Staged stenting strategy of acutely wide-neck ruptured intracranial aneurysms: A meta-analysis and systematic review.

Objective: In the study, we explored the safety and effectiveness of staged stenting strategy for acutely wide-neck ruptured intracranial aneurysms. Methods: Online databases, including PubMed, EMBASE, the Cochrane database, and Web of Science, were retrospectively and systematically searched. The main observation indicators were the procedure-related complication rate, complete occlusion rate, and favorable clinical outcome. Meta-analysis was performed using a random or fixed effect model based on heterogeneity. Results: A total of 5 studies with 143 patients were included. The hemorrhagic complication rate of the initial coiling and staged stenting was 2.8% (4 of 143) and 0, respectively. The ischemic complication rate of the coiling and supplemental stenting was 3.5% (5 of 143) and 2.9% (4 of 139), respectively. There were no deaths due to procedure-related complications in two stages. The aneurysm complete occlusion rate was 25% (95% CI, 0.13-0.03; I2 = 4.4%; P = 0.168) after initial coiling, 54% (95% CI, 0.63-0.64; I2 = 0%; P = 0.872) after staged stenting, and 74% (95% CI, 0.66-0.81; I2 = 56.4%; P = 0.562) at follow-up, respectively. Favorable clinical outcome rate 74% (95% CI, 0.61-0.86; I2 = 50.5%; P = 0.133) after discharge of initial coiling treatment, and 86% (95% CI, 0.80-0.92; I2 = 0; P = 0.410) after discharge from stenting, and 97% (95% CI, 0.93-1.01; I2 = 43.8%; P = 0.130) at follow-up. Conclusion: Staged stenting treatment of wide-neck RIA with coiling in the acute phase followed by delayed regular stent or flow-diverter stent had high aneurysm occlusion rate, favorable clinical outcome rate and low procedure-related complication rate. A more dedicated and well-designed controlled study is warranted for further evaluation of staged stenting treatment compared to SCA in wide-neck RIA.

Exact optical path difference and complete performance analysis of a spectral zooming imaging spectrometer.

The optical path difference (OPD) equations of the dual Wollaston prisms (DWP) with an adjustable air gap (AG) are derived by the wave normal tracing method, which is suitable for arbitrary incidence plane and angle. The spatial distribution of the OPD for various AG is presented. The validity of the OPD equation is verified by comparing the calculated interferograms with experimentally observed one. The performance of a novel static birefringent Fourier transform imaging spectrometer (SBFTIS) based on the DWP is investigated. The spectral resolution can be adjusted by changing the AG and the field of view can reach 10.0°, which is much larger than that predicted by our previous work. The results obtained in this article provide a theoretical basis for completely describing the optical transmission characteristic of the DWP and developing the high-performance birefringent spectral zooming imaging spectrometer.

Therapeutic aptamer targeting sclerostin loop3 for promoting bone formation without increasing cardiovascular risk in osteogenesis imperfecta mice.

Rationale: Sclerostin inhibition demonstrated bone anabolic potential in osteogenesis imperfecta (OI) mice, whereas humanized therapeutic sclerostin antibody romosozumab for postmenopausal osteoporosis imposed clinically severe cardiac ischemic events. Therefore, it is desirable to develop the next generation sclerostin inhibitors to promote bone formation without increasing cardiovascular risk for OI. Methods and Results: Our data showed that sclerostin suppressed inflammatory responses, prevented aortic aneurysm (AA) and atherosclerosis progression in hSOSTki.Col1a2+/G610C.ApoE-/- mice. Either loop2&3 deficiency or inhibition attenuated sclerostin's suppressive effects on expression of inflammatory cytokines and chemokines in vitro, whilst loop3 deficiency maintained the protective effect of sclerostin on cardiovascular system both in vitro and in vivo. Moreover, loop3 was critical for sclerostin's antagonistic effect on bone formation in Col1a2+/G610C mice. Accordingly, a sclerostin loop3-specific aptamer aptscl56 was identified by our lab. It could recognize both recombinant sclerostin and sclerostin in the serum of OI patients via targeting loop3. PEG40k conjugated aptscl56 (Apc001PE) demonstrated to promote bone formation, increase bone mass and improve bone microarchitecture integrity in Col1a2+/G610C mice via targeting loop3, while did not show influence in inflammatory response, AA and atherosclerosis progression in Col1a2+/G610C.ApoE-/- mice with Angiotensin II infusion. Further, Apc001PE had no influence in the protective effect of sclerostin on cardiovascular system in hSOSTki.Col1a2+/G610C.ApoE-/- mice, while it inhibited the antagonistic effect of sclerostin on bone formation in hSOSTki.Col1a2+/G610C mice via targeting loop3. Apc001PE was non-toxic to healthy rodents, even at ultrahigh dose. Apc001PE for OI was granted orphan drug designation by US-FDA in 2019 (DRU-2019-6966). Conclusion: Sclerostin loop3-specific aptamer Apc001PE promoted bone formation without increasing cardiovascular risk in OI mice.

Targeting loop3 of sclerostin preserves its cardiovascular protective action and promotes bone formation.

Sclerostin negatively regulates bone formation by antagonizing Wnt signalling. An antibody targeting sclerostin for the treatment of postmenopausal osteoporosis was approved by the U.S. Food and Drug Administration, with a boxed warning for cardiovascular risk. Here we demonstrate that sclerostin participates in protecting cardiovascular system and inhibiting bone formation via different loops. Loop3 deficiency by genetic truncation could maintain sclerostin's protective effect on the cardiovascular system while attenuating its inhibitory effect on bone formation. We identify an aptamer, named aptscl56, which specifically targets sclerostin loop3 and use a modified aptscl56 version, called Apc001PE, as specific in vivo pharmacologic tool to validate the above effect of loop3. Apc001PE has no effect on aortic aneurysm and atherosclerotic development in ApoE-/- mice and hSOSTki.ApoE-/- mice with angiotensin II infusion. Apc001PE can promote bone formation in hSOSTki mice and ovariectomy-induced osteoporotic rats. In summary, sclerostin loop3 cannot participate in protecting the cardiovascular system, but participates in inhibiting bone formation.

Dickkopf-1: A Promising Target for Cancer Immunotherapy.

Clinical studies in a range of cancers have detected elevated levels of the Wnt antagonist Dickkopf-1 (DKK1) in the serum or tumors of patients, and this was frequently associated with a poor prognosis. Our analysis of DKK1 gene profile using data from TCGA also proves the high expression of DKK1 in 14 types of cancers. Numerous preclinical studies have demonstrated the cancer-promoting effects of DKK1 in both in vitro cell models and in vivo animal models. Furthermore, DKK1 showed the ability to modulate immune cell activities as well as the immunosuppressive cancer microenvironment. Expression level of DKK1 is positively correlated with infiltrating levels of myeloid-derived suppressor cells (MDSCs) in 20 types of cancers, while negatively associated with CD8+ T cells in 4 of these 20 cancer types. Emerging experimental evidence indicates that DKK1 has been involved in T cell differentiation and induction of cancer evasion of immune surveillance by accumulating MDSCs. Consequently, DKK1 has become a promising target for cancer immunotherapy, and the mechanisms of DKK1 affecting cancers and immune cells have received great attention. This review introduces the rapidly growing body of literature revealing the cancer-promoting and immune regulatory activities of DKK1. In addition, this review also predicts that by understanding the interaction between different domains of DKK1 through computational modeling and functional studies, the underlying functional mechanism of DKK1 could be further elucidated, thus facilitating the development of anti-DKK1 drugs with more promising efficacy in cancer immunotherapy.

Structural Biology for the Molecular Insight between Aptamers and Target Proteins.

Aptamers are promising therapeutic and diagnostic agents for various diseases due to their high affinity and specificity against target proteins. Structural determination in combination with multiple biochemical and biophysical methods could help to explore the interacting mechanism between aptamers and their targets. Regrettably, structural studies for aptamer-target interactions are still the bottleneck in this field, which are facing various difficulties. In this review, we first reviewed the methods for resolving structures of aptamer-protein complexes and for analyzing the interactions between aptamers and target proteins. We summarized the general features of the interacting nucleotides and residues involved in the interactions between aptamers and proteins. Challenges and perspectives in current methodologies were discussed. Approaches for determining the binding affinity between aptamers and target proteins as well as modification strategies for stabilizing the binding affinity of aptamers to target proteins were also reviewed. The review could help to understand how aptamers interact with their targets and how alterations such as chemical modifications in the structures affect the affinity and function of aptamers, which could facilitate the optimization and translation of aptamers-based theranostics.

Connective Tissue Growth Factor: From Molecular Understandings to Drug Discovery.

Connective tissue growth factor (CTGF) is a key signaling and regulatory molecule involved in different biological processes, such as cell proliferation, angiogenesis, and wound healing, as well as multiple pathologies, such as tumor development and tissue fibrosis. Although the underlying mechanisms of CTGF remain incompletely understood, a commonly accepted theory is that the interactions between different protein domains in CTGF and other various regulatory proteins and ligands contribute to its variety of functions. Here, we highlight the structure of each domain of CTGF and its biology functions in physiological conditions. We further summarized main diseases that are deeply influenced by CTGF domains and the potential targets of these diseases. Finally, we address the advantages and disadvantages of current drugs targeting CTGF and provide the perspective for the drug discovery of the next generation of CTGF inhibitors based on aptamers.

Snapshot broadband polarization imaging based on Mach-Zehnder-grating interferometer.

Full polarization imaging plays an important role in remote sensing to distinguish artificial objects from the natural environment, recognizing objects in shadows and sun glint suppression. In this paper, we propose a broadband full Stokes channeled modulated polarization imaging system based on a Mach-Zehnder-grating interferometer (MZGI) with advantages such as compact size, low cost, snapshot ability, and high optical efficiency. It uses gratings to compensate for the dispersion of the carried frequency when inputting broadband light to generate interference fringes. Two detectors are assembled to the output plane to acquire the interference fringes. Each image obtained by the detectors can be individually demodulated into different Stokes parameters individually. When the two groups are combined together, the full Stokes parameters are obtained. The simulation and optical efficiency analysis demonstrate that the interference fringes can obtain the full polarization information simultaneously with high optical efficiency in broadband wavelengths.

Pros and Cons of Denosumab Treatment for Osteoporosis and Implication for RANKL Aptamer Therapy.

Osteoporosis is age-related deterioration in bone mass and micro-architecture. Denosumab is a novel human monoclonal antibody for osteoporosis. It is a receptor activator of nuclear factor-κB ligand (RANKL) inhibitor, which binds to and inhibits osteoblast-produced RANKL, in turn reduces the binding between RANKL and osteoclast receptor RANK, therefore decreases osteoclast-mediated bone resorption and turnover. However, adverse events have also been reported after denosumab treatment, including skin eczema, flatulence, cellulitis and osteonecrosis of the jaw (ONJ). Extensive researches on the mechanism of adverse reactions caused by denosumab have been conducted and may provide new insights into developing new RANKL inhibitors that achieve better specificity and safety. Aptamers are single-stranded oligonucleotides that can bind to target molecules with high specificity and affinity. They are screened from large single-stranded synthetic oligonucleotides and enriched by a technology named SELEX (systematic evolution of ligands by exponential enrichment). With extra advantages such as high stability, low immunogenicity and easy production over antibodies, aptamers are hypothesized to be promising candidates for therapeutic drugs targeting RANKL to counteract osteoporosis. In this review, we focus on the pros and cons of denosumab treatment in osteoporosis and the implication for novel aptamer treatment.

Bushen Yijing Fang Reduces Fall Risk in Late Postmenopausal Women with Osteopenia: A Randomized Double-blind and Placebo-controlled Trial.

Falls in late postmenopausal women with osteopenia usually cause fractures with severe consequences. This 36-month randomized, double-blind and placebo-controlled trial with a 10-year observational follow-up study aimed to investigate the long-term effect of herbal formula Bushen Yijing Fang (BSYJF) on fall risk in the late postmenopausal women with osteopenia. 140 late postmenopausal women (Femoral neck T-score, -2.5~-2 SD) were recruited and randomized to orally receive calcium carbonate 300 mg daily with either BSYJF or placebo for 36 months. The effect was further investigated for another 10-year follow-up. During the 36-month administration, there were 12 falls in BSYJF group and 28 falls in placebo group, respectively, indicating 64% lower risk of falls (RR 0.36 [95% CI, 0.18 to 0.71]; P = 0.004) in BSYJF group. During the 10-year follow-up, 36% lower fall risk (RR 0.64 [95% CI, 0.46 to 0.89]; P = 0.009) was observed in BSYJF group. No significant difference was found in safety profile between two groups. Thirty-six-month administration of BSYJF reduced fall risk with an increase in bone mass, and its latent effect on fall risk was continually observed in the 10-year follow-up in late postmenopausal women with osteopenia. This clinical trial was registered at Chinese clinical trial registry (ChiCTR-IOR-16008942).

Long Noncoding RNA lncMUMA Reverses Established Skeletal Muscle Atrophy following Mechanical Unloading.

Reversing established muscle atrophy following mechanical unloading is of great clinical challenge. Long noncoding RNAs (lncRNAs) have been demonstrated to play important roles in myogenesis. Here we identified a lncRNA (mechanical unloading-induced muscle atrophy-related lncRNA [lncMUMA]) enriched in muscle, which was the most downregulated lncRNA during muscle atrophy development in hindlimb suspension (HLS) mice. The in vitro and in vivo data demonstrated that the decreased expression levels of lncMUMA closely associated with a reduction of myogenesis during mechanical unloading. Mechanistically, lncMUMA promoted myogenic differentiation by functioning as a miR-762 sponge to regulate the core myogenic regulator MyoD in vitro. The enforced expression of lncMUMA relieved the decreases in MyoD protein and muscle mass in miR-762 knockin mice. Therapeutically, the enforced expression of lncMUMA improved the in vitro myogenic differentiation of myoblasts under microgravity simulation, prevented the muscle atrophy development, and reversed the established muscle atrophy in HLS mice. These findings identify lncMUMA as an anabolic regulator to reverse established muscle atrophy following mechanical unloading.

Transparent intersatellite optical wireless communication link with double sideband-suppressed carrier modulation and coherent homodyne detection.

In this paper, we present an intersatellite optical wireless communication (IsOWC) link with double sideband-suppressed carrier (DSB-SC) modulation and coherent homodyne detection (CD), which enables transparent transport of multiband radio frequency (RF) signals. The performance of transparent multiband IsOWC link employing DSB-SC/CD and phase modulation with CD (PM/CD) is investigated. The theoretical model considers the finite extinction ratio (ER) of a Mach-Zehnder modulator (MZM) and the saturation property of an optical booster amplifier. The expressions of RF gain, noise figure (NF) and third-order spurious-free dynamic range (SFDR) are derived considering the third-order intermodulation product and amplifier spontaneous emission noise for both architectures. Numerical results for RF gain, NF, and third-order SFDR are given for demonstration. Results indicate that DSB-SC/CD can provide higher linearity and better sensitivity than PM/CD. The performance of the DSB-SC/CD scheme is obviously influenced by the ER of MZM. The gain of the optical preamplifier and the power of a local oscillator optical signal should be optimized to obtain satisfactory performance.

Novel tetrahydrofuran derivatives from Trigonostemon howii with their potential anti-HIV-1 activities.

A novel tetrahydrofuran derivative, trigonohowine (1), together with five known tetrahydrofuran derivatives (2-6), were isolated from the stems and leaves of Trigonostemon howii. The structure of 1 was elucidated by extensive spectroscopic methods and the known compounds were identified by comparisons with the data reported in literature. Among them, trigonohowine (1) represents the first example of a new type of tetrahydrofuran derivative, possessing an unprecedented carbon skeleton containing 23 carbon atoms on the carbon skeleton and the known compouds (2-6) are rare tetrahydrofuran derivatives in the plant kingdom with various carbon skeletons. All isolated compounds were evaluated for their anti-HIV-1 activities. Compounds 1-6 showed significant anti-HIV-1 activities with EC50 ranged from 0.08 to 1.03 µM. These findings suggest that the discoveries of these tetrahydrofuran derivatives with significant anti-HIV-1 activities isolated from T. howii could be of great importance to the development of new anti-HIV agents.

A newly identified lncRNA MAR1 acts as a miR-487b sponge to promote skeletal muscle differentiation and regeneration.

BACKGROUND: Skeletal muscle atrophy induced by either aging (sarcopenia) or mechanical unloading is associated with serious health consequences. Long non-coding RNAs (lncRNAs) are implicated as important regulators in numerous physiological and pathological processes. METHODS: Microarray analysis was performed to identify the differentially expressed lncRNAs in skeletal muscle between adult and aged mice. The most decreased lncRNA in aged skeletal muscle was identified. The C2C12 mouse myoblast cells were used to assess the biological function of the lncRNA in vitro. The target microRNA of lncRNA and the target protein of microRNA were predicted by bioinformatics analysis and validated in vitro. Furthermore, the biology function of the lncRNA in vivo was investigated by local overexpression or knockdown the lncRNA in skeletal muscle. The therapeutic effect of the lncRNA overexpression in age-related or mechanical unloading-induced muscle atrophy was also evaluated. RESULTS: We identified a novel lncRNA (muscle anabolic regulator 1, MAR1) which was highly expressed in mice skeletal muscle and positively correlated with muscle differentiation and growth in vitro and in vivo. We predicted and validated that microRNA-487b (miR-487b) was a direct target of MAR1. We also predicted and validated that Wnt5a, an important regulator during myogenesis, was a target of miR-487b in C2C12 cells. Our findings further demonstrated that enforced MAR1 expression in myoblasts led to derepression of Wnt5a. Moreover, MAR1 promoted skeletal muscle mass/strength and Wnt5a protein level in mice. Enforced MAR1 expression in mice attenuated muscle atrophy induced by either aging or unloading. CONCLUSIONS: The newly identified lncRNA MAR1 acts as a miR-487b sponge to regulate Wnt5a protein, resulting in promoting muscle differentiation and regeneration. MAR1 could be a novel therapeutic target for treating muscle atrophy induced by either aging or mechanical unloading.

A water-soluble nucleolin aptamer-paclitaxel conjugate for tumor-specific targeting in ovarian cancer.

Paclitaxel (PTX) is among the most commonly used first-line drugs for cancer chemotherapy. However, its poor water solubility and indiscriminate distribution in normal tissues remain clinical challenges. Here we design and synthesize a highly water-soluble nucleolin aptamer-paclitaxel conjugate (NucA-PTX) that selectively delivers PTX to the tumor site. By connecting a tumor-targeting nucleolin aptamer (NucA) to the active hydroxyl group at 2' position of PTX via a cathepsin B sensitive dipeptide bond, NucA-PTX remains stable and inactive in the circulation. NucA facilitates the uptake of the conjugated PTX specifically in tumor cells. Once inside cells, the dipeptide bond linker of NucA-PTX is cleaved by cathepsin B and then the conjugated PTX is released for action. The NucA modification assists the selective accumulation of the conjugated PTX in ovarian tumor tissue rather than normal tissues, and subsequently resulting in notably improved antitumor activity and reduced toxicity.

Tumor cell-targeted delivery of CRISPR/Cas9 by aptamer-functionalized lipopolymer for therapeutic genome editing of VEGFA in osteosarcoma.

Osteosarcoma (OS) is a highly aggressive pediatric cancer, characterized by frequent lung metastasis and pathologic bone destruction. Vascular endothelial growth factor A (VEGFA), highly expressed in OS, not only contributes to angiogenesis within the tumor microenvironment via paracrine stimulation of vascular endothelial cells, but also acts as an autocrine survival factor for tumor cell themselves, thus making it a promising therapeutic target for OS. CRISPR/Cas9 is a versatile genome editing technology and holds tremendous promise for cancer treatment. However, a major bottleneck to achieve the therapeutic potential of the CRISPR/Cas9 is the lack of in vivo tumor-targeted delivery systems. Here, we screened an OS cell-specific aptamer (LC09) and developed a LC09-functionalized PEG-PEI-Cholesterol (PPC) lipopolymer encapsulating CRISPR/Cas9 plasmids encoding VEGFA gRNA and Cas9. Our results demonstrated that LC09 facilitated selective distribution of CRISPR/Cas9 in both orthotopic OS and lung metastasis, leading to effective VEGFA genome editing in tumor, decreased VEGFA expression and secretion, inhibited orthotopic OS malignancy and lung metastasis, as well as reduced angiogenesis and bone lesion with no detectable toxicity. The delivery system simultaneously restrained autocrine and paracrine VEGFA signaling in tumor cells and could facilitate translating CRISPR-Cas9 into clinical cancer treatment.

TAK1 inhibition attenuates both inflammation and fibrosis in experimental pneumoconiosis.

Pneumoconiosis, caused by inhalation of mineral dusts, is a major occupational disease worldwide. Currently, there are no effective drugs owing to a lack of potential therapeutic targets during either the inflammation or fibrosis molecular events in pneumoconiosis. Here, we performed microarrays to identify aberrantly expressed genes in the above molecular events in vitro and found a hub gene transforming growth factor-ß-activated kinase 1 (TAK1), which was highly expressed and activated in pneumoconiosis patients as well as silica-exposed rats with experimental pneumoconiosis. Genetic modulation of TAK1 by CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9, RNA interference and overexpression indicated the important role of TAK1 in both inflammation and fibrosis in experimental pneumoconiosis. To achieve pharmacological TAK1 inhibition, we virtually screened out a natural product resveratrol, which targeted TAK1 at both N161 and A107 residues, and significantly inhibited TAK1 activation to attenuate inflammation and fibrosis in vitro. Consistently, in vivo prevention and intervention studies showed that resveratrol could inhibit pulmonary inflammation and fibrosis in silica-exposed rats.

Effect of capsaicin-sensitive sensory neurons on bone architecture and mechanical properties in the rat hindlimb suspension model.

BACKGROUND/OBJECTIVE: The participation of sensory neural regulation in bone metabolism has been widely studied. However, the physiological role of sensory neural regulation in the functional adaptation to weight bearing is not clear. This study was conducted to investigate the effect of capsaicin-induced sensory neuron lesions on cancellous architecture properties in a hindlimb suspension (HLS) model. METHODS: Thirty-two female rats were randomly assigned to four groups. Groups b and d underwent systemic capsaicin treatment, whereas Groups a and c were treated with vehicle. Then, Groups c and d were subjected to HLS, whereas Groups a and b were allowed hindlimbs full loading. The proximal trabecular and mid-shaft cortical bone structure were evaluated via microcomputed tomography, and the biomechanical properties of the tibial mid-shaft were assessed using the four-point bending test. RESULTS: The trabecular bone volume was reduced by 40% and 50% in Groups b and c, respectively, and was also reduced significantly in Group d. Trabecular thickness and trabecular separation in Group b were not significantly different from those of Group a. The cortical bone area fraction showed no significant difference among all groups. Compared with Group a, the ultimate strength in Group b decreased by 20.3%, whereas it did not change significantly in Group c. CONCLUSION: The results suggest that capsaicin-sensitive sensory neurons play an important role in bone modelling. The effect of capsaicin is similar to HLS. However, HLS has no add-on effect to capsaicin in the reduction of bone density and mechanical properties.Translational potential of this article: This study gives clues to the function of sensory neurons in bone modelling.

Ochroborbone, A New Cytotoxic Indole Alkaloid from Ochrosia borbonica.

A new monoterpenoid indole alkaloid, ochroborbone (1), along with five known alkaloids (2-6), were isolated from the stems and leaves of Ochrosia borbonica. Among them, ochroborbone (1) is a rare C17-nor monoterpenoid indole alkaloid, and the known compounds (2-6) were isolated from Ochrosia for the first time-These structures were established on the basis of extensive spectroscopic methods. All isolated compounds were evaluated for their cytotoxicities against five human cancer cell lines: HL-60, SMMC-7721, A-549, MCF-7 and SW480 in vitro. Compounds 1 and 2 exhibited inhibitory effects with IC50 values comparable with those of cisplatin.

Ochroborbone, A New Cytotoxic Indole Alkaloid from Ochrosia borbonica.

A new monoterpenoid indole alkaloid, ochroborbone (1), along with five known alkaloids (2-6), were isolated from the stems and leaves of Ochrosia borbonica. Among them, ochroborbone (1) is a rare C17-nor monoterpenoid indole alkaloid, and the known compounds (2-6) were isolated from Ochrosia for the first time. These structures were established on the basis of extensive spectroscopic methods. All isolated compounds were evaluated for their cytotoxicities against five human cancer cell lines: HL-60, SMMC-7721, A-549, MCF-7 and SW480 in vitro. Compounds 1 and 2 exhibited inhibitory effects with IC50 values comparable with those of cisplatin.