Physiological Effects of Microgravity on Bone Cells

Life on Earth developed under the influence of normal gravity (1g). With evidence from previous studies, scientists have suggested that normal physiological processes, such as the functional integrity of muscles and bone mass, can be affected by microgravity during spaceflight. During the life span, bone not only develops as a structure designed specifically for mechanical tasks but also adapts for efficiency. The lack of weight-bearing forces makes microgravity an ideal physical stimulus to evaluate bone cell responses. One of the most serious problems induced by long-term weightlessness is bone mineral loss. Results from in vitro studies that entailed the use of bone cells in spaceflights showed modification in cell attachment structures and cytoskeletal reorganization, which may be involved in bone loss. Humans exposed to microgravity conditions experience various physiological changes, including loss of bone mass, muscle deterioration, and immunodeficiency. In vitro models can be used to extract valuable information about changes in mechanical stress to ultimately identify the different pathways of mechanotransduction in bone cells. Despite many in vivo and in vitro studies under both real microgravity and simulated conditions, the mechanism of bone loss is still not well defined. The objective of this review is to summarize the recent research on bone cells under microgravity conditions based on advances in the field.     

The chronic hepatotoxicity assessment of the herbal formula Zishen Yutai pill

Zishen Yutai pill (ZYP) is an oriental herbal formula, while hepatotoxicity assessment of ZYP was rarely evaluated. Therefore, our aim is to re-evaluate its hepatotoxicity in both normal and carbon tetrachloride (CCl₄) induced chronic liver injury rats. In the normal model, two doses of ZYP (1.575 and 9.450 g kg⁻¹ d⁻¹; i.e. 1 × , 6 × clinical doses) were given orally to rats for 24 weeks. In the chronic liver injury model, 10% CCl₄ was administered to rats abdominally twice a week at a dose of 5 mL kg⁻¹ for 12 consecutive weeks. Administration time started from 4 weeks after the beginning of CCl₄ treatment. Toxicological parameters included mortality, body weight, food consumption, clinical signs, biochemical parameters, gross observation, organ weight, necropsy findings and histopathology were monitored. In the normal model, we found no any mortality or abnormality in clinical signs, relative liver weight, biochemical parameters and histopathology in ZYP treatment groups. In the chronic liver injury model, liver damage related parameter such as ALT was elevated at the high dose of ZYP treatment in contrast to the CCl₄-treated group (P < 0.01). In histopathological assessment, there were no significant difference between ZYP treatment groups and CCl₄-treated group. No observed adverse effect on livers were established for 9.450 g kg⁻¹ d⁻¹ ZYP in the normal rats and 9.450 g kg⁻¹ d⁻¹ ZYP in the injury rats.     

The adsorption of preferential binding peptides to apatite-based materials

The objective of this work was to identify peptide sequences with high affinity to bone-like mineral (BLM) to provide alternative design methods for functional bone regeneration peptides. Adsorption of preferential binding peptide sequences on four apatite-based substrates [BLM and three sintered apatite disks pressed from powders containing 0% CO₃^2? (HA), 5.6% CO₃^2? (CA5), 10.5% CO₃^2? (CA10)] with varied compositions and morphologies was investigated. A combination of phage display, ELISA, and computational modeling was used to elucidate three 12-mer peptide sequences APWHLSSQYSRT (A), STLPIPHEFSRE (S), and VTKHLNQISQSY (V), from 243 candidates with preferential adsorption on BLM and HA. Overall, peptides S and V have a significantly higher adsorption to the apatite-based materials in comparison to peptide A (for S vs. A, BLM p = 0.001, CA5 p < 0.001, CA10 p < 0.001, HA p = 0.038; for V vs. A, BLM p = 0.006, CA5 p = 0.033, CA10 p = 0.029). FT-IR analysis displayed carbonate levels in CA5 and CA10 dropped to approximately 1.1–2.2% after sintering, whereas SEM imaging displayed CA5 and CA10 possess distinct morphologies. Adsorption results normalized to surface area indicate that small changes in carbonate percentage at a similar morphological scale did not provide enough carbonate incorporation to show statistical differences in peptide adsorption. Because the identified peptides (S and V) have preferential binding to apatite, their use can now be investigated in bone and dentin tissue engineering, tendon and ligament repair, and enamel formation.     

Impact of an autologous oxygenating matrix culture system on rat islet transplantation outcome

Disruption of the pancreatic islet environment combined with the decrease in oxygen supply that occurs during isolation leads to poor islet survival. The aim of this study was to validate the benefit of using a plasma-based scaffold supplemented with perfluorodecalin to improve islet transplantation outcome.Rat islets were cultured in three conditions: i) control group, ii) plasma based-matrix (P-matrix), and iii) P-matrix supplemented with emulsified perfluorodecalin. After 24 h culture, matrix/cell contacts (Integrinβ1, p-FAK/FAK, p-Akt/Akt), survival (caspase 3, TUNEL, FDA/PI), function, and HIF-1α translocation were assessed. Afterwards, P-matrices were dissolved and the islets were intraportally transplanted. Graft function was monitored for 31 days with glycaemia and C-peptide follow up. Inflammation was assessed by histology (macrophage and granulocyte staining) and thrombin/anti-thrombin complex measurement.Islet survival correlated with an increase in integrin, FAK, and Akt activation in P-matrices and function was maintained. Perfluorodecalin supplementation decreased translocation of HIF-1α in the nucleus and post-transplantation islet structure was better preserved in P-matrices, but a quicker activation of IBMIR resulted in early loss of graft function.“Oxygenating” P-matrices provided a real benefit to islet survival and resistance in vivo. However, intraportal transplantation is not suitable for this kind of culture due to IBMIR; thus, alternative sites must be explored.     

Drug discovery of sclerostin inhibitors

Sclerostin, a protein secreted from osteocytes, negatively regulates the WNT signaling pathway by binding to the LRP5/6 co-receptors and further inhibits bone formation and promotes bone resorption. Sclerostin contributes to musculoskeletal system-related diseases, making it a promising therapeutic target for the treatment of WNT-related bone diseases. Additionally, emerging evidence indicates that sclerostin contributes to the development of cancers, obesity, and diabetes, suggesting that it may be a promising therapeutic target for these diseases. Notably, cardiovascular diseases are related to the protective role of sclerostin. In this review, we summarize three distinct types of inhibitors targeting sclerostin, monoclonal antibodies, aptamers, and small-molecule inhibitors, from which monoclonal antibodies have been developed. As the first-in-class sclerostin inhibitor approved by the U.S. FDA, the monoclonal antibody romosozumab has demonstrated excellent effectiveness in the treatment of postmenopausal osteoporosis; however, it conferred high cardiovascular risk in clinical trials. Furthermore, romosozumab could only be administered by injection, which may cause compliance issues for patients who prefer oral therapy. Considering these above safety and compliance concerns, we therefore present relevant discussion and offer perspectives on the development of next-generation sclerostin inhibitors by following several ways, such as concomitant medication, artificial intelligence-based strategy, druggable modification, and bispecific inhibitors strategy.     

Ligustrazine attenuates inflammation and the associated chemokines and receptors in ovalbumine-induced mouse asthma model

Ligustrazine which is isolated from Chinese herb ligusticum chuanxiong hort, has been widely used in traditional Chinese medicine (TCM) for asthma treatment. In this study, we aim to observe the effect of ligustrazine on inflammation and the associated chemokines and receptors in ovalbumin (OVA)-induced mouse asthma model. Our data demonstrates that ligustrazine suppresses airway hyperresponsiveness to methacholine and lung inflammation in OVA-induced mouse asthma model. Ligustrazine also induces inhibition of inflammatory cells including neutrophils, lymphocytes and eosinophils. In addition, ligustrazine significantly reduces IL-4, IL-5, IL-17A, CCL3, CCL19 and CCL21 level in BALF of asthma mice. Furthermore, ligustrazine induces down-regulation of CCL19 receptor CCR7, STAT3 and p38 MAPK protein expression. Collectively, these results suggest that ligustrazine is effective in attenuation of allergic airway inflammatory changes and related chemokines and receptors in OVA-induced asthma model, and this action might be associated with inhibition of STAT3 and p38 MAPK pathway, which indicates that ligustrazine may be used as a potential therapeutic method to treat asthma.     

Deciphering Potential Correlations between New Biomarkers and Pattern Classification in Chinese Medicine by Bioinformatics: Two Examples of Rheumatoid Arthritis

Biological complexity and the need for personalized medicine means that biomarker development has become increasingly challenging. Thus, new paradigms for research need to be created that bring together a different classifier of individuals. One potential solution is collaboration between biomarker development and Chinese medicine pattern classification. In this article, two examples of rheumatoid arthritis are discussed, including a new biomarker candidate casein kinase 2 interacting protein 1 (CKIP-1) and a micro RNA 214. The authors obtained a "snapshot" of pattern classification with disease in biomarker identification. Bioinformatics analyses revealed underlying biological functions of two biomarker candidates, in varying degrees, are correlated with Chinese medicine pattern of rheumatoid arthritis. The authors'' initial attempt can provide a new window for studying the win-win potential correlation between the biomarkers and pattern classification in Chinese medicine.     

Physiological functions of CKIP-1: From molecular mechanisms to therapy implications

The casein kinase 2 interacting protein-1 (CKIP-1, also known as PLEKHO1) is initially identified as a specific CK2α subunit-interacting protein. Subsequently, various proteins, including CPα, PAK1, Arp2/3, HDAC1, c-Jun, ATM, Smurf1, Rpt6, Akt, IFP35, TRAF6, REGγ and CARMA1, were reported to interact with CKIP-1. Owing to the great diversity of interacted proteins, CKIP-1 exhibits multiple biologic functions in cell morphology, cell differentiation and cell apoptosis. Besides, these functions are subcellular localization, cell type, and regulatory signaling dependent. CKIP-1 is involved in biological processes consisting of bone formation, tumorigenesis and immune regulation. Importantly, deregulation of CKIP-1 results in osteoporosis, tumor, and atherosclerosis. In this review, we introduce the molecular functions, biological processes and promising of therapeutic strategies. Through summarizing the intrinsic mechanisms, we expect to open new therapeutic avenues for CKIP-1.