The Effect of TCM-Induced HAMP on Key Enzymes in the Hydrolysis of AD Model Cells

Neurochemical Research - Alzheimer’s disease (AD) process is characterized classically by two hallmark pathologies: β-amyloid (Aβ) plaque deposition and neurofibrillary tangles of...     

DIA-Based Proteomics Identifies IDH2 as a Targetable Regulator of Acquired Drug Resistance in Chronic Myeloid Leukemia

Drug resistance is a critical obstacle to effective treatment in patients with chronic myeloid leukemia. To understand the underlying resistance mechanisms in response to imatinib mesylate (IMA) and adriamycin (ADR), the parental K562 cells were treated with low doses of IMA or ADR for 2 months to generate derivative cells with mild, intermediate, and severe resistance to the drugs as defined by their increasing resistance index. PulseDIA-based (DIA [data-independent acquisition]) quantitative proteomics was then employed to reveal the proteome changes in these resistant cells. In total, 7082 proteins from 98,232 peptides were identified and quantified from the dataset using four DIA software tools including OpenSWATH, Spectronaut, DIA-NN, and EncyclopeDIA. Sirtuin signaling pathway was found to be significantly enriched in both ADR-resistant and IMA-resistant K562 cells. In particular, isocitrate dehydrogenase (NADP(+)) 2 was identified as a potential drug target correlated with the drug resistance phenotype, and its inhibition by the antagonist AGI-6780 reversed the acquired resistance in K562 cells to either ADR or IMA. Together, our study has implicated isocitrate dehydrogenase (NADP(+)) 2 as a potential target that can be therapeutically leveraged to alleviate the drug resistance in K562 cells when treated with IMA and ADR.     

Profiling Murine Tau with 0N, 1N and 2N Isoform-Specific Antibodies in Brain and Peripheral Organs Reveals Distinct Subcellular Localization,with the 1N Isoform Being Enriched in the Nucleus

In the adult murine brain, the microtubule-associated protein tau exists as three major isoforms, which have four microtubule-binding repeats (4R), with either no (0N), one (1N) or two (2N) amino-terminal inserts. The human brain expresses three additional isoforms with three microtubule-binding repeats (3R) each. However, little is known about the role of the amino-terminal inserts and how the 0N, 1N and 2N tau species differ. In order to investigate this, we generated a series of isoform-specific antibodies and performed a profiling by Western blotting and immunohistochemical analyses using wild-type mice in three age groups: two months, two weeks and postnatal day 0 (P0). This revealed that the brain is the only organ to express tau at significant levels, with 0N4R being the predominant isoform in the two month-old adult. Subcellular fractionation of the brain showed that the 1N isoform is over-represented in the soluble nuclear fraction. This is in agreement with the immunohistochemical analysis as the 1N isoform strongly localizes to the neuronal nucleus, although it is also found in cell bodies and dendrites, but not axons. The 0N isoform is mainly found in cell bodies and axons, whereas nuclei and dendrites are only slightly stained with the 0N antibody. The 2N isoform is highly expressed in axons and in cell bodies, with a detectable expression in dendrites and a very slight expression in nuclei. The 2N isoform that was undetectable at P0, in adult brain was mainly found localized to cell bodies and dendrites. Together these findings reveal significant differences between the three murine tau isoforms that are likely to reflect different neuronal functions.     

Balancing crosstalk between 20-hydroxyecdysone-induced autophagy and caspase activity in the fat body during Drosophila larval-prepupal transition

In the fruitfly, Drosophila melanogaster, autophagy and caspase activity function in parallel in the salivary gland during metamorphosis and in a common regulatory hierarchy during oogenesis. Both autophagy and caspase activity progressively increase in the remodeling fat body, and they are induced by a pulse of the molting hormone (20-hydroxyecdysone, 20E) during the larval-prepupal transition. Inhibition of autophagy and/or caspase activity in the remodeling fat body results in 25–40% pupal lethality, depending on the genotypes. Interestingly, a balancing crosstalk occurs between autophagy and caspase activity in this tissue: the inhibition of autophagy induces caspase activity and the inhibition of caspases induces autophagy. The Drosophila remodeling fat body provides an in vivo model for understanding the molecular mechanism of the balancing crosstalk between autophagy and caspase activity, which oppose with each other and are induced by the common stimulus 20E, and blockage of either path reinforces the other path.     

Mitogenomes provide new insights into the evolutionary history of Prodiamesinae (Diptera: Chironomidae)

Evolutionary analysis of Prodiamesinae has long been impeded by lack of information, and its phylogenetic relationship with Orthocladiinae remains questionable. Here, ten complete mitochondrial genomes (mitogenomes) of Orthocladiinae sensu lato were newly sequenced, including three Prodiamesinae species and seven Orthocladiinae species. Coupled with published mitogenomes, a total of 12 mitogenomes of Orthocladiinae sensu lato were selected for a comparative mitogenomic analysis and phylogenetic reconstruction. Mitogenomes of Orthocladiinae sensu lato are conserved in structure, and all genes arrange the same gene order as the ancestral insect mitogenome. Nucleotide composition is highly biased, and the control region displayed the highest A + T content. All protein-coding genes are under purifying selection, and the ATP8 evolves at the fastest rate. In addition, the mitogenomes of Orthocladiinae sensu lato are highly conserved, and they are practically useful for phylogenetic inference, suggesting a re-classification of Orthocladiinae by sinking Prodiamesinae as a subgroup of Orthocladiinae.     

Genome Sequence of the Aerobic Bacterium Bacillus sp. Strain FJAT-13831

Bacillus sp. strain FJAT-13831 was isolated from the no. 1 pit soil of Emperor Qin''s Terracotta Warriors in Xi''an City, People''s Republic of China. The isolate showed a close relationship to the Bacillus cereus group. The draft genome sequence of Bacillus sp. FJAT-13831 was 4,425,198 bp in size and consisted of 5,567 genes (protein-coding sequences [CDS]) with an average length of 782 bp and a G+C value of 36.36%.     

Synthesis,Biological Evaluation,and Docking Study of Ring-Opening Amide Analogs of Matrine as Antitumor Agents

In this article, we designed and synthesized two series of matrine analogs with ring-opening in the lactam portion of the molecule. Our in vitro cytotoxicity study showed that analog N-(3-bromophenyl)-4-[(1R,3aS,10aR,10bS)-decahydro-1H,4H-pyrido[3,2,1-ij][1,6]naphthyridin-1-yl]butanamide ( B11 ) with a meta-bromide on the phenyl ring displayed the best antiproliferative activity. Moreover, B11 induced cell cycle arrest in G1 phase and cell apoptosis in a dose-dependent manner in A549 cells. Molecular modeling revealed that B11 achieved a higher docking score compared to its precursor tert-butyl (1R,3aS,10aR,10bS)-1-[4-(3-bromoanilino)-4-oxobutyl]octahydro-1H,4H-pyrido[3,2,1-ij][1,6]naphthyridine-2(3H)-carboxylate ( A11 , an analog of B11 with a Boc group) and parent compound matrine, possibly because B11 formed a hydrogen bond with SER91 and a halogen bond with GLN320 on the binding site of annexin A2. Overall, we discovered the potential anticancer lead compound B11 , which can be used for further study both in vitro and in vivo.     

Comparative phylogeography of two co‐distributed but ecologically distinct rainbowfishes of far‐northern Australia

Aim

To test the influence of historical and contemporary environment in shaping the genetic diversity of freshwater fauna we contrast genetic structure in two co‐distributed, but ecologically distinct, rainbowfish; a habitat generalist (Melanotaenia splendida) and a habitat specialist (M. trifasciata).

Location

Fishes were sampled from far northern Australia (Queensland and Northern Territory).

Methods

We used sequence data from one mitochondrial gene and one nuclear gene to investigate patterns of genetic diversity in M. splendida and M. trifasciata to determine how differences in habitat preference and historical changes in drainage boundaries affected patterns of connectivity.

Results

Melanotaenia splendida showed high levels of genetic diversity and little population structure across its range. In contrast, M. trifasciata showed high levels of population structure. Whereas phylogeographic patterns differed, both species showed a strong relationship between geographical distance and genetic differentiation between populations. Melanotaenia splendida showed a shallower relationship with geographical distance, and genetic differentiation was best explained by stream length and a lower scaled ocean distance (11.98 times coast length). For M. trifasciata, genetic differentiation was best explained by overwater distance between catchments and ocean distance scaled at 1.16 × 10⁶ times coast length.

Main conclusions

Connectivity of freshwater populations inhabiting regions periodically interconnected during glacial periods appears to have been affected by ecological differences between species. Species‐specific differences are epitomized here by the contrast between co‐distributed congeners with different habitat requirements: for the habitat generalist, M. splendida, there was evidence for greater historical genetic connectivity with oceans as a weaker barrier to gene exchange in contrast with the habitat specialist, M. trifasciata.