Hecogenin alleviates LPS-induced osteolysis via regulating pyroptosis and ROS involved Nrf2 activation.

Reactive oxidative species (ROS) generation triggers pyroptosis and induces development of inflammatory osteolysis. Hecogenin (HG) has anti-inflammatory and antioxidative property, but its effects on inflammatory osteolysis remains unclear. In our study, we investigated the mechanism of HG on pyroptosis and its effect on inflammatory osteolysis in vitro and in vivo. The impact of HG on osteoclastogenesis was evaluated using cytotoxicity, TRAcP staining and bone resorption assays. The RNA-sequencing was employed to identify potential signaling pathways, and then RT-qPCR, western blot, immunofluorescence, and ELISA were used to verify. To determine the protective effect of HG in vivo, Lipopolysaccharide (LPS)-induced animal models were utilized, along with micro-CT and histological examination. HG suppressed RANKL-induced osteoclast differentiation, bone resorption, NFATc1 activity and downstream factors. RNA-sequencing results showed that HG inhibited osteoclastogenesis by modulating the inflammatory response and macrophage polarization. Furthermore, HG inhibited the NF-κB pathway, and deactivated the NLRP3 inflammasome. HG activated the expression of nuclear factor E2-related factor 2 (Nrf2) to eliminate ROS generation. Importantly, the inhibitory effect of HG on NLRP3 inflammasome could be reversed by treatment with the Nrf2 inhibitor ML385. In vivo, HG prevented the mice against LPS-induced osteolysis by suppressing osteoclastogenesis and inflammatory factors. In conclusion, HG could activate Nrf2 to eliminate ROS generation, inactivate NLRP3 inflammasome and inhibit pyroptosis, thereby suppressing osteoclastogenesis in vitro and alleviating inflammatory osteolysis in vivo, which indicating that HG might be a promising candidate to treat inflammatory osteolysis.

Fault-Tolerant Cubature Kalman Filter for Engineering Estimation Control Systems.

The cubature Kalman filter (CKF) overcomes the limitations of the Kalman filter in strong nonlinear systems, which has been widely used in many fields. However, in practical engineering, the abnormal measurement information obtained by the sensor causes the measurement noise covariance to change, which may deteriorate the filtering performance and even cause the filter failure. The fault-tolerant filter can deal with the state estimation problem for the systems with abnormal measurements. The key of the fault-tolerant filter is to forcefully correct filter innovation by using a fading factor. The fault-tolerant filter technology has been extensively applied in many practical systems, but it is still lack of reasonable theoretical analysis. To this end, the measurement noise model is established and the magnitude of the noise deviation is analyzed. The filtering performance under abnormal measurement is analyzed by three mean squared errors (MSEs), which are the ideal MSE, the filter calculated MSE and the true MSE. In order to solve the influence of sampling approximation deviation of CKF on fault detection, an improved fault detection algorithm is proposed. The performance of fault-tolerant CKF is analyzed from two views. The first view is about comparing the filter calculated MSEs of CKF and of fault-tolerant CKF, the second view is about comparing the relative closeness of the filter calculated MSE to the true MSE for the two algorithms. Numerical examples further verify these conclusions.

Cichoric acid targets RANKL to inhibit osteoclastogenesis and prevent ovariectomy-induced bone loss.

BACKGROUND AND AIM: Osteoporosis, a systemic metabolic bone disease, is characterized by the decline of bone mass and quality due to excessive osteoclast activity. Currently, drug-targeting osteoclasts show promising therapy for osteoporosis. In this study, we investigated the effect of cichoric acid (CA) on receptor activator of nuclear kappa-B ligand (RANKL)-induced osteoclastogenesis and the bone loss induced by ovariectomy in mice. EXPERIMENTAL PROCEDURE: Molecular docking technologies were employed to examine the interaction between CA and RANKL. CCK8 assay was used to evaluate the cell viability under CA treatment. TRAcP staining, podosome belt staining, and bone resorption assays were used to test the effect of CA on osteoclastogenesis and osteoclast function. Further, an OVX-induced osteoporosis mice model was employed to identify the effect of CA on bone loss using micro-CT scanning and histological examination. To investigate underlying mechanisms, network pharmacology was applied to predict the downstream signaling pathways, which were verified by Western blot and immunofluorescence staining. KEY RESULTS: The molecular docking analysis revealed that CA exhibited a specific binding affinity to RANKL, engaging multiple binding sites. CA inhibited RANKL-induced osteoclastogenesis and bone resorption without cytotoxic effects. Mechanistically, CA suppressed RANKL-induced intracellular reactive oxygen species, nuclear factor-kappa B, and mitogen-activated protein kinase pathways, followed by abrogated nuclear factor activated T-cells 1 activity. Consistent with this finding, CA attenuated post-ovariectomy-induced osteoporosis by ameliorating osteoclastogenesis. CONCLUSIONS AND IMPLICATIONS: CA inhibited osteoclast activity and bone loss by targeting RANKL. CA might represent a promising candidate for treating osteoclast-related diseases, such as osteoporosis.

Tussilagone inhibits osteoclastogenesis by modulating mitochondrial function and ROS production involved Nrf2 activation.

Reactive Oxygen Species (ROS) play an essential role in the pathogenesis of osteoporosis mainly characterized by excessive osteoclasts (OCs) activity. OCs are rich in mitochondria for energy support, which is a major source of total ROS. Tussilagone (TSG), a natural Sesquiterpenes from the flower of Tussilago farfara, has plentiful beneficial pharmacological characteristics with anti-inflammatory and anti-oxidative activity, but its effects and mechanism in osteopathology are still unclear. In our study, we investigated the regulation of ROS generated from the mitochondria in OCs. We found that TSG inhibited OCs differentiation and bone resorption without any cytotoxicity. Mechanistically, TSG reduced RANKL-mediated total ROS level by down-regulating intracellular ROS production and mitochondrial function, leading to the suppression of NFATc1 transcription. We also found that nuclear factor erythroid 2-related factor 2 (Nrf2) could enhance ROS scavenging enzymes in response to RANKL-induced oxidative stress. Furthermore, TSG up-regulated the expression of Nrf2 by inhibiting its proteosomal degradation. Interestingly, Nrf2 deficiency reversed the suppressive effect of TSG on mitochondrial activity and ROS signaling in OCs. Consistent with this finding, TSG attenuated post-ovariectomy (OVX)- and lipopolysaccharide (LPS) induced bone loss by ameliorating osteoclastogenesis. Taken together, TSG has an anti-bone resorptive effect by modulating mitochondrial function and ROS production involved Nrf2 activation.

UPLC/Q-TOF-MS-based metabolomics evaluate the efficacy of oroxylin A against postmenopausal osteoporosis.

Post-menopausal osteoporosis (PMOP) is a common metabolic bone malady characterized by bone mass loss and bone microarchitectural deterioration; however, there is currently no effective drug for its management. According to our previous study, oroxylin A (OA) could effectively protect ovariectomized (OVX)-osteoporotic mice from bone loss; however, its therapeutic targets are still unclear. From a metabolomic perspective, we studied serum metabolic profiles to discover potential biomarkers and OVX-related metabolic networks, which could assist us to comprehend the impact of OA on OVX. Five metabolites were identified as biomarkers associated with 10 related metabolic pathways, including phenylalanine, tyrosine and tryptophan biosynthesis, and phenylalanine, tryptophan and glycerophospholipid metabolism. After OA treatment, the expression of multiple biomarkers changed, with lysophosphatidylcholine (18:2) being a major significantly regulated biomarker. Our study demonstrated that OA's effects on OVX are probably related to the regulation of phenylalanine, tyrosine and tryptophan biosynthesis. Our findings explain the role of OA against PMOP in terms of metabolism and pharmacology and provide a pharmacological foundation for OA treatment of PMOP.

Divergent Aminocarbonylations of Alkynes Enabled by Photoredox/Nickel Dual Catalysis.

A metallaphotoredox-catalyzed strategy for the selective and divergent aminocarbonylation of alkynes with amines and 1 atm of CO is reported. This synergistic protocol not only enables the Markovnikov-selective hydroaminocarbonylation of alkynes to afford α,ß-unsaturated amides, but also facilitates a sequential four-component hydroaminocarbonylation/radical alkylation in the presence of tertiary and secondary alkyl boronate esters, which allows for straightforward conversion of alkynes into corresponding amides. Preliminary mechanistic studies disclose that a photoinduced oxidative insertion of aniline and CO into nickel followed by a migratory insertion of (carbamoyl)nickel species could be involved.

Oroxylin A reduces osteoclast formation and bone resorption via suppressing RANKL-induced ROS and NFATc1 activation.

Excessive bone erosion by osteoclasts is associated with osteoporosis, rheumatoid arthritis, and periprosthetic osteolysis. Targeting osteoclasts may serve as an effective treatment for osteolytic diseases. Although drugs are currently available for the treatment of these diseases, exploring potential anti-osteoclast natural compounds with safe and effective treatment remains needed. Oroxylin A (OA), a natural flavonoid isolated from the root of Scutellaria baicalensis Georgi, has numerous beneficial pharmacological characteristics, including anti-inflammatory and antioxidant activity. However, its effects and mechanisms on osteoclast formation and bone resorption have not yet been clarified. Our research showed that OA attenuated the formation and function of osteoclast induced by RANKL in a time- and concentration-dependent manner without any cytotoxicity. Mechanistically, OA suppressed intracellular reactive oxygen species (ROS) levels through the Nrf2-mediated antioxidant response. Moreover, OA inhibited the activity of NFATc1, the master transcriptional regulator of RANKL-induced osteoclastogenesis. OA exhibited protective effects in mouse models of post-ovariectomy (OVX)- and lipopolysaccharide (LPS)-induced bone loss, in accordance with its in vitro anti-osteoclastogenic effect. Collectively, our findings highlight the potential of OA as a pharmacological agent for the prevention of osteoclast-mediated osteolytic diseases.

The Anatomy of the Temporal and Zygomatic Branches of the Facial Nerve: Application to Crow's Feet Wrinkles.

BACKGROUND: Advances in the understanding of wrinkling crow's feet while improving the safety and efficacy of botulinum toxin type A injection has pointed to drug dispersion in the lateral orbital wrinkles as a cause of adverse events of botulinum toxin type A injection. The purpose of this study is to identify the distribution of temporal and zygomatic branches of facial nerve in the orbicularis oculi muscles. METHODS: Anatomical dissection of cadavers was performed in 31 cadavers, 13 females and 18 males, with ages ranging from 20 to 60 years, which of all had been embalmed by 10% formalin solution. The facial nerve was identified within subcutaneous tissue close periorbital region and both traced proximal and distal. Its temporal branch, zygomatic branch, facial and muscular entrance were located and accurately measured relative to established surface landmarks. RESULTS: Dissection of the facial nerve revealed 2 to 6 entrances of the temporal branch into the orbicularis oculi and 1 to 5 entrances of the zygomatic branch into the orbicularis oculi. Concerning the measurements of neural entering points, distance and angle from orbicularis oculi muscle to lateral ocular angle, a distribution map of its muscular entrance and their patterns of distribution were constructed. According to the dense area of the coordinate map, there were 3 points determined as the muscular entrance points to established surface landmarks. CONCLUSIONS: An anatomical dissection of cadavers was performed to identify the distribution of temporal and zygomatic branches of the facial nerve in the orbicularis oculi. According to the dense area of the coordinate map, the surface landmarks of 3 points were established as the muscular entrance of the facial nerve (MEF).

Sequential C-O decarboxylative vinylation/C-H arylation of cyclic oxalates via a nickel-catalyzed multicomponent radical cascade.

A selective, sequential C-O decarboxylative vinylation/C-H arylation of cyclic alcohol derivatives enabled by visible-light photoredox/nickel dual catalysis is described. This protocol utilizes a multicomponent radical cascade process, i.e. decarboxylative vinylation/1,5-HAT/aryl cross-coupling, to achieve efficient, site-selective dual-functionalization of saturated cyclic hydrocarbons in one single operation. This synergistic protocol provides straightforward access to sp3-enriched scaffolds and an alternative retrosynthetic disconnection to diversely functionalized saturated ring systems from the simple starting materials.

Visible-Light-Enabled Stereodivergent Synthesis of E- and Z-Configured 1,4-Dienes by Photoredox/Nickel Dual Catalysis.

A stereodivergent reductive coupling reaction between allylic carbonates and vinyl triflates to furnish both E- and Z-configured 1,4-dienes has been achieved by visible-light-induced photoredox/nickel dual catalysis. The mild reaction conditions allow good compatibility of both vinyl triflates and allylic carbonates. Notably, the stereoselectivity of this synergistic cross-electrophile coupling can be tuned by an appropriate photocatalyst with a suitable triplet-state energy, providing a practical and stereodivergent means to alkene synthesis. Preliminary mechanistic studies shed some light on the coupling step as well as the control of the stereoselectivity step.

An EKF-Based Fixed-Point Iterative Filter for Nonlinear Systems.

In this paper, a fixed-point iterative filter developed from the classical extended Kalman filter (EKF) was proposed for general nonlinear systems. As a nonlinear filter developed from EKF, the state estimate was obtained by applying the Kalman filter to the linearized system by discarding the higher-order Taylor series items of the original nonlinear system. In order to reduce the influence of the discarded higher-order Taylor series items and improve the filtering accuracy of the obtained state estimate of the steady-state EKF, a fixed-point function was solved though a nested iterative method, which resulted in a fixed-point iterative filter. The convergence of the fixed-point function is also discussed, which provided the existing conditions of the fixed-point iterative filter. Then, Steffensen's iterative method is presented to accelerate the solution of the fixed-point function. The final simulation is provided to illustrate the feasibility and the effectiveness of the proposed nonlinear filtering method.

Cylindrical shaped ZnO combined Cu catalysts for the hydrogenation of CO2 to methanol.

Hydrogenation of CO2 to chemicals is of great importance in the reduction of greenhouse gas emission. And the interaction and/or the boundary between Cu and ZnO played a crucial role in the performance of the Cu-ZnO catalyst for CO2 hydrogenation to methanol. In this work, cylindrical shaped ZnO was first synthesized via controlled hydrothermal precipitation of Zn(CO2CH3)2·2H2O, and Cu was further deposited on ZnO via in situ reduction in aqueous solution. Characterizations indicated that the crystallization degree of ZnO decreased with the increasing content of Cu, while the exposed surface area of Cu exhibited a volcano shaped curve. It was found that the cylindrical shaped ZnO combined Cu catalysts were active for the hydrogenation of CO2, and the space time yield of methanol reached 0.50 g-MeOH (g-cat h)-1 at H2/CO2 = 3, 240 °C, 3.0 MPa, and 0.54 mol (g-cat h)-1, but the methanol selectivity decreases with the reduction of the (002) polar plane of ZnO. The conversion of CO2 and methanol selectivity were discussed with the detected exposed Cu surface area and the number of oxygen vacancies.

Hybrid Adaptive Cubature Kalman Filter with Unknown Variance of Measurement Noise.

This paper is concerned with the filtering problem caused by the inaccuracy variance of measurement noise in real nonlinear systems. A novel weighted fusion estimation method of multiple different variance estimators is presented to estimate the variance of the measurement noise. On this basis, a hybrid adaptive cubature Kalman filtering structure is proposed. Furthermore, the information filter of the hybrid adaptive cubature Kalman filter is also studied, and the stability and filtering accuracy of the filter are theoretically discussed. The final simulation examples verify the validity and effectiveness of the hybrid adaptive cubature Kalman filtering methods proposed in this paper.

Fire Source Range Localization Based on the Dynamic Optimization Method for Large-Space Buildings.

This paper is concerned to the fire localization problem for large-space buildings. Two kinds of circular fire source arrangement localization methods are proposed on the basis of the dynamic optimization technology. In the Range-Point-Range frame, a dynamic optimization localization is proposed to globally estimate the circle center of the circular arrangement to be determined based on all the point estimates of the fire source. In the Range-Range-Range frame, a dynamic optimization localization method is developed by solving a non-convex optimization problem. In this way, the circle center and the radius are obtained simultaneously. Additionally, the dynamic angle bisector method is evaluated. Finally, a simulation with three simulation scenes is provided to illustrate the effectiveness and availability of the proposed methods.

Vasculature Characterization of a Multiterritory Perforator Flap: An Experimental Study.

Background Tip necrosis in the perforator flap is a significant problem in clinical practice. This study aimed to characterize the vasculature of a multiterritory perforator flap using a rat model and to investigate the impact of the vasculature on flap survival. Methods In total, 105 Sprague Dawley rats were divided into seven groups, including the control, 3 hours postoperative (PO), 12 hours PO, 1 day PO, 3 days PO, 5 days PO, and 7 days PO. A perforator flap with three territories based on the deep iliac circumflex artery was performed. Flaps with only skin incisions and vessel exposure were performed in the control group. The first choke zone (FCZ) was located between the anatomical and dynamic territories, and the second choke zone (SCZ) was located between the dynamic and potential territories. Sodium fluorescein and lead oxide-gelatin angiography and histological examination were performed in each group. Results Sodium fluorescein angiography revealed delayed staining in the perforator flap PO, particularly in the FCZ and SCZ. The delay phenomenon disappeared after 12 hours PO in the FCZ and after 1 day PO in the SCZ. Nonfluorescein-stained areas were found distal to the potential territory. In the FCZ PO, the choke vessels were dilated, while the number of microvessels was increased in the SCZ without choke vessel dilation. Conclusions The remodeling of choke vessels and increase in microvessel number represent arteriogenesis and angiogenesis, respectively. This neovascularization was responsible for flap survival in the entire dynamic territory and part of the potential territory.

Comparison of a Small Central versus a Large Peripheral Perforator in a Rat Model of Extended Dorsal Three-Vascular Territory Perforator Flap.

BACKGROUND: Selection of suitable perforators is critical for satisfactory postreconstructive surgery outcome. This study aims to compare a small central versus a large peripheral perforator flap in a rat extended dorsal three-vascular territory perforator flap model. METHODS: An extended intercostal artery perforator flap with three vascular territories was used to model a small central perforator flap. An extended deep circumflex iliac artery flap with three vascular territories was used to model a large peripheral perforator flap. Flap viability, angiography, and perfusion were compared. RESULTS: Intercostal artery flaps showed significantly higher relative viable area than deep circumflex iliac artery flaps (98.5 ± 3.2 percent versus 87.1 ± 7.3 percent; p < 0.01). Angiography revealed that the anatomical and the first adjacent territories were perfused successfully in both types of flap, but the second adjacent territory of deep circumflex iliac artery flaps was not perfused sufficiently, thus ultimately leading to flap necrosis. Perfusion at the anatomical and the first adjacent territories of both types of flap increased significantly for 3 days (p < 0.05) and became stable 5 to 7 days after surgery. Perfusion at the second adjacent territory of deep circumflex iliac artery flaps diminished continuously. CONCLUSIONS: A small central perforator may supply a larger vascular territory than a large peripheral perforator. Both the size and the location of a perforator should be considered for optimizing the design of an extended perforator flap.

Postoperative Growth in Radial Polydactyly: A Clinical Study.

PURPOSE: This study was designed to evaluate thumb growth after surgical management of a duplicate thumb and investigate its developmental pattern. METHODS: We compared the thumbs and index fingers of 486 normal children (aged 1-18 y) (group A) with 15 children showing radial polydactyly (group B). All duplicate thumbs were treated with excision of the radial thumb and reconstruction of the ulnar thumb. Radiographs of groups A and B were used to compute the thumb-to-index finger length ratio and width ratio, and the thumb-to-index finger phalanx length ratio and phalanx width ratio. RESULTS: In group A, the length ratio, width ratio, phalanx length ratio, and phalanx width ratio did not change with age, and remained constant in males and females. In group B, after an average follow-up period of 41.0 months, the original findings were also similar to the final ratios. In group B, only the phalanx width ratio was obviously smaller than normal. CONCLUSIONS: A permanent developmental stability exists between the thumb and the index finger, even in patients with radial polydactyly. The development of the retained digit is not influenced by the ablation of the extra digit. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

The Effect of Inducible Nitric Oxide Synthase on Multiterritory Perforator Flap Survival in Rats.

Background Inducible nitric oxide synthase (iNOS) plays an important role in vasodilation, angiogenesis, and ischemia-reperfusion injury. We investigated the effects of iNOS on the survival and choke vessels of multiterritory perforator flaps in rats. Methods In this study, 84 rats were divided into two groups of 42 rats each and subjected to multiterritory perforator flap operations. Rats in group A received daily intraperitoneal doses of 100 mg per kg of aminoguanidine (AG) and rats in group B received daily intraperitoneal injections of the same volume of saline solution. On postoperative day 7, the surviving flap area was calculated as a percentage of the total flap dimensions using DP2-BSW software. The diameter and density of microvessels in the second choke zone of the flap were calculated from histology studies. The nitric oxide (NO) content was measured using NO concentration assay kits, and the levels of vascular endothelial growth factor (VEGF) and iNOS were assessed using western blotting. Superoxide dismutase (SOD) activity and malondialdehyde (MDA) content were measured using test kits. Laser Doppler imaging was used to evaluate flap perfusion in the second choke zone for 7 days after surgery. Results The flap survival area, diameter and density of microvessels, iNOS and VEGF levels, NO content, blood perfusion, and MDA content were significantly higher in the control group compared with the AG group, whereas SOD activity was significantly lower in the control group. Conclusions iNOS has a beneficial effect on the survival of multiterritory perforator flaps.

[EFFECTIVENESS OF DORSAL PENTAGONAL FLAP FOR RECONSTRUCTION OF THE WEB SPACE IN CONGENITAL TOE SYNDACTYLY].

OBJECTIVE: To investigate the effectiveness of dorsal pentagonal flap for reconstruction of the web space in congenital toe syndactyly. METHODS: Between January 2009 and June 2014, 10 patients with congenital toe syndactyly were treated for web space reconstruction with dorsal pentagonal flap. There were 6 boys and 4 girls with the average age of 42 months (range, 8 months to 9 years). The congenital toe syndactyly located at the left foot in 5 cases, the right foot in 4 cases, and both feet in 1 case; 7 patients had polydactyly and 1 patient had brachydactylia. During follow-up, the toe function and web space appearance, web space depth, and web space gradient were observed to evaluate the effectiveness. RESULTS: All 13 flaps survived and incisions healed by first intention. Ten patients were followed up 6-50 months (mean, 26 months). The skin color and texture in 13 reconstructed web spaces were close to normal web space. in 9 patients undergoing web spaces reconstruction of single foot, the abduction angle of toes was (42.879±3.703) at the injured side, showing no significant difference when compared with the normal side [(45.922±2.657)°] (t= -2.004, P=0.062); the web space depth was (1.881±0.266) cm at the injured side and was (1.631±0.202) cm at the normal side, showing significant difference (t=2.248, P=0.039); and the web space gradient was (42.733±3.421)° at the injured side and was (41.189±5.593)° at the normal side, showing no significant difference (t=0.707, P=0.490). The web space appearance, web space depth, and web space gradient were close to those of the normal web space in 1 patient undergoing bilateral web spaces reconstruction. CONCLUSION: Web space reconstruction with dorsal pentagonal flap is easy to perform with reliable blood supply and low re-operated rate. The cosmetic and functional results are satisfactory.

Comparative Analysis of the Volatile Components of Agrimonia eupatoria from Leaves and Roots by Gas Chromatography-Mass Spectrometry and Multivariate Curve Resolution.

Gas chromatography-mass spectrometry and multivariate curve resolution were applied to the differential analysis of the volatile components in Agrimonia eupatoria specimens from different plant parts. After extracted with water distillation method, the volatile components in Agrimonia eupatoria from leaves and roots were detected by GC-MS. Then the qualitative and quantitative analysis of the volatile components in the main root of Agrimonia eupatoria was completed with the help of subwindow factor analysis resolving two-dimensional original data into mass spectra and chromatograms. 68 of 87 separated constituents in the total ion chromatogram of the volatile components were identified and quantified, accounting for about 87.03% of the total content. Then, the common peaks in leaf were extracted with orthogonal projection resolution method. Among the components determined, there were 52 components coexisting in the studied samples although the relative content of each component showed difference to some extent. The results showed a fair consistency in their GC-MS fingerprint. It was the first time to apply orthogonal projection method to compare different plant parts of Agrimonia eupatoria, and it reduced the burden of qualitative analysis as well as the subjectivity. The obtained results proved the combined approach powerful for the analysis of complex Agrimonia eupatoria samples. The developed method can be used to further study and quality control of Agrimonia eupatoria.