Expression profiling of planarians shed light on a dual role of programmed cell death during the regeneration.

Most animals hold the ability to regenerate damaged cells, tissues, and even any lost part of their bodies. To date, there is little known about the precise regulatory mechanism of regeneration and many fundamental questions remain unanswered. To further understand the precise regulatory mechanism of regeneration, we used planarian Dugesia japonica as a model and sequenced the transcriptomes of their regenerated tissues at different regeneration stages. Through de novo assembly and expression profiling, we found that Heat shock protein and MAPK pathway were involved into early response of regeneration in D. japonica. In addition, immune response, cell proliferation, and migration were activated during regeneration. Of notes, our results revealed a specific functional role of programmed cell death (PCD) in regeneration of D. japonica. PCD may not only remove the damaged and superfluous tissues for further patterning with regenerated tissues, but also provide signals to trigger neoblasts proliferation and differentiation directly. Together, our results revealed Heat shock protein and MAPK pathway mediated early response of regeneration and found a dual role of PCD in regeneration D. japonica. Meanwhile, we constructed regulatory networks of apoptosis, autophagy, and related signaling pathways and proposed a schematic model, which provided a global landscape of regeneration.

Inhibition of disheveled-2 resensitizes cisplatin-resistant lung cancer cells through down-regulating Wnt/ß-catenin signaling.

Cisplatin (CDDP) is currently recommended as the front-line chemotherapeutic agent for lung cancer. However, the resistance to cisplatin is widespread in patients with advanced lung cancer, and the molecular mechanism of such resistance remains incompletely understood. Disheveled (DVL), a key mediator of Wnt/ß-catenin, has been linked to cancer progression, while the role of DVL in cancer drug resistance is not clear. Here, we found that DVL2 was over-expressed in cisplatin-resistant human lung cancer cells A549/CDDP compared to the parental A549 cells. Inhibition of DVL2 by its inhibitor (3289-8625) or shDVL2 resensitized A549/CDDP cells to cisplatin. In addition, over-expression of DVL2 in A549 cells increased the protein levels of BCRP, MRP4, and Survivin, which are known to be associated with chemoresistance, while inhibition of DVL2 in A549/CDDP cells decreased these protein levels, and reduced the accumulation and nuclear translocation of ß-catenin. In addition, shß-catenin abolished the DVL2-induced the expression of BCRP, MRP4, and Survivin. Furthermore, our data showed that GSK3ß/ß-catenin signals were aberrantly activated by DVL2, and inactivation of GSK3ß reversed the shDVL2-induced down-regulation of ß-catenin. Taken together, these results suggested that inhibition of DVL2 can sensitize cisplatin-resistant lung cancer cells through down-regulating Wnt/ß-catenin signaling and inhibiting BCRP, MRP4, and Survivin expression. It promises a new strategy to chemosensitize cisplatin-induced cytotoxicity in lung cancer.

Inhibition of ferroptosis through regulating neuronal calcium homeostasis: An emerging therapeutic target for Alzheimer's disease.

Alzheimer's disease (AD), a chronic and progressive neurodegenerative disease, generates a serious threat to the health of the elderly. The AD brain is microscopically characterized by amyloid plaques and neurofibrillary tangles. There are still no effective therapeutic drugs to restrain the progression of AD though much attention has been paid to exploit AD treatments. Ferroptosis, a type of programmed cell death, has been reported to promote the pathological occurrence and development of AD, and inhibition of neuronal ferroptosis can effectively improve the cognitive impairment of AD. Studies have shown that calcium (Ca2+) dyshomeostasis is closely related to the pathology of AD, and can drive the occurrence of ferroptosis through several pathways, such as interacting with iron, and regulating the crosstalk between endoplasmic reticulum (ER) and mitochondria. This paper mainly reviews the roles of ferroptosis and Ca2+ in the pathology of AD, and highlights that restraining ferroptosis through maintaining the homeostasis of Ca2+ may be an innovative target for the treatment of AD.

Molecular evidence for the subspecific differentiation of blue sheep (Pseudois nayaur) and polyphyletic origin of dwarf blue sheep (Pseudois schaeferi).

Blue sheep (Pseudois nayaur), a Central Asian ungulate with restricted geographic distribution, exhibits unclear variation in morphology and phylogeographic structure. The composition of species and subspecies in the genus Pseudois is controversial, particularly with respect to the taxonomic designation of geographically restricted populations. Here, 26 specimens including 5 dwarf blue sheep (Pseudois schaeferi), which were collected from a broad geographic region in China, were analyzed for 2 mitochondrial DNA fragments (cytochrome b and control region sequences). In a pattern consistent with geographically defined subspecies, we found three deeply divergent mitochondrial lineages restricted to different geographic regions. The currently designated two subspecies of blue sheep, Pseudois nayaur nayaur and Pseudois nayaur szechuanensis, were recognized in the phylogenetic trees. In addition, the Helan Mountain population showed distinct genetic characteristics from other geographic populations, and thus should be classified as a new subspecies. In contrast, dwarf blue sheep clustered closely with some blue sheep from Sichuan Province in the phylogenetic trees. Therefore, dwarf blue sheep appear to be a subset of Pseudois nayaur szechuanensis. After considering both population genetic information and molecular clock analysis, we obtained some relevant molecular phylogeographic information concerning the historical biogeography of blue sheep. These results also indicate that western Sichuan was a potential refugium for blue sheep during the Quaternary period.

Screening of Key Fungal Strains in the Fermentation Process of the Chinese Medicinal Preparation "Lianzhifan Solution" Based on Metabolic Profiling and High-Throughput Sequencing Technology.

"Lianzhifan solution" (LZF) is produced by the natural fermentation of coptis root and gardenia fruit, and it is a classic prescription for external use in anorectal department. During the fermentation process, the structural evolution of microbial communities led to significant changes in the chemical profile. In this study, we first analyzed the dynamic changes of chemical components as well as the composition and succession of microbial community during the whole fermentation process of LZF, and confirmed the changes of characteristics of nine compounds during the whole fermentation process by metabolic profile. Further analysis found that there was no significant change of alkaloids in all stages of fermentation of LZF, but there were significant changes of iridoids in the middle and late stage of fermentation by deglycosylation. Genipin gentiobioside and geniposide were converted to genipin by biotransformation, showing that deglycosylation was the main event occurring in the fermentation. The community composition and abundance of species in 10 and 19days LZF fermentation broth were analyzed with high-throughput sequencing technology, and 16 dominant bacterial genera and 15 dominant fungal genera involved in the fermentation process were identified. Correlation analysis revealed that Penicillium expansum and Aspergillus niger involved in the fermentation were the dominant genera closely related to the dynamic changes of the deglycosylation of the main chemical components, and P. expansum YY-46 and A. niger YY-9 strains were obtained by the further fractionation. Then the monoculture fermentation process was evaluated, whereby we found that the deglycoside conversion rate of iridoid glycosides was greatly improved and the fermentation cycle was shortened by 3-4 times. This finding combined with equivalence evaluation of chemical component and pharmacodynamics to confirm that P. expansum YY-46 and A. niger YY-9 strains were key strains for fermentation concoction. This study established an efficient and practical screening strategy "Microfauna communities-Chemical component-Pharmacodynamic" axis for key strain, to improve the production process and formulating good manufacturing practice (GMP) work, and it is also applicable to the whole fermentation drugs industry. Graphical AbstractThe figure highly summarizes the research content of this study and shows the screening process of key strains in LZF fermentation.

Correction: Dishevelled1-3 contribute to multidrug resistance in colorectal cancer via activating Wnt/ß-catenin signaling.

[This corrects the article DOI: 10.18632/oncotarget.23253.].

Molecular phylogeny and phylogeography of genus Pseudois (Bovidae, Cetartiodactyla): New insights into the contrasting phylogeographic structure.

Blue sheep, Pseudois nayaur, is endemic to the Tibetan Plateau and the surrounding mountains, which are the highest-elevation areas in the world. Classical morphological taxonomy suggests that there are two subspecies in genus Pseudois (Bovidae, Artiodactyla), namely Pseudois nayaur nayaur and Pseudois nayaur szechuanensis. However, the validity and geographic characteristics of these subspecies have never been carefully discussed and analyzed. This may be partially because previous studies have mainly focused on the vague taxonomic status of Pseudois schaeferi (dwarf blue sheep). Thus, there is an urgent need to investigate the evolutionary relationship and taxonomy system of this genus. This study enriches a previous dataset by providing a large number of new samples, based on a total of 225 samples covering almost the entire distribution of blue sheep. Molecular data from cytochrome b and the mitochondrial control region sequences were used to reconstruct the phylogeny of this species. The phylogenetic inferences show that vicariance plays an important role in diversification within this genus. In terms of molecular dating results and biogeographic analyses, the striking biogeographic pattern coincides significantly with major geophysical events. Although the results raise doubt about the present recognized distribution range of blue sheep, they have corroborated the validity of the identified subspecies in genus Pseudois. Meanwhile, these results demonstrate that the two geographically distinct populations, the Helan Mountains and Pamir Plateau populations, have been significantly differentiated from the identified subspecies, a finding that challenges the conventional taxonomy of blue sheep.

Dishevelled1-3 contribute to multidrug resistance in colorectal cancer via activating Wnt/ß-catenin signaling.

Multidrug resistance is a great obstacle in successful chemotherapy of colorectal cancer. However, the molecular mechanism underlying multidrug resistance is not fully understood. Dishevelled, a pivot in Wnt signaling, has been linked to cancer progression, while its role in chemoresistance remains unclear. Here, we found that Dishevelled1-3 was over-expressed in multidrug-resistant colorectal cancer cells (HCT-8/VCR) compared to their parental cells. Silencing Dishevelled1-3 resensitized HCT-8/VCR cells to multiple drugs including vincristine, 5-fluorouracil and oxaliplatin. Moreover, Dishevelled1-3 increased the protein levels of multidrug resistance protein 1 (P-gp/MDR1), multidrug resistance-associated protein 2 (MRP2), and breast cancer resistance protein (BCRP), Survivin and Bcl-2 which are correlated with multidrug resistance. shß-catenin abolished Dishevelled-mediated these protein expressions. Unexpectedly, none of Dishevelled1-3 controlled ß-catenin accumulation and nuclear translocation. Furthermore, the nuclear translocations of Dishevelled1-3 were promoted in HCT-8/VCR cells compared to HCT-8. Dishevelled1-3 bound to ß-catenin in nucleus, and promoted nuclear complex formation and transcription activity of ß-catenin/TCF. Taken together, Dishevelled1-3 contributed to multidrug resistance in colorectal cancer via activating Wnt/ß-catenin signaling and inducing the expressions of P-gp, MRP2, BCRP, Survivin and Bcl-2, independently of ß-catenin accumulation and nuclear translocation. Silencing Dishevelled1-3 resensitized multidrug-resistant colorectal cancer cells, providing a novel therapeutic target for successful chemotherapy of colorectal cancer.

Complete mitochondrial genome of Himalayan buzzard (Buteo buteo burmanicus).

In this study, the complete sequence of the mitochondrial (mt) genome of Buteo buteo burmanicus was determined. This mitogenome was 18,231 bp in length, containing 13 protein-coding genes, 2 rRNA genes, 22 tRNA genes, a control region (CR) and a pseudo-control region (ψCR). The overall base composition of the heavy strand was A, 30.8%; G, 13.2%; C, 31.8%; and T, 24.2%, with a slight AT bias of 65.1%. The complete mitogenomic data may provide more informative for phylogenetic approach for soft corals phylogeny especially for Buteo species.

The complete mitochondrial genome of leopard cat, Prionailurus bengalensis chinensis (Carnivora:Felidae).

The full-length of the mitochondrial (mt) genome of Prionailurus bengalensis chinensis was first determined in this study and consisted of a 16,990 bp fragment, including 13 protein-coding genes, two rRNA genes, 22 tRNA genes, a control region (CR), and an origin of L-strand replication (OLR). The total base composition of the heavy strand was A, 33.0%; G, 13.6%; C, 26.0%; and T, 27.4%, with a slight AT bias of 60.4%. The complete mitogenomic data of P. b. chinensis may provide an important data set for further phylogenetic and taxonomic analyses of Genus Prionailurus species.

Phylogenetic and molecular dating analysis of Taiwan Blue Pheasant (Lophura swinhoii).

The Swinhoe's Pheasant (Lophura swinhoii) is an endemic and most endangered species to Taiwan, China. It belongs to the genus Lophura, family Phasianidae. To further investigate the evolutionary history of L. swinhoii, we determined its complete mitochondrial genome and reconstructed a single, robust phylogenetic tree. Our results showed that L. swinhoii is clustered with Lophura nycthemera and forms a sister group of Lophura ignita. The genus Lophura is strongly supported as the sister taxon of the genus Crossoptilon. The molecular clock analysis showed that the genetic divergence of L. swinhoii occurred in 2.71 (1.31-4.22) Mya. The most common ancestor of L. swinhoii might have migrated from mainland of South East Asia to Taiwan Island by the land bridge at 2.71 Mya ago. Taiwan Island is separated from the mainland by the sea (Taiwan Strait) and formed a separate island at around 2.5 Mya because of the transgression and regression. Therefore, geographical isolation and climate change may accelerate the evolution of L. swinhoii. In this study, we propose a biogeographic hypothesis for speciation of the L. swinhoii based on known events of the geographic and geological history of South East Asia and southeast China, which would benefit the understanding of evolutionary history of L. swinhoii as well as other galliform birds.

The complete mitochondrial genome sequence analysis of Tibetan argali (Ovis ammon hodgsoni): implications of Tibetan argali and Gansu argali as the same subspecies.

The genus Ovis (Bovidae, Artiodactyla) includes six species, i.e. Ovis ammon, Ovis aries, Ovis canadensis, Ovis dalli, Ovis nivicola and Ovis vignei. Based on morphology, geographical location, habitat, etc., the species O. ammon is divided into nine subspecies. The near threatened Tibetan argali is distributed across the Tibetan Plateau and its peripheral mountains, and believed to be one of the O. ammon subspecies (O. a. hodgsoni). However, considering its morphological features and distributions, a question has been proposed by some researchers about the subspecies status of Tibetan argali. In this study, we employed complete mitochondrial DNA (mtDNA) to explore the phylogenetic relationship and population genetic structure of Tibetan argali. The results revealed that the nucleotide composition, gene arrangement and codon usage pattern of the mitochondrial genome of Tibetan argali are similar to those of other caprines. Phylogenetic analyses showed that Tibetan argali was clustered with O. ammon. Interestingly, five Tibetan argali individuals and one of the three Gansu argali (O. a. dalailamae) individuals were clustered in the same branch, which is a sister group to other two Gansu argali individuals. Together with morphological characteristics, our results suggested that Tibetan argali and Gansu argali may belong to the same subspecies (O. a. hodgsoni) of O. ammon, rather than two different subspecies.

Mitogenomic analysis of the genus Pseudois: evidence of adaptive evolution of morphological variation in the ATP synthase genes.

The genus Pseudois includes two variable taxa, blue sheep (Pseudois nayaur) and dwarf blue sheep (Pseudois schaeferi), that exhibit notable geographic variation in morphology and ecological niche, suggesting the potential for significant adaptive differentiation between these two goats. Blue sheep are broadly distributed in the Tibetan Plateau and peripheral mountains through Central Asia, while dwarf blue sheep are only found in the gorges of the upper Yangtze River (Jinsha River) near Batang county, Sichuan province and adjacent mountains. Although they are all adapted to high altitude environments, endangered dwarf blue sheep show unique morphological variation and niche shifts compared to blue sheep. Mitochondria play important roles in oxygen usage and energy metabolism. The energetically demanding lifestyles of these high altitude species may have altered the selective regimes on mitochondrial genes encoding proteins related to cellular respiration. Here, we compared the sequences of 13 protein-coding genes in the mitochondrial genome of dwarf blue sheep with those of blue sheep to understand the genetic basis of morphological variation. Using neighbor-joining, maximum-likelihood and Bayesian approaches, we estimated rates of synonymous (d(S)) and nonsynonymous (d(N)) substitutions. Independent analyses showed that no ω ratio was larger than 1, suggesting that all mitochondrial 13 genes were under the purifying selection. Surprisingly, we found that the ω ratio (d(N)/d(S)) of the ATP synthase complex (ATP6 and ATP8) in blue sheep is sixteen times that of dwarf blue sheep (0.340 compared to 0.021). This result was confirmed by a separate analysis of ATP synthase genes from two additional P. schaeferi individuals and two P. nayaur individuals. We hypothesize that the large body size and diverse feeding styles are factors influencing the nonsynonymous substitutions in the ATP synthase complex of blue sheep.