Bark of Piptadeniastrum africanum (Hook.f.) Brenan

Piptadenin ( 1 ), a new triterpene along with piptadenamide ( 10 ), a new ceramide, have been isolated from the AcOEt‐soluble fraction of the MeOH extract of the stem bark of Piptadeniastrum africanum along with nine known compounds, 1‐O‐[(3β,22β)‐3,22‐dihydroxy‐28‐oxoolean‐12‐en‐28‐yl]‐β‐d ‐glucopyranose ( 2 ), 22β‐hydroxyoleanic acid ( 3 ), oleanic acid ( 4 ), lupeol ( 5 ), betulinic acid ( 6 ), 5α‐stigmasta‐7,22‐dien‐3β‐ol ( 7 ), 5α‐stigmasta‐7,22‐dien‐3‐one ( 8 ), (3β)‐stigmast‐5‐en‐3‐yl β‐d ‐glucopyranoside ( 9 ) and 2,3‐dihydroxypropyl hexacosanoate ( 11 ). Except for compound 11 , all the isolated compounds are reported for the first time from this plant. The structures of the isolated compounds were elucidated by spectroscopic data including 1D and 2D NMR. The pure compounds 1 – 11 were subjected to the pharmacological screening and compounds 2 , 5 – 7 and 9 exhibited potent urease inhibitory activity with IC₅₀ value of 25.8, 28.9, 30.1, 31.8 and 32.7 μm , respectively, whereas compound 1 showed moderate activity (IC₅₀ = 98.7 μm ). The potent urease inhibitory activity supplemented the previous literature reports and medicinal uses of this plant.     

Analysis of the main active ingredients and bioactivities of essential oil from <Emphasis Type="Italic">Osmanthus fragrans</Emphasis> Var. <Emphasis Type="Italic">thunbergii</Emphasis> using a complex network approach

Background

Osmanthus fragrans has been used as folk medicine for thousands of years. The extracts of Osmanthus fragrans flowers were reported to have various bioactivities including free radical scavenging, anti-inflammation, neuroprotection and antitumor effects. However, there is still lack of knowledge about its essential oil.

Methods

In this work, we analyzed the chemical composition of the essential oil from Osmanthus fragrans var. thunbergii by GC-MS. A complex network approach was applied to investigate the interrelationships between the ingredients, target proteins, and related pathways for the essential oil. Statistical characteristics of the networks were further studied to explore the main active ingredients and potential bioactivities of O. fragrans var. thunbergii essential oil.

Results

A total of 44 ingredients were selected from the chemical composition of O. fragrans var. thunbergii essential oil, and that 191 potential target proteins together with 70 pathways were collected for these compounds. An ingredient-target-pathway network was constructed based on these data and showed scale-free property as well as power-law degree distribution. Eugenol and geraniol were screened as main active ingredients with much higher degree values. Potential neuroprotective and anti-tumor effect of the essential oil were also found. A core subnetwork was extracted from the ingredient-target-pathway network, and indicated that eugenol and geraniol contributed most to the neuroprotection of this essential oil. Furthermore, a pathway-based protein association network was built and exhibited small-world property. MAPK1 and MAPK3 were considered as key proteins with highest scores of centrality indices, which might play an important role in the anti-tumor effect of the essential oil.

Conclusions

This work predicted the main active ingredients and bioactivities of O. fragrans var. thunbergii essential oil, which would benefit the development and utilization of Osmanthus fragrans flowers. The application of complex network theory was proved to be effective in bioactivities studies of essential oil. Moreover, it provides a novel strategy for exploring the molecular mechanisms of traditional medicines.

     

Long non-coding RNA H19 regulates E2F1 expression by competitively sponging endogenous miR-29a-3p in clear cell renal cell carcinoma

Background

Numerous recent studies indicate that the long non-coding RNAs (lncRNAs) are frequently abnormal expressed and take critical roles in many cancers. Renal cell carcinoma is the secondary malignant tumors in the urinary system and has high mortality and morbidity. Around 80% of RCCs is clear cell renal cell carcinoma (ccRCC) and is characterized by high metastasis and relapse rate. However, the clinical significances of lncRNAs in ccRCC are still unknown.

Methods

The human cancer lncRNA PCR array (Yingbio) was performed to detect the differentially expressed lncRNAs in human ccRCC samples. Real-time PCR (RT-PCR), dual-luciferase assay, RNA binding protein immunoprecipitation (RIP) assay, transwell assay, CCK-8 assay, and western blot were performed to explore the molecular mechanism of lncRNAs in ccRCC cell migration and invasion.

Results

In this study, lncRNA-H19 was high expressed and negatively correlated with miR-29a-3p in ccRCC. By bioinformatics software, dual-luciferase reporter and RIP assays, we verified that miR-29a-3p was identified as a direct target of lncRNA-H19. RT-PCR and western blot demonstrated that down-regulated lncRNA-H19 could affect the expression of miR-29a-3p targeting E2F1 with competitively binding miR-29a-3p. Furthermore, transwell assays indicated that lncRNA-H19 knockdown inhibited cells migration and invasion, but this effect was attenuated by co-transfection of lncRNA-H19 siRNA and miR-29a-3p inhibitor. Over expression of E2F1 could rescue lncRNA-H19 siRNA induced suppression on cell migration and invasion in ccRCC cells.

Conclusions

These results show a possible competing endogenous RNAs regulatory network involving lncRNA-H19 regulates E2F1 expression by competitively sponging endogenous miR-29a-3p in ccRCC. This mechanism may contribute to a better understanding of ccRCC pathogenesis, and lncRNA-H19 may be further considered as a potential therapeutic target for ccRCC intervention.

     

Loss of nucleoplasmic LAP2alpha-lamin A complexes causes erythroid and epidermal progenitor hyperproliferation

Lamina-associated polypeptide (LAP) 2alpha is a chromatin-associated protein that binds A-type lamins. Mutations in both LAP2alpha and A-type lamins are linked to human diseases called laminopathies, but the molecular mechanisms are poorly understood. The A-type lamin-LAP2alpha complex interacts with and regulates retinoblastoma protein (pRb), but the significance of this interaction in vivo is unknown. Here we address the function of the A-type lamin-LAP2alpha complex with the use of LAP2alpha-deficient mice. We show that LAP2alpha loss causes relocalization of nucleoplasmic A-type lamins to the nuclear envelope and impairs pRb function. This causes inefficient cell-cycle arrest in dense fibroblast cultures and hyperproliferation of epidermal and erythroid progenitor cells in vivo, leading to tissue hyperplasia. Our results support a disease-relevant model in which LAP2alpha defines A-type lamin localization in the nucleoplasm, which in turn affects pRb-mediated regulation of progenitor cell proliferation and differentiation in highly regenerative tissues.     

Protein tyrosine phosphatase SHP2 is involved in Semaphorin 4D-induced axon repulsion

Semaphorin-4D (Sema4D), a member of class 4 membrane-bound Semaphorins, acts as a chemorepellant to the axons of retinal ganglion cells and hippocampal neurons. Plexin-B1, a neuronal Sema4D receptor, associates with either one of receptor tyrosine kinases, c-Met or ErbB2, to mediate Sema4D-signaling. In contrast to this significance, the involvement of protein tyrosine phosphatases in Semaphorin-signaling remains unknown. We here show that Src homology 2-containing protein-tyrosine phosphatase 2 (SHP2) participates in Sema4D-signaling. SHP2 was localized in the growth cones of chick embryonic retinal ganglion neurons. Phenylarsine oxide, a protein tyrosine phosphatase inhibitor, suppressed Sema4D-induced contractile response in COS-7 cells expressing Plexin-B1. Ectopic expression of a phosphatase-inactive mutant of SHP2 in the retinal ganglion cells attenuated Sema4D-induced growth cone collapse response. A SHP1/2 specific inhibitor, 8-hydroxy-7-(6-sulfonaphthalen-2-yl)diazenyl-quinoline-5-sulfonic acid (NSC-87877), also suppressed this collapse response. These results suggest that SHP2-mediated tyrosine dephosphorylation is an important step in Sema4D-induced axon repulsion.