Many approaches to cancer management are often ineffective due to adverse reactions, drug resistance, or inadequate target specificity of single anti-cancer agents. In contrast, a combinatorial ...approach with the application of two or more anti-cancer agents at their respective effective dosages can achieve a synergistic effect that boosts cytotoxicity to cancer cells. In cancer, aberrant apoptotic pathways allow cells that should be killed to survive with genetic abnormalities, leading to cancer progression. Mutations in apoptotic mechanism arising during the treatment of cancer through cancer progression can consequently lead to chemoresistance. Natural compound mixtures that are believed to have multiple specific targets with minimal acceptable side-effects are now of interest to many researchers due to their cytotoxic and chemosensitizing activities. Synergistic interactions within a drug mixture enhance the search for potential molecular targets in cancer cells. Nonetheless, biased/flawed scientific evidence from natural products can suggest false positive therapeutic benefits during drug screening. In this review, we have taken these factors into consideration when discussing the evidence for these compounds and their synergistic therapeutic benefits in cancer. While there is limited evidence for clinical efficacy for these mixtures, in vitro data suggest that these preparations merit further investigation, both in vitro and in vivo.
In this work, polycrystalline-like lattice structures that are inspired by the geometry of polycrystalline materials are designed. They are generated by filling periodic lattice structures into a ...Voronoi diagram. Then, finite element analyses of two periodic and eight polycrystalline-like lattice structures are performed to compare their mechanical properties. The numerical results show that polycrystalline-like lattice structures consisting of anisotropic rectangular X-type periodic unit cells are isotropic at the macroscale. Moreover, they have a higher specific stiffness and specific strength than periodic lattice structures under compression. Then, the energy absorption capability is investigated. Five energy absorption indicators (energy absorption, energy absorption per unit volume, specific energy absorption per unit mass, crush stress efficiency, and plateau stress) reveal that polycrystalline-like lattice structures are better energy absorption structures. Furthermore, the defect sensitivity of missing struts is discussed. The findings of this work offer a new route for designing novel lattice structures.
Long noncoding RNAs (lncRNAs) are emerging as important regulators in plant development, but few of them have been functionally characterized in fruit ripening. Here, we have identified 25,613 ...lncRNAs from strawberry ripening fruits based on RNA-seq data from poly(A)-depleted libraries and rRNA-depleted libraries, most of which exhibited distinct temporal expression patterns. A novel lncRNA, FRILAIR harbours the miR397 binding site that is highly conserved in diverse strawberry species. FRILAIR overexpression promoted fruit maturation in the Falandi strawberry, which was consistent with the finding from knocking down miR397, which can guide the mRNA cleavage of both FRILAIR and LAC11a (encoding a putative laccase-11-like protein). Moreover, LAC11a mRNA levels were increased in both FRILAIR overexpressing and miR397 knockdown fruits, and accelerated fruit maturation was also found in LAC11a overexpressing fruits. Overall, our study demonstrates that FRILAIR can act as a noncanonical target mimic of miR397 to modulate the expression of LAC11a in the strawberry fruit ripening process.
Summary
Noncoding RNAs have been extensively described in plant and animal transcriptomes by using high‐throughput sequencing technology. Of these noncoding RNAs, a growing number of long intergenic ...noncoding RNAs (lincRNAs) have been described in multicellular organisms, however the origins and functions of many lincRNAs remain to be explored. In many eukaryotic genomes, transposable elements (TEs) are widely distributed and often account for large fractions of plant and animal genomes yet the contribution of TEs to lincRNAs is largely unknown. By using strand‐specific RNA‐sequencing, we profiled the expression patterns of lincRNAs in Arabidopsis, rice and maize, and identified 47 611 and 398 TE‐associated lincRNAs (TE‐lincRNAs), respectively. TE‐lincRNAs were more often derived from retrotransposons than DNA transposons and as retrotransposon copy number in both rice and maize genomes so did TE‐lincRNAs. We validated the expression of these TE‐lincRNAs by strand‐specific RT‐PCR and also demonstrated tissue‐specific transcription and stress‐induced TE‐lincRNAs either after salt, abscisic acid (ABA) or cold treatments. For Arabidopsis TE‐lincRNA11195, mutants had reduced sensitivity to ABA as demonstrated by longer roots and higher shoot biomass when compared to wild‐type. Finally, by altering the chromatin state in the Arabidopsis chromatin remodelling mutant ddm1, unique lincRNAs including TE‐lincRNAs were generated from the preceding untranscribed regions and interestingly inherited in a wild‐type background in subsequent generations. Our findings not only demonstrate that TE‐associated lincRNAs play important roles in plant abiotic stress responses but lincRNAs and TE‐lincRNAs might act as an adaptive reservoir in eukaryotes.
Significance Statement
Noncoding RNAs have been extensively described, but the origins and functions of many long intergenic noncoding RNAs (lincRNAs) remain to be explored. Here we describe hundreds of transposable element‐associated lincRNAs (TE‐lincRNAs) in rice, maize and Arabidopsis and demonstrate their tissue‐specific transcription. By perturbing chromatin structure, we show that novel TE‐lincRNAs are transcribed and inherited across generations, suggesting that lincRNAs might act as an adaptive reservoir in eukaryotes; indeed we show that loss of function of a TE‐lincRNA attenuates abiotic stress tolerance.
Elephantids are the world’s most iconic megafaunal family, yet there is no comprehensive genomic assessment of their relationships. We report a total of 14 genomes, including 2 from the American ...mastodon, which is an extinct elephantid relative, and 12 spanning all three extant and three extinct elephantid species including an ∼120,000-y-old straight-tusked elephant, a Columbian mammoth, and woolly mammoths. Earlier genetic studies modeled elephantid evolution via simple bifurcating trees, but here we show that interspecies hybridization has been a recurrent feature of elephantid evolution. We found that the genetic makeup of the straight-tusked elephant, previously placed as a sister group to African forest elephants based on lower coverage data, in fact comprises three major components. Most of the straight-tusked elephant’s ancestry derives from a lineage related to the ancestor of African elephants while its remaining ancestry consists of a large contribution from a lineage related to forest elephants and another related to mammoths. Columbian and woolly mammoths also showed evidence of interbreeding, likely following a latitudinal cline across North America. While hybridization events have shaped elephantid history in profound ways, isolation also appears to have played an important role. Our data reveal nearly complete isolation between the ancestors of the African forest and savanna elephants for ∼500,000 y, providing compelling justification for the conservation of forest and savanna elephants as separate species.
Soybean is the world's most important cultivated crop, and drought can affect their growth and, eventually, yields. Foliar application of mepiquat chloride (MC) can potentially alleviate the damage ...caused by drought stress in plants; however, the mechanism of MC regulation of soybean drought response has not been studied.
This study investigated the mechanism of soybean drought response regulation by mepiquat chloride in two varieties of soybean, sensitive Heinong 65 (HN65) and drought-tolerant Heinong44 (HN44), under three treatment scenarios, normal, drought stress, and drought stress + MC conditions.
MC promoted dry matter accumulation under drought stress, reduced plant height, decreased antioxidant enzyme activity, and significantly decreased malondialdehyde content. The light capture processes, photosystems I and II, were inhibited; however, accumulation and upregulation of several amino acids and flavonoids by MC was observed. Multi-omics joint analysis indicated 2-oxocarboxylic acid metabolism and isoflavone biosynthetic pathways to be the core pathways by which MC regulated soybean drought response. Candidate genes such as
, and
were identified to be crucial for the drought resistance of soybeans. Finally, a model was constructed to systematically describe the regulatory mechanism of MC application in soybean under drought stress. This study fills the research gap of MC in the field of soybean resistance.
In this report we examine candidate pathways perturbed by Compound Kushen Injection (CKI), a Traditional Chinese Medicine (TCM) that we have previously shown to alter the gene expression patterns of ...multiple pathways and induce apoptosis in cancer cells.
We have measured protein levels in Hep G2 and MDA-MB-231 cells for genes in the cell cycle pathway, DNA repair pathway and DNA double strand breaks (DSBs) previously shown to have altered expression by CKI. We have also examined energy metabolism by measuring ADP/ATP ratio (cell energy charge), lactate production and glucose consumption. Our results demonstrate that CKI can suppress protein levels for cell cycle regulatory proteins and DNA repair while increasing the level of DSBs. We also show that energy metabolism is reduced based on reduced glucose consumption and reduced cellular energy charge.
Our results validate these pathways as important targets for CKI. We also examined the effect of the major alkaloid component of CKI, oxymatrine and determined that it had no effect on DSBs, a small effect on the cell cycle and increased the cell energy charge.
Our results indicate that CKI likely acts through the effect of multiple compounds on multiple targets where the observed phenotype is the integration of these effects and synergistic interactions.
In addition to responding to environmental entrainment with diurnal variation, metabolism is also tightly controlled by cell-autonomous circadian clock. Extensive studies have revealed key roles of ...transcription in circadian control. Post-transcriptional regulation for the rhythmic gating of metabolic enzymes remains elusive. Here, we show that arginine biosynthesis and subsequent ureagenesis are collectively regulated by CLOCK (circadian locomotor output cycles kaput) in circadian rhythms. Facilitated by BMAL1 (brain and muscle Arnt-like protein), CLOCK directly acetylates K165 and K176 of argininosuccinate synthase (ASS1) to inactivate ASS1, which catalyzes the rate-limiting step of arginine biosynthesis. ASS1 acetylation by CLOCK exhibits circadian oscillation in human cells and mouse liver, possibly caused by rhythmic interaction between CLOCK and ASS1, leading to the circadian regulation of ASS1 and ureagenesis. Furthermore, we also identified NADH dehydrogenase ubiquinone 1 alpha subcomplex subunit 9 (NDUFA9) and inosine-5′-monophosphate dehydrogenase 2 (IMPDH2) as acetylation substrates of CLOCK. Taken together, CLOCK modulates metabolic rhythmicity by acting as a rhythmic acetyl-transferase for metabolic enzymes.
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•CLOCK acetylates metabolic enzymes to modulate their activity•CLOCK drives the cycle of acetylation and activation of metabolic enzymes•Interaction between CLOCK and metabolic enzymes is rhythmic•Arginine biogenesis and ureagenesis are rhythmically controlled by ASS1 acetylation
Lin et al. reported that CLOCK acetylates ASS1 to inactivate its function in arginine biosynthesis. ASS1 acetylation by CLOCK exhibits rhythmicity, possibly caused by rhythmic interaction between CLOCK and ASS1, leading to the cycle of ASS1 activation. Two more enzymes, NDUFA9 and IMPDH2, were recognized as acetylation substrates of CLOCK.
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