lncRNA-Gm5532 regulates osteoclast differentiation through the miR-125a-3p/TRAF6 axis.

Long noncoding RNAs (lncRNAs) are important regulators of bone metabolism. In this study, lncRNA microarray analysis was used to identify differentially expressed lncRNAs in differentiated osteoclasts. lncRNA-Gm5532 is highly expressed during osteoclast differentiation. lncRNA-Gm5532 knockdown impairs osteoclast formation and bone resorption. Mechanistic experiments show that lncRNA-Gm5532 functions as a competing endogenous RNA (ceRNA) and acts as a sponge for miR-125a-3p, which promotes TNF receptor-associated factor 6 (TRAF6) expression. miR-125a-3p mimics suppress osteoclast differentiation and TAK1/NF-κB/MAPK signaling. The miR-125a-3p inhibitor reverses the negative effects of siGm5532 on osteoclast differentiation. In summary, our study reveals that lncRNA-Gm5532 functions as an activator in osteoclast differentiation by targeting the miR-125a-3p/TRAF6 axis, making it a novel biomarker and potential therapeutic target for osteoporosis.

Artesunate inhibits osteoclast differentiation by inducing ferroptosis and prevents iron overload-induced bone loss.

Artemisinin compounds have been demonstrated to have anti-osteoporosis effects by inhibiting bone resorption. During osteoclast differentiation, osteoclasts take up a large amount of iron through transferrin receptor 1 (TfR1) mediated endocytosis of transferrin (Tf). Since iron-dependent cleavage of endoperoxide bridge is of great importance for the antimalarial effects of artemisinin compounds, we raised a hypothesis that the cytotoxic effects of artemisinin compounds on osteoclasts were associated with enhanced iron uptake. In the present study, we found that Tf aggravated the inhibitory effects of artesunate (ART) on osteoclast viability and differentiation. ART induced the production of malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) in a dose-dependent manner and led to the appearance of mitochondrial features of ferroptotic cells. TfR1 knockdown alleviated these cytotoxic effects of ART on osteoclasts. In addition, ART effectively prevented bone loss induced by iron overload. Our results indicate that ART inhibits iron-uptake stimulated osteoclast differentiation by inducing ferroptosis. Artemisinin compounds are potential drugs for treating iron overload-induced osteoporosis.

Nrf2 Is a Potential Modulator for Orchestrating Iron Homeostasis and Redox Balance in Cancer Cells.

Iron is an essential trace mineral element in almost all living cells and organisms. However, cellular iron metabolism pathways are disturbed in most cancer cell types. Cancer cells have a high demand of iron. To maintain rapid growth and proliferation, cancer cells absorb large amounts of iron by altering expression of iron metabolism related proteins. However, iron can catalyze the production of reactive oxygen species (ROS) through Fenton reaction. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is an important player in the resistance to oxidative damage by inducing the transcription of antioxidant genes. Aberrant activation of Nrf2 is observed in most cancer cell types. It has been revealed that the over-activation of Nrf2 promotes cell proliferation, suppresses cell apoptosis, enhances the self-renewal capability of cancer stem cells, and even increases the chemoresistance and radioresistance of cancer cells. Recently, several genes involving cellular iron homeostasis are identified under the control of Nrf2. Since cancer cells require amounts of iron and Nrf2 plays pivotal roles in oxidative defense and iron metabolism, it is highly probable that Nrf2 is a potential modulator orchestrating iron homeostasis and redox balance in cancer cells. In this hypothesis, we summarize the recent findings of the role of iron and Nrf2 in cancer cells and demonstrate how Nrf2 balances the oxidative stress induced by iron through regulating antioxidant enzymes and iron metabolism. This hypothesis provides new insights into the role of Nrf2 in cancer progression. Since ferroptosis is dependent on lipid peroxide and iron accumulation, Nrf2 inhibition may dramatically increase sensitivity to ferroptosis. The combination of Nrf2 inhibitors with ferroptosis inducers may exert greater efficacy on cancer therapy.

Therapeutic potential of iron chelators on osteoporosis and their cellular mechanisms.

Iron is an essential trace element in the metabolism of almost all living organisms. Iron overload can disrupt bone homeostasis by significant inhibition of osteogenic differentiation and stimulation of osteoclastogenesis, consequently leading to osteoporosis. Iron accumulation is also involved in the osteoporosis induced by multiple factors, such as estrogen deficiency, ionizing radiation, and mechanical unloading. Iron chelators are first developed for treating iron overloaded disorders. However, growing evidence suggests that iron chelators can be potentially used for the treatment of bone loss. In this review, we focus on the therapeutic effects of iron chelators on bone loss. Iron chelators have therapeutic effects not only on iron overload induced osteoporosis, but also on osteoporosis induced by estrogen deficiency, ionizing radiation, and mechanical unloading, and in Alzheimer's disease-associated osteoporotic deficits. Iron chelators differently affect the cellular behaviors of bone cells. For osteoblast lineage cells (bone mesenchymal stem cells and osteoblasts), iron chelation stimulates osteogenic differentiation. Conversely, iron chelation significantly inhibits osteoclast differentiation. These different responses may be associated with the different needs of iron during differentiation. Fibroblast growth factor 23, angiogenesis, and antioxidant capability are also involved in the osteoprotective effects of iron chelators.

Next generation sequencing yields the complete mitogenome of Smith's zokor (Eospalax smithii).

Sequencing analysis of mitochondrial genomes is useful for understanding the genome structures. In this study, complete mitochondrial genomes of the Eospalax smithii was obtained by using next generation sequencing method. The complete mitogenome of E. smithii was 16,350 bp long, containing 13 protein-coding genes (PCGs), 2 ribosomal RNA (rRNA) genes, 22 transfer RNA (tRNA) genes, and 1 non-coding control region (D-loop). The overall base composition of the heavy strand is A (33.65%), C (23.80%), T (30.31%), and G (12.24%). The base compositions present highly biased toward A + T nucleotides. The result of phylogenetic analysis showed the five Eospalax species formed a monophyly with the high bootstrap value and as a sister group of the genus Myospalax. This is the first report of the complete mitochondrial genomes of E. smithii and the mitogenome is potentially important for evolutionary biology, population genetics, and species diagnosis studies of the Mysopalacinae.

Ionizing Radiation Exacerbates the Bone Loss Induced by Iron Overload in Mice.

Patients with radiotherapy are at significant risks of bone loss and fracture. On the other hand, osteoporosis often occurs in disorders characterized by iron overload. Either ionizing radiation (IR) or iron overload alone has detrimental effects on bone metabolism, but their combined effects are not well defined. In this study, we evaluated the effects of IR on bone loss in an iron-overload mouse model induced by intraperitoneal injection of ferric ammonium citrate (FAC). In the present study, we found that IR additively aggravated iron overload induced by FAC injections. Iron overload stimulated hepcidin synthesis, while IR had an inhibitory effect and even inhibited the stimulatory effects of iron overload. Micro-CT analysis demonstrated that the loss of bone mineral density and bone volume, and the deterioration of bone microarchitecture were greatest in combined treatment group. Iron altered the responses of bone cells to IR. Iron enhanced the responses of osteoclasts to IR with elevated osteoclast differentiation, but did not affect osteoblast differentiation. Our study indicates that IR and iron in combination lead to a more severe impact on the bone homeostasis when compared with their respective effects. IR aggravated iron overload induced bone loss by heightened bone resorption relative to formation. The addictive effects may be associated with the exacerbated iron accumulation and osteoclast differentiation.

Lithobius (Ezembius) hualongensis sp. nov. and Lithobius (Ezembius) sui sp. nov. (Lithobiomorpha, Lithobiidae), two new species of centipede from northwest China.

Lithobius (Ezembius) hualongensissp. nov. and Lithobius (Ezembius) suisp. nov. (Lithobiomorpha, Lithobiidae) recently discovered from the Qinghai-Tibet Plateau, China are described. Morphologically, the two new species are very similar but can be distinguished by the number of coxosternal teeth: L. (E.) hualongensissp. nov. has 2 + 2 while L. (E.) suisp. nov. has 3 + 3. The two new species resemble L. (E.) multispinipesPei et al., 2016, from the Xinjiang Autonomous Region, but can be readily distinguished by having the Tömösváry's organ slightly larger than the adjoining ocelli rather than smaller, 3 + 3 spurs on female gonopods versus 2 + 2, and the simple terminal claw of female gonopods with a small triangular protuberance on the basal ventral side versus simple, without a small triangular protuberance on the basal ventral side. We also compare the main morphological characters of the two new species with the other Lithobius (Ezembius) species known in Qinghai Province. A key to the Chinese species of Ezembius is presented.

Two new species of Lithobius on Qinghai-Tibetan plateau identified from morphology and COI sequences (Lithobiomorpha: Lithobiidae).

Lithobius (Ezembius) longibasitarsussp. n. and Lithobius (Ezembius) datongensissp. n. (Lithobiomorpha: Lithobiidae), recently discovered from Qinghai-Tibet Plateau, China, are described. A key to the species of the subgenus Ezembius in China is presented. The partial mitochondrial cytochrome c oxidase subunit I barcoding gene was amplified and sequenced for eight individuals of the two new species and the dataset was used for molecular phylogenetic analysis and genetic distance determination. Both morphology and molecular data show that the specimens examined should be referred to Lithobius (Ezembius).

Two new species of the genus Hessebius Verhoeff, 1941 from China (Lithobiomorpha, Lithobiidae).

Two new species, Hessebius luquensissp. n. and Hessebius ruoergaiensissp. n., are described based on material from Qinghai-Tibet Plateau. A key to the Chinese species of Hessebius is presented. The partial mitochondrial cytochrome c oxidase subunit I (COI) barcoding gene was amplified and sequenced for nine individuals of both species and the dataset was used for molecular phylogenetic analysis and genetic distance determination.

Population structure, historical biogeography and demographic history of the alpine toad Scutiger ningshanensis in the Tsinling Mountains of Central China.

Population genetic structure, historical biogeography and historical demography of the alpine toad Scutiger ningshanensis were studied using the combined data mtDNA cytochrome b (cyt b) and the mtDNA cytochrome c oxidase subunit I (COI) as the molecular markers. This species has high genetic variation. There was a significant genetic differentiation among most populations. Three lineages were detected. The phylogenetic relationship analyses and the SAMOVA (spatial analysis of molecular variance) results showed significant phylogeographic structure. 82.15% genetic variation occurred among populations whereas differentiation within populations only contributed 17.85% to the total. Mantel test results showed a significant correlation between the pairwise calculated genetic distance and pairwise calculated geographical distance of the populations (regression coefficient  = 0.001286, correlation coefficient  = 0.77051, p (rrand≥robs)  = 0.0185<0.05), indicating the existence of isolation-by-distance pattern of genetic divergence for cyt b + COI sequence, which suggests that the distribution of genetic variation is due to geographical separation rather than natural selection. The population expansion or contraction and genetic differentiation between populations or lineages could be explained by topography and the repetitive uplifts of the Tsinling Mountains and the climatic cycles during the late Pliocene and Pleistocene. S. ningshanensis experienced a rapid population expansion about 40,000 years before present. The current decline in population size was probably caused by anthropogenic disturbance. Current populations of S. ningshanensis are from different refugia though the location of these refugia could not be determined in our study. Topography, climatic changes and repetitive population expansion/contraction together led to the high level of genetic variation in S. ningshanensis. A total of three management units (MUs) was determined, which must be considered when conservation policy is made in the future.

Echiniscus semifoveolatus (Heterotardigrada: Echiniscidae), a newly recorded species from China.

Echiniscus semifoveolatus Ito, 1993 (Tardigrada: Echiniscidae) is reported as a new record for China, and was collected from the Mt. Jinggang, Jiangxi, and the Wuyi Mountains, south-eastern China. This is the first report of this species from outside the type locality, Mt. Fuji, central Japan. The number of dorsal spines that arise from the posterior edge of the scapular plate ranges from zero to five while the type specimen has two symmetrically arranged spines at Bd. The distance between the spines varies. These variations in both the number of spines and the distance between the spines could be considered as individual variation. We provide a detailed supplementary description for this species based on the Chinese specimens and supply a key to all known Chinese species of the genus Echiniscus.