A novel protein CYTB-187AA encoded by the mitochondrial gene CYTB modulates mammalian early development.

The mitochondrial genome transcribes 13 mRNAs coding for well-known proteins essential for oxidative phosphorylation. We demonstrate here that cytochrome b (CYTB), the only mitochondrial-DNA-encoded transcript among complex III, also encodes an unrecognized 187-amino-acid-long protein, CYTB-187AA, using the standard genetic code of cytosolic ribosomes rather than the mitochondrial genetic code. After validating the existence of this mtDNA-encoded protein arising from cytosolic translation (mPACT) using mass spectrometry and antibodies, we show that CYTB-187AA is mainly localized in the mitochondrial matrix and promotes the pluripotent state in primed-to-naive transition by interacting with solute carrier family 25 member 3 (SLC25A3) to modulate ATP production. We further generated a transgenic knockin mouse model of CYTB-187AA silencing and found that reduction of CYTB-187AA impairs females' fertility by decreasing the number of ovarian follicles. For the first time, we uncovered the novel mPACT pattern of a mitochondrial mRNA and demonstrated the physiological function of this 14th protein encoded by mtDNA.

Canonical pathways for validating steroid-associated osteonecrosis in mice.

The present study aimed to establish and evaluate a preclinical model of steroid-associated osteonecrosis (SAON) in mice. Sixteen 24-week-old male C57BL/6 mice were used to establish SAON by two intraperitoneal injections of lipopolysaccharide (LPS), followed by three subcutaneous injections of methylprednisolone (MPS). Each injection was conducted on working day, with an interval of 24 h. Six cycles of injections were conducted. Additional twelve mice (age- and gender-matched) were used as normal controls. At 2 and 6 weeks after completing induction, bilateral femora and bilateral tibiae were collected for histological examination, micro-CT scanning, and bulk RNA sequencing. All mice were alive until sacrificed at the indicated time points. The typical SAON lesion was identified by histological evaluation at week 2 and week 6 with increased lacunae and TUNEL+ osteocytes. Micro-CT showed significant bone degeneration at week 6 in SAON model. Histology and histomorphometry showed significantly lower Runx2+ area, mineralizing surface (MS/BS), mineral apposition rate (MAR), bone formation rate (BFR/BS), type H vessels, Ki67+ (proliferating) cells, and higher marrow fat fraction, osteoclast number and TNFα+ areas in SAON group. Bulk RNA-seq revealed changed canonical signaling pathways regulating cell cycle, angiogenesis, osteogenesis, and osteoclastogenesis in the SAON group. The present study successfully established SAON in mice with a combination treatment of LPS and MPS, which could be considered a reliable and reproducible animal model to study the pathophysiology and molecular mechanism of early-stage SAON and to develop potential therapeutic approaches for the prevention and treatment of SAON.

Single-cell RNA-seq of in vitro expanded cells from cranial neural crest reveals a rare odontogenic sub-population.

Ecto-mesenchymal cells of mammalian tooth germ develops from cranial neural crest cells. These cells are recognised as a promising source for tooth development and regeneration. Despite the high heterogeneity of the neural crest, the cellular landscape of in vitro cultured cranial neural crest cells (CNCCs) for odontogenesis remains unclear. In this study, we used large-scale single-cell RNA sequencing to analyse the cellular landscape of in vitro cultured mouse CNCCs for odontogenesis. We revealed distinct cell trajectories from primary cells to passage 5 and identified a rare Alx3+/Barx1+ sub-population in primary CNCCs that differentiated into two odontogenic clusters characterised by the up-regulation of Pax9/Bmp3 and Lhx6/Dmp1. We successfully induced whole tooth-like structures containing enamel, dentin, and pulp under the mouse renal capsule using in vitro cultured cells from both cranial and trunk neural crests with induction rates of 26.7% and 22.1%, respectively. Importantly, we confirmed only cells sorted from odontogenic path can induce tooth-like structures. Cell cycle and DNA replication genes were concomitantly upregulated in the cultured NCCs of the tooth induction groups. Our data provide valuable insights into the cell heterogeneity of in vitro cultured CNCCs and their potential as a source for tooth regeneration.

FARSB Facilitates Hepatocellular Carcinoma Progression by Activating the mTORC1 Signaling Pathway.

Hepatocellular carcinoma (HCC) is a common malignant tumor with high mortality. Human phenylalanine tRNA synthetase (PheRS) comprises two α catalytic subunits encoded by the FARSA gene and two ß regulatory subunits encoded by the FARSB gene. FARSB is a potential oncogene, but no experimental data show the relationship between FARSB and HCC progression. We found that the high expression of FARSB in liver cancer is closely related to patients' low survival and poor prognosis. In liver cancer cells, the mRNA and protein expression levels of FARSB are increased and promote cell proliferation and migration. Mechanistically, FARSB activates the mTOR complex 1 (mTORC1) signaling pathway by binding to the component Raptor of the mTORC1 complex to play a role in promoting cancer. In addition, we found that FARSB can inhibit erastin-induced ferroptosis by regulating the mTOR signaling pathway, which may be another mechanism by which FARSB promotes HCC progression. In summary, FARSB promotes HCC progression and is associated with the poor prognosis of patients. FARSB is expected to be a biomarker for early screening and treatment of HCC.

Immunomodulatory roles of metalloproteinases in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic, autoimmune pathology characterized by persistent synovial inflammation and gradually advancing bone destruction. Matrix metalloproteinases (MMPs), as a family of zinc-containing enzymes, have been found to play an important role in degradation and remodeling of extracellular matrix (ECM). MMPs participate in processes of cell proliferation, migration, inflammation, and cell metabolism. A growing number of persons have paid attention to their function in inflammatory and immune diseases. In this review, the details of regulation of MMPs expression and its expression in RA are summarized. The role of MMPs in ECM remodeling, angiogenesis, oxidative and nitrosative stress, cell migration and invasion, cytokine and chemokine production, PANoptosis and bone destruction in RA disease are discussed. Additionally, the review summarizes clinical trials targeting MMPs in inflammatory disease and discusses the potential of MMP inhibition in the therapeutic context of RA. MMPs may serve as biomarkers for drug response, pathology stratification, and precision medicine to improve clinical management of rheumatoid arthritis.

Circular RNAs in vascular diseases.

Vascular diseases are the leading cause of morbidity and mortality worldwide and are urgently in need of diagnostic biomarkers and therapeutic strategies. Circular RNAs (circRNAs) represent a unique class of RNAs characterized by a circular loop configuration and have recently been identified to possess a wide variety of biological functions. CircRNAs exhibit exceptional stability, tissue specificity, and are detectable in body fluids, thus holding promise as potential biomarkers. Their encoding function and stable gene expression also position circRNAs as an excellent alternative to gene therapy. Here, we briefly review the biogenesis, degradation, and functions of circRNAs. We summarize circRNAs discovered in major vascular diseases such as atherosclerosis and aneurysms, with a particular focus on molecular mechanisms of circRNAs identified in vascular endothelial cells and smooth muscle cells, in the hope to reveal new directions for mechanism, prognosis and therapeutic targets of vascular diseases.

Nuclear respiratory factor 1 drives hepatocellular carcinoma progression by activating LPCAT1-ERK1/2-CREB axis.

BACKGROUND: Nuclear respiratory factor 1 (NRF1) is a transcription factor that participates in several kinds of tumor, but its role in hepatocellular carcinoma (HCC) remains elusive. This study aims to explore the role of NRF1 in HCC progression and investigate the underlying mechanisms. RESULTS: NRF1 was overexpressed and hyperactive in HCC tissue and cell lines and high expression of NRF1 indicated unfavorable prognosis of HCC patients. NRF1 promoted proliferation, migration and invasion of HCC cells both in vitro and in vivo. Mechanistically, NRF1 activated ERK1/2-CREB signaling pathway by transactivating lysophosphatidylcholine acyltransferase 1 (LPCAT1), thus promoting cell cycle progression and epithelial mesenchymal transition (EMT) of HCC cells. Meanwhile, LPCAT1 upregulated the expression of NRF1 by activating ERK1/2-CREB signaling pathway, forming a positive feedback loop. CONCLUSIONS: NRF1 is overexpressed in HCC and promotes HCC progression by activating LPCAT1-ERK1/2-CREB axis. NRF1 is a promising therapeutic target for HCC patients.

Inhibition of mammalian target of rapamycin complex 1 in the brain microvascular endothelium ameliorates diabetic Aß brain deposition and cognitive impairment via the sterol-regulatory element-binding protein 1/lipoprotein receptor-associated protein 1 signaling pathway.

AIMS: Mammalian target of rapamycin complex 1 (mTORC1) is highly activated in diabetes, and the decrease of low-density lipoprotein receptor-associated protein 1 (LRP1) in brain microvascular endothelial cells (BMECs) is a key factor leading to amyloid-ß (Aß) deposition in the brain and diabetic cognitive impairment, but the relationship between them is still unknown. METHODS: In vitro, BMECs were cultured with high glucose, and the activation of mTORC1 and sterol-regulatory element-binding protein 1 (SREBP1) was observed. mTORC1 was inhibited by rapamycin and small interfering RNA (siRNA) in BMECs. Betulin and siRNA inhibited SREBP1, observed the mechanism of mTORC1-mediated effects on Aß efflux in BMECs through LRP1 under high-glucose conditions. Constructed cerebrovascular endothelial cell-specific Raptor-knockout (Raptorfl/+ ) mice to investigate the role of mTORC1 in regulating LRP1-mediated Aß efflux and diabetic cognitive impairment at the tissue level. RESULTS: mTORC1 activation was observed in HBMECs cultured in high glucose, and this change was confirmed in diabetic mice. Inhibiting mTORC1 corrected the reduction in Aß efflux under high-glucose stimulation. In addition, high glucose activated the expression of SREBP1, and inhibiting of mTORC1 reduced the activation and expression of SREBP1. After inhibiting the activity of SREBP1, the presentation of LRP1 was improved, and the decrease of Aß efflux mediated by high glucose was corrected. Raptorfl/+ diabetic mice had significantly inhibited activation of mTORC1 and SREBP1, increased LRP1 expression, increased Aß efflux, and improved cognitive impairment. CONCLUSION: Inhibiting mTORC1 in the brain microvascular endothelium ameliorates diabetic Aß brain deposition and cognitive impairment via the SREBP1/LRP1 signaling pathway, suggesting that mTORC1 may be a potential target for the treatment of diabetic cognitive impairment.

Alpha-ketoglutarate alleviates cadmium-induced inflammation by inhibiting the HIF1A-TNFAIP3 pathway in hepatocytes.

The threat to public health posed by rapidly increasing levels of cadmium (Cd) in the environment is receiving worldwide attention. Although, Cd is known to be absorbed into the body and causes non-negligible damage to the liver, the detailed mechanisms underlying its hepatoxicity are incompletely understood. In the present study, investigated the effect of TNFAIP3 and α-ketoglutarate (AKG) on Cd-induced liver inflammation and hepatocyte death. Male C57BL/6 mice were exposed to cadmium chloride (1.0 mg/kg) while being fed a diet with 2 % AKG for two weeks. We found that Cd induced hepatocyte injury and inflammatory infiltration. In addition, TNFAIP3 expression was inhibited in the liver tissues and cells of CdCl2-treated mice. Mouse hepatocyte-specific TNFAIP3 overexpression by tail vein injection of an adeno-associated virus (AAV) vector effectively alleviated Cd-induced hepatic necrosis and inflammation, which was mediated by the NF-κB signaling pathway. Notably, this inhibitory effect of TNFAIP3 on Cd-induced liver injury was dependent on AKG. Exogenous addition of AKG prevented Cd exposure-induced increases in serum ALT, AST and LDH levels, production of pro-inflammatory cytokines, activation of the NF-κB signaling pathway, and even significantly reduced Cd-induced oxidative stress and hepatocyte death. Mechanistically, AKG exerted its anti-inflammatory effect by promoting the hydroxylation and degradation of HIF1A to reduce its Cd-induced overexpression in vivo and in vitro, avoiding the inhibition of the TNFAIP3 promoter by HIF1A. Moreover, the protective effect of AKG was significantly weaker in Cd-treated primary hepatocytes transfected with HIF1A pcDNA. Overall, our results reveal a novel mechanism of Cd-induced hepatotoxicity.

Long Non-Coding RNA Malat1 Increases the Rescuing Effect of Quercetin on TNFα-Impaired Bone Marrow Stem Cell Osteogenesis and Ovariectomy-Induced Osteoporosis.

Osteoporosis, a common systematic bone homeostasis disorder related disease, still urgently needs innovative treatment methods. Several natural small molecules were found to be effective therapeutics in osteoporosis. In the present study, quercetin was screened out from a library of natural small molecular compounds by a dual luciferase reporter system. Quercetin was found to upregulate Wnt/ß-catenin while inhibiting NF-κB signaling activities, and thereby rescuing osteoporosis-induced tumor necrosis factor alpha (TNFα) impaired BMSCs osteogenesis. Furthermore, a putative functional lncRNA, Malat1, was shown to be a key mediator in quercetin regulated signaling activities and TNFα-impaired BMSCs osteogenesis, as mentioned above. In an ovariectomy (OVX)-induced osteoporosis mouse model, quercetin administration could significantly rescue OVX-induced bone loss and structure deterioration. Serum levels of Malat1 were also obviously rescued in the OVX model after quercetin treatment. In conclusion, our study demonstrated that quercetin could rescue TNFα-impaired BMSCs osteogenesis in vitro and osteoporosis-induced bone loss in vivo, in a Malat1-dependent manner, suggesting that quercetin may serve as a therapeutic candidate for osteoporosis treatment.

Adjustment of W-O-Zr Boundaries Boosts Efficient Nitrilation of Dimethyl Adipate with Ammonia on WOx/ZrO2 Catalysts.

In this study, a tungstated zirconia (WOx/ZrO2) catalyst was developed for the continuous synthesis of adiponitrile (ADN) by gas-phase nitrilation of dimethyl adipate (DMA) with NH3. The highest TOFADN could be reached on WOx/ZrO2 bearing ∼1D WOx species (highly dispersed and discontinuous status) at the surface, which, however, delivered the poorest selectivity toward nitrilation (SADN+MCP). In comparison, both efficient and selective transformation of DMA to ADN was achieved by fabricating WOx/ZrO2 with continuously distributed oligomeric WOx species (∼2D) at the surface, either by varying the dosage of the W-reagent in the preparation of WOx(m)/ZrO2 or by doping a proper amount of the Mn element into WOx(5.0)/ZrO2, bearing WO3 NPs. Furthermore, the in situ diffuse reflectance infrared Fourier transform spectroscopy investigations of both independent and competitive adsorptions of ester functionality and NH3 over W-O-Zr, W-O-W, and Zr-O-Zr boundaries at the surface clarified the synergistic effect of these species in the activation of DMA/NH3 and thereby nitrilation.

Sn-Ag Synergistic Effect Enhances High-Rate Electrocatalytic CO2 -to-Formate Conversion on Porous Poly(Ionic Liquid) Support.

The electrocatalytic transformation of carbon dioxide (CO2 ) to formate is a promising route for highly efficient conversion and utilization of CO2 gas, due to the low production cost and the ease of storage of formate. In this work, porous poly(ionic liquid) (PPIL)-based tin-silver (Sn-Ag) bimetallic hybrids (PPILm -Snx Ag10- x ) are prepared for high-performance formate electrolytic generation. Under optimal conditions, an excellent formate Faradaic efficiency of 95.5% with a high partial current density of 214.9 mA cm-2 is obtained at -1.03 V (vs reversible hydrogen electrode). Meanwhile, the high selectivity of formate (>≈83%) is maintained in a wide potential range (>630 mV). Mechanistic studies demonstrate that the presence of Ag-species is vital for the formation, maintenance, and high dispersion of tetravalent Sn(IV)-species, which accounts for the active sites for CO2 -to-formate conversion. Further, the introduction of Ag-species significantly enhances the activity by increasing the electron density near the Fermi energy level.

A systematic analysis in efficacy and safety of nimotuzumab combined with chemoradiotherapy in treatment of advanced nasopharyngeal carcinoma.

OBJECTIVE: To analyze the clinical effect of nitorzumab injection combined with chemoradiotherapy in the treatment of advanced nasopharyngeal carcinoma. METHODS: The databases, such as CNKI, Wanfang, VIP, China Biology Medicine (CBM), PubMed, Cochrane Library, Wiley Online Library, and Google Academic were searched. The randomized controlled trials (RCT) of nimotuzumab combined with concurrent chemoradiotherapy (experimental group) and concurrent chemoradiotherapy (control group) were searched. The between-group differences of objective remission rate (ORR), disease control rate (DCR), and drug-related adverse reactions were analyzed by RevMan5.3 software. RESULTS: Totally, 11 studies were included in meta-analysis, including 655 patients. All 11 articles mentioned random grouping and no blind method was used. The objective remission rate, disease control rate, and adverse drug reactions are given in 11 articles. In this study, 11 literatures were analyzed by fixed effect model after heterogeneity and sensitivity analysis. The meta analysis showed that in 10 literatures, the objective remission rate and disease control rate of patients in the experimental group were significantly higher than those in the control group (RR = 1.32, 95% CI: 1.2-1.45, Z = 5.72, P < 0.00001); (RR = 1.07, 95% CI: 1.02-1.11, Z = 3.04, P = 0.002 < 0.01. There was no significant difference in adverse reactions between the two groups (RR = 0.95, 95% CI: 0.79-1.15, Z = 0.52, P = 0.6 > 0.05). CONCLUSION: The efficacy and safety of nituozumab injection combined with concurrent chemoradiotherapy are reliable and definite.

Single cell atlas of developing mouse dental germs reveals populations of CD24+ and Plac8+ odontogenic cells.

The spatiotemporal relationships in high-resolution during odontogenesis remain poorly understood. We report a cell lineage and atlas of developing mouse teeth. We performed a large-scale (92,688 cells) single cell RNA sequencing, tracing the cell trajectories during odontogenesis from embryonic days 10.5 to 16.5. Combined with an assay for transposase-accessible chromatin with high-throughput sequencing, our results suggest that mesenchymal cells show the specific transcriptome profiles to distinguish the tooth types. Subsequently, we identified key gene regulatory networks in teeth and bone formation and uncovered spatiotemporal patterns of odontogenic mesenchymal cells. CD24+ and Plac8+ cells from the mesenchyme at the bell stage were distributed in the upper half and preodontoblast layer of the dental papilla, respectively, which could individually induce nonodontogenic epithelia to form tooth-like structures. Specifically, the Plac8+ tissue we discovered is the smallest piece with the most homogenous cells that could induce tooth regeneration to date. Our work reveals previously unknown heterogeneity and spatiotemporal patterns of tooth germs that may lead to tooth regeneration for regenerative dentistry.

Low-dose AAV-CRISPR-mediated liver-specific knock-in restored hemostasis in neonatal hemophilia B mice with subtle antibody response.

AAV-delivered CRISPR/Cas9 (AAV-CRISPR) has shown promising potentials in preclinical models to efficiently insert therapeutic gene sequences in somatic tissues. However, the AAV input doses required were prohibitively high and posed serious risk of toxicity. Here, we performed AAV-CRISPR mediated homology-independent knock-in at a new target site in mAlb 3'UTR and demonstrated that single dose of AAVs enabled long-term integration and expression of hF9 transgene in both adult and neonatal hemophilia B mice (mF9 -/-), yielding high levels of circulating human Factor IX (hFIX) and stable hemostasis restoration during entire 48-week observation period. Furthermore, we achieved hemostasis correction with a significantly lower AAV dose (2 × 109 vg/neonate and 1 × 1010 vg/adult mouse) through liver-specific gene knock-in using hyperactive hF9R338L variant. The plasma antibodies against Cas9 and AAV in the neonatal mice receiving low-dose AAV-CRISPR were negligible, which lent support to the development of AAV-CRISPR mediated somatic knock-in for treating inherited diseases.

Malat1 attenuated the rescuing effects of docosahexaenoic acid on osteoarthritis treatment via repressing its chondroprotective and chondrogenesis activities.

Osteoarthritis (OA) is a degenerative disease associated with joint inflammation, articular cartilage degeneration and subchondral hypertrophy. Small molecules which both ameliorate chondrocyte OA phenotype and activate bone marrow-derived mesenchymal stem cells (BMSCs) chondrogenesis under inflammatory conditions have the therapeutical potential for OA treatment. In this study, we characterized a novel small molecule which could ameliorate OA progression via novel regulating mechanisms. Docosahexaenoic acid (DHA), a bioactive molecule, was screened from a small molecule library and showed anti-inflammatory and chondroprotective effects in OA chondrocytes, as well as ameliorated IL-1ß impaired BMSCs chondrogenesis in Wnt/ß-catenin and NF-κB signaling dependent manners. Furthermore, Malat1 was found to be the key mediator of DHA-mediating anti-inflammation chondroprotection and chondrogenesis. DHA also rescued cartilage loss and damage in a surgery-induced OA mice model. The elevation of serum Malat1 levels caused by OA was also downregulated by DHA treatment. Taken together, our findings demonstrated that DHA, with a dual-signaling repression property, exerted its anti-inflammation, chondroprotection and chondrogenesis function possibly via regulating Malat1 level, suggesting that it may be a possible drug candidate for OA patients with elevated MALAT1 expression levels.

Metamagnetic transition and a loss of magnetic hysteresis caused by electron trapping in monolayers of single-molecule magnet Tb2@C79N.

Realization of stable spin states in surface-supported magnetic molecules is crucial for their applications in molecular spintronics, memory storage or quantum information processing. In this work, we studied the surface magnetism of dimetallo-azafullerene Tb2@C79N, showing a broad magnetic hysteresis in a bulk form. Surprisingly, monolayers of Tb2@C79N exhibited a completely different behavior, with the prevalence of a ground state with antiferromagnetic coupling at low magnetic field and a metamagnetic transition in the magnetic field of 2.5-4 T. Monolayers of Tb2@C79N were deposited onto Cu(111) and Au(111) by evaporation in ultra-high vacuum conditions, and their topography and electronic structure were characterized by scanning tunneling microscopy and spectroscopy (STM/STS). X-ray photoelectron spectroscopy (XPS), in combination with DFT studies, revealed that the nitrogen atom of the azafullerene cage tends to avoid metallic surfaces. Magnetic properties of the (sub)monolayers were then studied by X-ray magnetic circular dichroism (XMCD) at the Tb-M4,5 absorption edge. While in bulk powder samples Tb2@C79N behaves as a single-molecule magnet with ferromagnetically coupled magnetic moments and blocking of magnetization at 28 K, its monolayers exhibited a different ground state with antiferromagnetic coupling of Tb magnetic moments. To understand if this unexpected behavior is caused by a strong hybridization of fullerenes with metallic substrates, XMCD measurements were also performed for Tb2@C79N adsorbed on h-BN|Rh(111) and MgO|Ag(100). The co-existence of two forms of Tb2@C79N was found on these substrates as well, but magnetization curves showed narrow magnetic hysteresis detectable up to 25 K. The non-magnetic state of Tb2@C79N in monolayers is assigned to anionic Tb2@C79N- species with doubly-occupied Tb-Tb bonding orbital and antiferromagnetic coupling of the Tb moments. A charge transfer from the substrate or trapping of secondary electrons are discussed as a plausible origin of these species.

Sesamin Promotes Osteoporotic Fracture Healing by Activating Chondrogenesis and Angiogenesis Pathways.

Osteoporotic fracture has been regarded as one of the most common bone disorders in the aging society. The natural herb-derived small molecules were revealed as potential treatment approaches for osteoporotic fracture healing. Sesamin is a member of lignan family, which possesses estrogenic activity and plays a significant role in modulating bone homeostasis. Our previous study reported the promoting effect of sesamin on postmenopausal osteoporosis treatment. However, the role of sesamin in osteoporotic fracture healing has not been well studied yet. In this study, we further investigated the putative treatment effect of sesamin on osteoporotic fracture healing. Our study indicated that sesamin could activate bone morphogenetic protein 2 (BMP2) signaling pathway and further promotes in vitro chondrogenesis and angiogenesis activities. This promoting effect was abolished by the treatment of ERα inhibitor. In the osteoporotic bone fracture model, we demonstrated that sesamin markedly improves the callus formation and increases the cartilaginous area at the early-stage, as well as narrowing the fracture gap, and expands callus volume at the late-stage fracture healing site of the OVX mice femur. Furthermore, the angiogenesis at the osteoporotic fracture site was also significantly improved by sesamin treatment. In conclusion, our research illustrated the therapeutic potential and underlying regulation mechanisms of sesamin on osteoporotic fracture healing. Our studies shed light on developing herb-derived bioactive compounds as novel drugs for the treatment of osteoporotic fracture healing, especially for postmenopausal women with low estrogen level.

DANCR Mediates the Rescuing Effects of Sesamin on Postmenopausal Osteoporosis Treatment via Orchestrating Osteogenesis and Osteoclastogenesis.

As one of the leading causes of bone fracture in postmenopausal women and in older men, osteoporosis worldwide is attracting more attention in recent decades. Osteoporosis is a common disease mainly resulting from an imbalance of bone formation and bone resorption. Pharmaceutically active compounds that both activate osteogenesis, while repressing osteoclastogenesis hold the potential of being therapeutic medications for osteoporosis treatment. In the present study, sesamin, a bioactive ingredient derived from the seed of Sesamum Indicum, was screened out from a bioactive compound library and shown to exhibit dual-regulating functions on these two processes. Sesamin was demonstrated to promote osteogenesis by upregulating Wnt/ß-catenin, while repressing osteoclastogenesis via downregulating NF-κB signaling . Furthermore, DANCR was found to be the key regulator in sesamin-mediated bone formation and resorption . In an ovariectomy (OVX)-induced osteoporotic mouse model, sesamin could rescue OVX-induced bone loss and impairment. The increased serum level of DANCR caused by OVX was also downregulated upon sesamin treatment. In conclusion, our results demonstrate that sesamin plays a dual-functional role in both osteogenesis activation and osteoclastogenesis de-activation in a DANCR-dependent manner, suggesting that it may be a possible medication candidate for osteoporotic patients with elevated DNACR expression levels.

Electrophilic Trifluoromethylation of Dimetallofullerene Anions en Route to Air-Stable Single-Molecule Magnets with High Blocking Temperature of Magnetization.

Lanthanide dimetallofullerenes with single-electron M-M bonds are an important class of single molecular magnets and qubit candidates, but stabilization of their unique electronic and spin structure in the form of a neutral molecule requires functionalization of the fullerene cage with a single radical group. The lack of selectivity of the currently available procedure results in a complicated and tedious separation process. Here we demonstrate that electrophilic trifluoromethylation of a mixture of metallofullerene anions with Umemoto reagent II is highly selective toward M2@C80- (M = Tb, Y) anions, yielding M2@C80(CF3) monoadducts as the main reaction product. Single-crystal X-ray diffraction study proved attachment of the CF3 group to the pentagon/hexagon/hexagon junction and revealed that positions of metal atoms inside the fullerene cage in the cocrystal with NiOEP are strongly related to the position of the porphyrin moieties. Magnetic characterization of Tb2@C80(CF3) showed that it is a robust single-molecule magnet with broad magnetic hysteresis, 100 s blocking temperature of 25 K, and the relaxation barrier of 801(4) K, corresponding to the flipping of the Tb magnetic moment in the strongly ferromagnetically coupled [Tb3+-e-Tb3+] spin system.