Codonopsis pilosula polysaccharides promote osteogenic differentiation and inhibit lipogenic differentiation of rat bone marrow stem cells by activating ß-catenin.

Aberrant bone marrow mesenchymal stem cell (BMSC) lineage differentiation leads to osteoporosis. Codonopsis pilosula polysaccharides (CPPs) have been widely used in traditional Chinese medicines, due to their multiple pharmacological actions. However, little is known regarding their effects on BMSC differentiation. This study aimed to identify the effects and mechanisms of CPPs on osteogenic and adipogenic differentiation in rat BMSCs. An osteoporosis model was established in Sprague-Dawley (SD) rats through bilateral ovariectomy (OVX), and be applied to observe the effect of CPPs on osteoporosis in vivo. The ability of CPPs to affect rBMSC proliferation was determined using the CCK-8 assay, and the osteogenic differentiation of rBMSCs measured by ALP and Alizarin Red S staining. The adipogenic differentiation of rBMSCs was measured by Oil Red O staining. The mRNA and protein levels related to osteogenesis and adipogenic differentiation of rBMSCs were measured using qRT-PCR and western blotting, respectively. Cellular immunofluorescence was used to detect cytokine expression and localisation in rBMSCs. We observed that CPPs ameliorated bone loss in OVX rats. CPPs considerably enhanced osteogenic differentiation by increasing ALP activity and the prevalence of mineralised nodules and promoting the mRNA and protein expression of osteogenic differentiation markers (RUNX2, COL I, ALP, and OPN). Furthermore, it inhibited the accumulation of lipid vesicles in the cytoplasm and the mRNA and protein expression levels of adipogenic differentiation markers (PPARγ and C/EBPα) in a concentration-dependent manner. Meanwhile, CPPs notably increased the mRNA and protein expression of ß-catenin, the core protein of the Wnt/ß-catenin signaling pathway, in a concentration-dependent manner. Adding DKK1, a mature inhibitor of the Wnt/ß-catenin signaling pathway, partially suppressed CPP-stimulated ß-catenin activation, and reversed the acceleration of osteogenic differentiation and the inhibition of lipogenic differentiation. Our observations demonstrated CPPs ameliorate bone loss in OVX rats in vivo, and favour osteogenic differentiation while inhibit adipogenic differentiation of rBMSCs in vitro. The findings suggested that CPPs could serve as functional foods for bone health, and have great potential for the prevention and treatment of osteoporosis.

Thioredoxin-interacting protein: A new therapeutic target in bone metabolism disorders?

Target identification is essential for developing novel therapeutic strategies in diseases. Thioredoxin-interacting protein (TXNIP), also known as thioredoxin-binding protein-2, is a member of the α-arrestin protein family and is regulated by several cellular stress factors. TXNIP overexpression coupled with thioredoxin inhibits its antioxidant functions, thereby increasing oxidative stress. TXNIP is directly involved in inflammatory activation by interacting with Nod-like receptor protein 3 inflammasome. Bone metabolic disorders are associated with aging, oxidative stress, and inflammation. They are characterized by an imbalance between bone formation involving osteoblasts and bone resorption by osteoclasts, and by chondrocyte destruction. The role of TXNIP in bone metabolic diseases has been extensively investigated. Here, we discuss the roles of TXNIP in the regulatory mechanisms of transcription and protein levels and summarize its involvement in bone metabolic disorders such as osteoporosis, osteoarthritis, and rheumatoid arthritis. TXNIP is expressed in osteoblasts, osteoclasts, and chondrocytes and affects the differentiation and functioning of skeletal cells through both redox-dependent and -independent regulatory mechanisms. Therefore, TXNIP is a potential regulatory and functional factor in bone metabolism and a possible new target for the treatment of bone metabolism-related diseases.

Bibliometric study of soluble guanylate cyclase stimulators in cardiovascular research based on web of science from 1992 to 2021.

Background: Several studies have shown that soluble guanylate cyclase (sGC) stimulators have cardiovascular (CV) benefits. However, few bibliometric analyses have examined this field systematically. Our study aimed to examine the publications to determine the trends and hotspots in CV research on sGC stimulators. Methods: Publications on sGC stimulators in CV research were retrieved from the Web of Science Core Collection. VOSviewer and CiteSpace visualization software were used to analyze publication trends, countries (regions) and institutions, journals and cited journals, authors and cited references, as well as keywords. Results: A total of 1,212 literatures were obtained. From its first appearance in 1992-2021 (based on WOSCC record), the overall volume of publications has shown a gradual increasing trend. Nearly one-third were authored by American scholars, and most were published in Circulation, Circulation Research, and Proceedings of the National Academy of Sciences of the United States of America. Bayer Agency in Germany was the leading driving force, and has a high academic reputation in this field. Stasch JP has published the most related articles and been cited most frequently. Half of the top 10 co-cited references were published in the leading highly co-cited journal Circulation and New England Journal of Medicine. "NO," "allosteric regulation" and "free radicals" were the focus of previous research, "chronic thromboembolic pulmonary hypertension," "pulmonary hypertension" and "heart failure" were the main research hotspots. The key words "chronic thromboembolic pulmonary hypertension," "Pulmonary hypertension," "preserved ejection fraction" and "heart failure" appeared most recently as research frontiers. Conclusion: The research in the CV field of sGC stimulators was relatively comprehensive, and there was a close relationship among countries, research institutions and authors, but it is still in the exploratory stage in the treatment of CV disease. At present, most studies focus on the results of clinical trials. sGC stimulators in the treatment of heart failure, especially heart failure with preserved ejection fraction, may be the hotpots and Frontier at present and in the future, and should be closely monitored.

The Role of NRF2 in Bone Metabolism - Friend or Foe?

Bone metabolism is closely related to oxidative stress. As one of the core regulatory factors of oxidative stress, NRF2 itself and its regulation of oxidative stress are both involved in bone metabolism. NRF2 plays an important and controversial role in the regulation of bone homeostasis in osteoblasts, osteoclasts and other bone cells. The role of NRF2 in bone is complex and affected by several factors, such as its expression levels, age, sex, the presence of various physiological and pathological conditions, as well as its interaction with certains transcription factors that maintain the normal physiological function of the bone tissue. The properties of NRF2 agonists have protective effects on the survival of osteogenic cells, including osteoblasts, osteocytes and stem cells. Activation of NRF2 directly inhibits osteoclast differentiation by resisting oxidative stress. The effects of NRF2 inhibition and hyperactivation on animal skeleton are still controversial, the majority of the studies suggest that the presence of NRF2 is indispensable for the acquisition and maintenance of bone mass, as well as the protection of bone mass under various stress conditions. More studies show that hyperactivation of NRF2 may cause damage to bone formation, while moderate activation of NRF2 promotes increased bone mass. In addition, the effects of NRF2 on the bone phenotype are characterized by sexual dimorphism. The efficacy of NRF2-activated drugs for bone protection and maintenance has been verified in a large number of in vivo and in vitro studies. Additional research on the role of NRF2 in bone metabolism will provide novel targets for the etiology and treatment of osteoporosis.

Metabolic (Dysfunction)-Associated Fatty Liver Disease in Chinese Patients with Type 2 Diabetes from a Subcenter of the National Metabolic Management Center.

BACKGROUND: Few studies have investigated the epidemiological metabolic (dysfunction) associated with fatty liver disease (MAFLD) in China, especially among those with type 2 diabetes. METHODS: We recruited 3553 patients aged 18-75 years with type 2 diabetes who underwent abdominal ultrasound and serum biochemical analyses. Patient information including demographic and anthropometric parameters was also collected. RESULTS: Overall, 63.2% of type 2 diabetic patients had MAFLD. Among the MAFLD patients, the proportions of lean, nonobese, and obese MAFLD were 23.1%, 75.7%, and 24.3%, respectively, and the percentage of previously undiagnosed MAFLD was 42.2%. MAFLD patients were younger, had shorter diabetic duration, and had greater BMI, aspartate aminotransferase (AST), alanine aminotransferase (ALT), fasting insulin, postprandial insulin, total cholesterol, and insulin resistance levels (HOMA-IR and TyG index). Liver fibrosis diagnostic panels revealed that the proportions of elevated AST (≥40 U/L) and ALT (≥40 U/L) were 7.3% and 18.5%, respectively. The distributions of AST-to-platelet ratio index (APRI), fibrosis-4 (FIB-4) index, and nonalcoholic fatty liver disease fibrosis score (NFS) per stage were as follows: APRI-low 55.1%, indeterminate 35.3%, and high 9.5%; FIB-4-low 48.2%, indeterminate 45.3%, and high 6.5%; and NFS-low 15.0%, indeterminate 70.0%, and high 13.0%. CONCLUSIONS: MAFLD is a very common condition and generally had greater frequency of metabolic characteristics among type 2 diabetics in China. Many MAFLD patients were in the "indeterminate" or "high" stage when APRI, FIB-4, and NFS were assessed. Assessment of MAFLD should be included in the management of type 2 diabetes.

NLRP3 Inflammasome: A New Target for Prevention and Control of Osteoporosis?

Osteoporosis is a systemic bone metabolism disease that often causes complications, such as fractures, and increases the risk of death. The nucleotide-binding oligomerization domain-like-receptor family pyrin domain-containing 3 (NLRP3) inflammasome is an intracellular multiprotein complex that regulates the maturation and secretion of Caspase-1 dependent proinflammatory cytokines interleukin (IL)-1ß and IL-18, mediates inflammation, and induces pyroptosis. The chronic inflammatory microenvironment induced by aging or estrogen deficiency activates the NLRP3 inflammasome, promotes inflammatory factor production, and enhances the inflammatory response. We summarize the related research and demonstrate that the NLRP3 inflammasome plays a vital role in the pathogenesis of osteoporosis by affecting the differentiation of osteoblasts and osteoclasts. IL-1ß and IL-18 can accelerate osteoclast differentiation by expanding inflammatory response, and can also inhibit the expression of osteogenic related proteins or transcription factors. In vivo and in vitro experiments showed that the overexpression of NLRP3 protein was closely related to aggravated bone resorption and osteogenesis deficiency. In addition, abnormal activation of NLRP3 inflammasome can not only produce inflammation, but also lead to pyroptosis and dysfunction of osteoblasts by upregulating the expression of Caspase-1 and gasdermin D (GSDMD). In conclusion, NLRP3 inflammasome overall not only accelerates bone resorption, but also inhibits bone formation, thus increasing the risk of osteoporosis. Thus, this review highlights the recent studies on the function of NLRP3 inflammasome in osteoporosis, provides information on new strategies for managing osteoporosis, and investigates the ideal therapeutic target to treat osteoporosis.