Corrigendum to: Mechanism of HSP90 Inhibitor in the Treatment of DSS-induced Colitis in Mice by Inhibiting MAPK Pathway and Synergistic Effect of Compound Sophorae Decoction.

A typographical error appeared in the title of the article "Mechanism of HSP90 Inhibitor in the Treatment of DSS-induced Colitis in Mice by Inhibiting MAPK Pathway and Synergistic Effect of Compound Sophora Decoction", published in Current Pharmaceutical Design, 2022; 28(42): 3456-3468 [1]. Details of the error and a correction are provided below. Original: Mechanism of HSP90 Inhibitor in the Treatment of DSS-induced Colitis in Mice by Inhibiting MAPK Pathway and Synergistic Effect of Compound Sophora Decoction Corrected: Mechanism of HSP90 Inhibitor in the Treatment of DSS-induced Colitis in Mice by Inhibiting MAPK Pathway and Synergistic Effect of Compound Sophorae Decoction We regret the error and apologize to readers. The original article can be found online at: https://www.eurekaselect.com/article/127740.

Filling the gaps in icosahedral superatomic metal clusters.

Chemically modified superatoms have emerged as promising candidates in the new periodic table, in which Au13 and its doped M n Au13- n have been widely studied. However, their important counterpart, Ag13 artificial element, has not yet been synthesized. In this work, we report the synthesis of Ag13 nanoclusters using strong chelating ability and rigid ligands, that fills the gaps in the icosahedral superatomic metal clusters. After further doping Ag13 template with different degrees of Au atoms, we gained insight into the evolution of their optical properties. Theoretical calculations show that the kernel metal doping can modulate the transition of the excited-state electronic structure, and the electron transfer process changes from local excitation (LE) to charge transfer (CT) to LE. This study not only enriches the families of artificial superatoms, but also contributes to the understanding of the electronic states of superatomic clusters.

Quercetin ameliorates ulcerative colitis by restoring the balance of M2/M1 and repairing the intestinal barrier via downregulating cGAS‒STING pathway.

Macrophage polarization is closely associated with the pathogenesis of ulcerative colitis (UC). Quercetin, a flavonoid, has shown promise as a treatment for inflammatory diseases, but its specific mechanism of action remains unclear. This study investigates whether quercetin can regulate intestinal macrophage polarization and promote intestinal tissue repair via the cGAS-STING pathway for the treatment of UC. In vivo, mice with 3% DSS-induced UC were intraperitoneally injected with quercetin and RU.521 for 7 days, following which their general conditions and corresponding therapeutic effects were assessed. The impact of interferon-stimulated DNA (ISD) and quercetin on macrophage polarization and the cGAS-STING pathway was investigated using RAW264.7 cells and bone marrow-derived macrophages (BMDMs) in vitro. The results demonstrated that ISD induced M1 macrophage polarization and activated the cGAS-STING pathway in vitro, while quercetin reversed ISD's inflammatory effects. In vivo, quercetin suppressed the cGAS-STING pathway in the intestinal macrophages of DSS-induced UC mice, which reduced M1 macrophage polarization, increased M2 polarization, and facilitated intestinal barrier repair in UC. Taken together, these findings provide new insights into the mechanisms via which quercetin could be used to treat UC.

In Silico Prediction of Quercetin Analogs for Targeting Death-Associated Protein Kinase 1 (DAPK1) Against Alzheimer's Disease.

Alzheimer's Disease (AD) is a progressive neurodegenerative disorder that greatly affects the health and life quality of the elderly population. Existing drugs mainly alleviate symptoms but fail to halt disease progression, underscoring the urgent need for the development of novel drugs. Based on the neuroprotective effects of flavonoid quercetin in AD, this study was designed to identify potential AD-related targets for quercetin and perform in silico prediction of promising analogs for the treatment of AD. Database mining suggested death-associated protein kinase 1 (DAPK1) as the most promising AD-related target for quercetin among seven protein candidates. To achieve better biological effects for the treatment of AD, we devised a series of quercetin analogs as ligands for DAPK1, and molecular docking analyses, absorption, distribution, metabolism, and excretion (ADME) predictions, as well as molecular dynamics (MD) simulations, were performed. The energy for drug-protein interaction was predicted and ranked. As a result, quercetin-A1a and quercetin-A1a1 out of 19 quercetin analogs exhibited the lowest interaction energy for binding to DAPK1 than quercetin, and they had similar dynamics performance with quercetin. In addition, quercetin-A1a and quercetin-A1a1 were predicted to have better water solubility. Thus, quercetin-A1a and quercetin-A1a1 could be promising agents for the treatment of AD. Our findings paved the way for further experimental studies and the development of novel drugs.

Diclofenac sodium nanomedicine results in pain-relief and differential expression of the RNA transcriptome in the spinal cord of SNI rats.

Neuropathic pain is chronic pain caused by a lesion or disease of the somatosensory nervous system. Neuropathic pain, with a high incidence and complex pathogenesis, is one of the most significant areas of clinical medicine and basic research. Currently, prescribed treatments are still unsatisfactory or have limited effectiveness. A medicinal preparation is required that relieves the neuropathic pain and prolongs action time, which has not yet been discovered. In this study, MIL-101 (Fe) was employed as a drug carrier to regulate the release of diclofenac sodium, thereby achieving the effect of analgesia and sustained release. The release curves demonstrated that diclofenac sodium could be continuously released from MIL-101 (Fe) for more than 48 h. There was no toxicity in vitro and in vivo, and the safety of MIL-101 (Fe) was confirmed by hematoxylin and eosin as well as ELISA tests in vivo. The results of behavioral testing, pharmacokinetics, and RNA sequencing analysis showed that MIL-101 (Fe) loaded with diclofenac sodium could enhance the mechanical withdrawal threshold and alleviate cold allodynia induced by Spared Nerve Injury, prolonging the work time by three days. The results indicated that MIL-101 (Fe) exhibited excellent biocompatibility, while the MIL-101 (Fe)-DS demonstrated analgesic and controlled-release properties. These findings provide a scientific foundation for the clinical management of neuropathic pain and the development of a novel formulation.

Construction of the underlying circRNA-miRNA-mRNA regulatory network and a new diagnostic model in ulcerative colitis by bioinformatics analysis.

BACKGROUND: Circular RNAs (circRNAs) are involved in the pathogenesis of many diseases through competing endogenous RNA (ceRNA) regulatory mechanisms. AIM: To investigate a circRNA-related ceRNA regulatory network and a new predictive model by circRNA to understand the diagnostic mechanism of circRNAs in ulcerative colitis (UC). METHODS: We obtained gene expression profiles of circRNAs, miRNAs, and mRNAs in UC from the Gene Expression Omnibus dataset. The circRNA-miRNA-mRNA network was constructed based on circRNA-miRNA and miRNA-mRNA interactions. Functional enrichment analysis was performed to identify the biological mechanisms involved in circRNAs. We identified the most relevant differential circRNAs for diagnosing UC and constructed a new predictive nomogram, whose efficacy was tested with the C-index, receiver operating characteristic curve (ROC), and decision curve analysis (DCA). RESULTS: A circRNA-miRNA-mRNA regulatory network was obtained, containing 12 circRNAs, three miRNAs, and 38 mRNAs. Two optimal prognostic-related differentially expressed circRNAs, hsa_circ_0085323 and hsa_circ_0036906, were included to construct a predictive nomogram. The model showed good discrimination, with a C-index of 1(> 0.9, high accuracy). ROC and DCA suggested that the nomogram had a beneficial diagnostic ability. CONCLUSION: This novel predictive nomogram incorporating hsa_circ_0085323 and hsa_circ_0036906 can be conveniently used to predict the risk of UC. The circRNa-miRNA-mRNA network in UC could be more clinically significant.

Current comprehensive understanding of denosumab (the RANKL neutralizing antibody) in the treatment of bone metastasis of malignant tumors, including pharmacological mechanism and clinical trials.

Denosumab, a fully humanized monoclonal neutralizing antibody, inhibits activation of the RANK/RANKL/OPG signaling pathway through competitive binding with RANKL, thereby inhibiting osteoclast-mediated bone resorption. Denosumab inhibits bone loss; therefore, it is used to treat metabolic bone diseases (including postmenopausal osteoporosis, male osteoporosis, and glucocorticoid-induced osteoporosis), in clinical practice. Since then, multiple effects of denosumab have been discovered. A growing body of evidence suggests that denosumab has a variety of pharmacological activities and broad potential in clinical diseases such as osteoarthritis, bone tumors, and other autoimmune diseases. Currently, Denosumab is emerging as a treatment for patients with malignancy bone metastases, and it also shows direct or indirect anti-tumor effects in preclinical models and clinical applications. However, as an innovative drug, its clinical use for bone metastasis of malignant tumors is still insufficient, and its mechanism of action needs to be further investigated. This review systematically summarizes the pharmacological mechanism of action of denosumab and the current understanding and clinical practice of the use of denosumab for bone metastasis of malignant tumors to help clinicians and researchers deepen their understanding of denosumab.

The Role of AMPK Signaling in Ulcerative Colitis.

Ulcerative colitis (UC) is a chronic non-specific inflammatory bowel disease characterized by inflammation and ulcer formation of the intestinal mucosa. Due to its high recurrence rate, prolonged course, limited curative options, and significant impact on patients' quality of life, along with a notable potential for malignant transformation, UC is designated as a refractory global health challenge by the World Health Organization (WHO). The elucidation of the pathogenesis and therapeutic strategies for UC requires further in-depth investigation. AMP-activated protein kinase (AMPK) serves as a central regulator of cellular energy metabolic homeostasis. Emerging evidence indicates that interventions involving traditional Chinese medicine (TCM) components, as well as other pharmacological measures, exert beneficial effects on the intestinal mucosal inflammation and epithelial barrier dysfunction in UC by modulating AMPK signaling, thereby influencing biological processes such as cellular autophagy, apoptosis, inflammatory responses, macrophage polarization, and NLRP3 inflammasome-mediated pyroptosis. The role of AMPK in UC is of significant importance. This manuscript provides a comprehensive overview of the mechanisms through which AMPK is involved in UC, as well as a compilation of pharmacological agents capable of activating the AMPK signaling pathway within the context of UC. The primary objective is to facilitate a deeper comprehension of the pivotal role of AMPK in UC among researchers and clinical practitioners, thereby advancing the identification of novel therapeutic targets for interventions in UC.

Hypoxic mesenchymal stem cell-derived exosomes alleviate ulcerative colitis injury by limiting intestinal epithelial cells reactive oxygen species accumulation and DNA damage through HIF-1α.

Ulcerative colitis (UC) is an inflammatory disease with a complex pathogenic mechanism. Mounting evidence suggests that UC pathogenesis is linked to excessive production of reactive oxygen species (ROS) and cellular DNA damage. Recent studies have shown that bone mesenchymal stem cells (BMSCs) mainly exert their therapeutic effects through paracrine exosomes, and oxygen concentration is extremely important to BMSCs and exosomes. The main objective of this study was to determine whether exosomes from BMSCs under hypoxic conditions (HP-Exos) exhibit a greater therapeutic effect on UC compared to exosomes under normoxic conditions (Exos) and to resolve the mechanism of HP-Exos. We observed that hypoxia enhances the activity and migration of BMSCs and inhibits BMSC apoptosis without changing their morphological characteristics. Furthermore, HP-Exos significantly relieved UC symptoms and pathological damage. In order to further understand the mechanism of HP-Exos in UC, findings from in vivo experiments demonstrated that HP-Exos reduces ROS production, DNA damage and apoptosis in intestinal epithelial cells. As hypoxia-inducible factor 1α (HIF-1α) plays an important role in hypoxia, we knocked down HIF-1α in BMSCs. HIF-1α knockout reversed the effects of hypoxia on the activity, migration and apoptosis of BMSCs. Moreover, inhibition of HIF-1α expression also reversed the regulation of UC by HP-Exos. Therefore, we conclude that HP-Exos regulates ROS accumulation, DNA damage and immune homeostasis in intestinal epithelial cells via HIF-1α.

Translation regulatory factor BZW1 regulates preimplantation embryo development and compaction by restricting global non-AUG Initiation.

Protein synthesis is an essential step in gene expression during the development of mammalian preimplantation embryos. This is a complex and highly regulated process. The accuracy of the translation initiation codon is important in various gene expression programs. However, the mechanisms that regulate AUG and non-AUG codon initiation in early embryos remain poorly understood. BZW1 is a key factor in determining the mRNA translation start codon. Here, we show that BZW1 is essential for early embryonic development in mice. Bzw1-knockdown embryos fail to undergo compaction, and show decreased blastocyst formation rates. We also observe defects in the differentiation capacity and implantation potential after Bzw1 interference. Further investigation revealed that Bzw1 knockdown causes the levels of translation initiation with CUG as the start codon to increase. The decline in BZW1 levels result in a decrease in protein synthesis in preimplantation embryos, whereas the total mRNA levels are not altered. Therefore, we concluded that BZW1 contributes to protein synthesis during early embryonic development by restricting non-AUG translational initiation.

Mechanism of HSP90 Inhibitor in the Treatment of DSS-induced Colitis in Mice by Inhibiting MAPK Pathway and Synergistic Effect of Compound Sophora Decoction.

BACKGROUND: The mechanism of Heat Shock Protein 90 (HSP90) in Ulcerative Colitis (UC) has been studied, and mitogenic-activated protein kinases (MAPK) also contribute to the pathogenesis of UC. However, the effect of the HSP90/MAPK pathway in UC is still unclear. Therefore, the mainstay of this research is to explore the mechanism of action of this pathway in UC. Compound sophorae decoction (CSD), as a Chinese herbal decoction, can synergistically affect the above process. OBJECTIVE: This study aimed to uncover the synergistic effects of HSP90 inhibitors regulating the MAPK pathway for treating DSS-induced colitis in mice and the synergistic effects of CSD. METHODS: This experiment used oral administration of standard diets containing 3% dextran sodium sulfate (DSS) to establish an experimental colitis model in mice. The model was treated with HSP90 inhibitor, CSD, or dexamethasone. Mouse feces, mobility, body weight, colon length, and colon histopathology scores were recorded daily to assess the degree of colitis inflammation. Expression levels of HSP90 and MAPK pathway-related genes and proteins were evaluated by Western blot and qPCR. The evaluation of intestinal mucosal permeability was measured by enzyme-linked immunosorbent assay (ELISA), which could detect the protein level of D-Amino Acid Oxidase (DAO) and D-lactic acid (D-LA). The same went for downstream molecules AFT-2, p53, and apoptosis-related proteins BAX, BCL-2, Caspase3, and survivin in the MAPK pathway. Immunohistochemical measured p-38, p-JNK, and p-ERK expressions. JAM-A and claudin-1 connexin were tested by immunofluorescence staining. The TUNEL method was for measuring the apoptosis rate of colonic epithelial cells. CBA kit determined the level of inflammatory factors of colons. RESULTS: HSP90 inhibitor can improve the degree of pathological damage in the colon of mice treated with DSS, increase the mice's weight and the length of the colon, and significantly reduce the disease activity index (DAI) score. Intraperitoneal injection of HSP90 inhibitor can reduce the expression of MAPK pathway markers P38, JNK, ERK, and their phosphorylation and decrease the content of AFT-2 and p53, which is downstream of the MAPK pathway. In addition, treatment of the HSP90 inhibitor up-regulated the expression of anti-apoptotic proteins BCL-2 and survivin, as well as down-regulated apoptotic protein caspase3, BAX in the colon of mice with colitis. Lower levels of inflammatory factors such as IL-6, MCP-1, IFN-γ, TNF, IL-12p70, and increased IL-10 were observed after HSP90 inhibitor therapy. Furthermore, the combination treatment of CSD can enhance the effect of the single HSP90 inhibitor treatment and play a synergistic effect. CONCLUSION: These data suggest that an HSP90 inhibitor is available to treat UC by inhibiting the MAPK signaling pathway. This axis can restore the intestinal mucosa barrier's function by reducing intestinal mucosa's permeability and inhibiting apoptosis of intestinal epithelial cells. The specific mechanism is that HSP90 inhibitor can reduce the pathological damage and inflammation levels of colitis mice, and reduce the apoptosis rate of colonic epithelial cells and the mucosal permeability, thereby restoring the mucosal barrier function. During this process, CSD works synergistically to improve the therapeutic effect of the HSP90 inhibitor.

Taraxasterol Inhibits Tumor Growth by Inducing Apoptosis and Modulating the Tumor Microenvironment in Non-Small Cell Lung Cancer.

Taraxasterol (TAX), one of the active components in Dandelion, demonstrated strong antitumor properties in several cancers. However, the effect and underlying mechanism of TAX in non-small cell lung cancer (NSCLC) is unclear. In this study, we showed that TAX inhibited the proliferation of cells by inducing S-phase cell cycle arrest and prevented cell migration by interfering epithelial-mesenchymal transition (EMT) in Lewis lung cancer (LLC) cells and lung carcinoma SPC-A1 cells. The pharmacological network analysis predicted that induction of apoptosis might be the potential mechanism of TAX-mediated cell deaths. Further in vitro experiments showed that TAX could significantly induce cancer cell apoptosis as verified by increased pro-apoptotic molecules including Bax, caspase-9, and PARP1 downregulated anti-apoptotic protein Bcl-2; and decreased mitochondrial potential. The LLC subcutaneous tumor model demonstrated that TAX inhibited tumor growth by induction of apoptosis and inhibition of proliferation in vivo, which is consistent with the in vitro data. Importantly, TAX administration downregulated the proportion of Treg cells and upregulated CD107a+ NK cells in the tumor microenvironment in the tumor model. Together, these data reveal that TAX performs its antitumor effect by inducing apoptosis and modulating the tumor microenvironment, providing evidence that TAX could serve as a potential natural drug for lung cancer therapy.

PABPN1 functions as a hub in the assembly of nuclear poly(A) domains that are essential for mouse oocyte development.

Growing oocytes store a large amount of maternal mRNA to support the subsequent "maternal-zygotic transition" process. At present, it is not clear how the growing oocytes store and process the newly transcribed mRNA under physiological conditions. In this study, we report non-membrane-bound compartments, nuclear poly(A) domains (NPADs), as the hub for newly transcribed mRNA, in developing mouse oocytes. The RNA binding protein PABPN1 promotes the formation of NPAD through its N-terminal disordered domain and RNA-recognized motif by means of liquid phase separation. Pabpn1-null growing oocytes cannot form NPAD normally in vivo and have defects in stability of oocyte growing-related transcripts and formation of long 3' untranslated region isoform transcripts. Ultimately, Pabpn1fl/fl;Gdf9-Cre mice are completely sterile with primary ovarian insufficiency. These results demonstrate that NPAD formed by the phase separation properties of PABPN1-mRNA are the hub of the newly transcribed mRNA and essential for the development of oocytes and female reproduction.

Modified Qing' e Pills exerts anti-osteoporosis effects and prevents bone loss by enhancing type H blood vessel formation.

Objective: To explore whether the modified Qing' e Pills (MQEP) exerts anti-osteoporotic effects and prevents bone loss by enhancing angiogenesis. Methods: Network pharmacology was used to assess whether MQEP has a pro-angiogenic capacity and to predict its potential targets. Human umbilical vein endothelial cells were treated with glucocorticoids and MQEP to assess cell viability. The expression of angiotensin II type 1 receptor, angiotensin II type 2 receptor, and angiotensin converting enzyme, which are associated with the activation of the renin-angiotensin-aldosterone system, and the expression of vascular endothelial growth factor and hypoxia-inducible factor 1 alpha, which are associated with the formation of type H blood vessels, were examined by western blot and RT-qPCR. Thereafter, the glucocorticoid-induced osteoporosis model was established and intervened with MQEP. Femur scanning was performed with micro-computed tomography; trabecular spacing, trabecular thickness, and trabecular number were observed and calculated; the expression of nuclear factor-kappa B ligand and osteoprotegerin was detected by ELISA, and the ratio was calculated to evaluate the degree of bone resorption. Finally, type H blood vessels that were highly coupled to osteogenic cells were identified by immunohistochemistry staining and flow cytometry. Results: This is the first study to reveal and confirm that MQEP could prevent bone loss in glucocorticoid-induced osteoporosis by promoting the expression of hypoxia-inducible factor 1 alpha and vascular endothelial growth factor, which are highly associated with type H blood vessel formation. In vitro experiments confirmed that MQEP could effectively promote the proliferation of vascular endothelial cells and alleviate glucocorticoids-induced activation of the renin-angiotensin-aldosterone system, thereby reducing vascular injury. Conclusion: MQEP exerts anti-osteoporosis effects and prevents bone loss by alleviating vascular injury caused by renin-angiotensin-aldosterone system activation and promoting type H blood vessel formation.

The analysis of Modified Qing' E Formula on the differential expression of exosomal miRNAs in the femoral head bone tissue of mice with steroid-induced ischemic necrosis of femoral head.

Objective: To investigate the differential expression of exosomal miRNAs in the bone marrow tissue of Modified Qing' E Formula (MQEF) on steroid-induced ischemic necrosis of the femoral head (INFH) model. Methods: Steroid hormones were used to establish the INFH model and treated with MQEF. After successful modeling, femoral tissue exosomes were isolated for miRNA sequencing to obtain femoral tissue exosomal differential miRNAs. By GO analysis and KEGG analysis of the differential genes in both groups, the major exosomal miRNAs of MQEF exerting anti-INFH as well as the major signaling pathways were identified. Next, a quantitative metabolomic validation of MQEF with broad targeting was performed to obtain the main active components of MQEF and to perform biological analysis and signaling pathway prediction of the active components by network pharmacology. Finally, the sequencing results were validated by using RT-qPCR. The results of miRNA sequencing were verified by double examination of network pharmacology and RT-qPCR, and the exosomal miRNAs regulated by the anti-INFH effect of MQEF and the specific signaling pathway of the effect were clarified. Results: A total of 65,389 target genes were predicted in the exosomes of two groups of mice, and 18 significant differentially expressed miRNAs were obtained, of which 14 were up-regulated and 4 down-regulated. GO enrichment analysis showed that these predicted target genes were enriched in 12371 biological processes, 1727 cell components, and 4112 molecular functions. KEGG analysis showed that the predicted miRNA target genes were annotated to 342 signal pathways, in which the highly enriched pathways closely related to bone metabolism were PI3K-Akt signal pathway, MAPK signal pathway, and Wnt signal pathway. The most significantly up-regulated miRNAs were miR-185-3p and miR-1b-5p and the most significantly down-regulated miRNAs were miR-129b-5p and miR-223-5p, of which the targeted genes were closely related to the PI3K-Akt signal pathway. MQEF aqueous decoction extract targeted metabolomics quantitatively combined with network pharmacology predicted targets also closely related to PI3K-Akt signaling pathway. Real-time quantitative PCR validation showed that miR-185-3p was up-regulated 7.2-fold and miR-129b-5p was down-regulated 2.2-fold in the treatment group, and the difference was significant (P < 0.05). Conclusions: MQEF can regulate exosomal miRNA expression in steroid-induced INFH models, miR-185-3p or miR-129b-5p/PI3K-Akt signal axis may be part of the mechanism of MQEF against steroid-induced INFH.

[Umbelliferone improves chronic hypoxia-induced pulmonary hypertension by inhibiting the RhoA/ROCK signaling pathway and autophagy].

This study aimed to investigate the effects of hypoxia on RhoA/Rho-kinase (ROCK) signaling pathway and autophagy in pulmonary artery smooth muscle cells (PASMCs), and to explore the underlying mechanism of Umbelliferone (Umb) in ameliorating chronic hypoxic pulmonary hypertension. PASMCs were cultured from Sprague-Dawley (SD) rats and randomly divided into control group, hypoxia group, hypoxia + Umb intervention group and normoxia + Umb intervention group. Alpha smooth muscle actin (α-SMA) and LC3 were assessed by immunofluorescence staining. Protein expression of RhoA, ROCK2, p-MYPT1, LC3-II, Beclin-1, p62, C-Caspase 3, Bax and Bcl-2 was analyzed by Western blotting. In in vivo study, SD rats were divided into control group, hypoxia group and hypoxia + Umb intervention group. Weight ratio of the right ventricle (RV)/left ventricle plus septum (LV+S) was detected, and pulmonary arterial morphological features were examined by HE staining. The results indicated that compared with the control group, the LC3-II/LC3-I ratio and expression of Beclin-1 were significantly increased, while p62 expression was significantly decreased, and the expressions of RhoA, ROCK2 and p-MYPT1 were significantly increased in PASMCs of hypoxia group (P < 0.05). The changes of LC3-II/LC3-I ratio, the expressions of Beclin-1, p62, RhoA, ROCK2 and p-MYPT1 in PASMCs were reversed by Umb treatment (P < 0.05). Consistently, the pulmonary arterial wall was thickened and the RV/(LV+S) ratio was increased in hypoxic rats, which were significantly improved by Umb treatment (P < 0.05). These results suggest that Umb can improve hypoxia-induced pulmonary hypertension by inhibiting the RhoA/ROCK signaling pathway and autophagy in PASMCs.

Network-Based Pharmacology and Bioinformatics Study on the Mechanism of Action of Gujiansan in the Treatment of Steroid-Induced Avascular Necrosis of the Femoral Head.

Objective: To investigate the main pharmacological basis and mechanism of action of Gujiansan in the treatment of steroid-induced avascular necrosis of the femoral head (SANFH). Methods: The active constituents and targets of Gujiansan were screened by using TCMSP and other databases, and relevant disease targets were obtained by analyzing the microarray of SANFH in the GEO database. The intersection of the two was taken to obtain the potential targets of Gujiansan for the treatment of SANFH, and key active constituents were screened with the "active constituent-target" network constructed by the Cytoscape software; then, the STRING database was used to construct the protein interaction network to screen the key targets. The Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses of key targets were performed by the DAVID database, and the relationship between the "key active constituent-key target-key signaling pathway" was explored. Finally, the molecular docking between key active constituents and key targets was verified. In addition, qPCR detection technology was used to evaluate the preventive and therapeutic effects of key active constituents of Gujiansan in a rat osteoblast model of SANFH to verify the possible mechanism of the effect of Gujiansan in the treatment of SANFH. Results: (1) 106 active constituents and 55 targets were obtained for the treatment of SANFH. (2) Quercetin, luteolin, kaempferol, cryptotanshinone, and naringenin were the key active constituents for the treatment of SANFH. (3) IL1B, STAT3, CAT, PTGS2, and MAPK3 were the key targets for the treatment of SANFH. (4) IL1B, STAT3, CAT, PTGS2, MAPK3, and HMOX1 are key targets in the protein interaction network. (5) DAVID enrichment analysis mainly covers the regulation of DNA-binding transcription factor activity, positive regulation of cytokine production, and response to oxidative stress and other biological processes, involving IL-17, AGE-RAGE, C-type lectin receptor, and other signaling pathways. (6) Gujiansan is a multitarget and multisignaling pathway for the treatment of SANFH. (7) Good binding activity exists between key active constituents and key targets. Conclusion: This study analyzes the potential mechanism of action of Gujiansan in the treatment of SANFH with network pharmacology, which can provide a reference for the further study of its pharmacological basis and targets.

Advances in Our Understanding of the Mechanism of Action of Drugs (including Traditional Chinese Medicines) for the Intervention and Treatment of Osteoporosis.

Osteoporosis (OP) is known as a silent disease in which the loss of bone mass and bone density does not cause obvious symptoms, resulting in insufficient treatment and preventive measures. The losses of bone mass and bone density become more severe over time and an only small percentage of patients are diagnosed when OP-related fractures occur. The high disability and mortality rates of OP-related fractures cause great psychological and physical damage and impose a heavy economic burden on individuals and society. Therefore, early intervention and treatment must be emphasized to achieve the overall goal of reducing the fracture risk. Anti-OP drugs are currently divided into three classes: antiresorptive agents, anabolic agents, and drugs with other mechanisms. In this review, research progress related to common anti-OP drugs in these three classes as well as targeted therapies is summarized to help researchers and clinicians understand their mechanisms of action and to promote pharmacological research and novel drug development.

Diosmetin has therapeutic efficacy in colitis regulating gut microbiota, inflammation, and oxidative stress via the circ-Sirt1/Sirt1 axis.

Diosmetin (3',5,7 -trihydroxy-4'-methoxy flavone) is a natural flavonoid compound in the citrus species, it exhibits a variety of pharmacological activities, but little is known of its effects on colitis. In this study we evaluated the therapeutic effects of diosmetin on mouse models of chronic and acute colitis. Chronic colitis was induced in mice by drinking water containing 3% dextran sulfate sodium (DSS) from D0 to D8, followed by administration of diosmetin (25, 50 mg · kg-1 · d-1) for another 8 days. Acute colitis was induced by drinking water containing 5% DSS from D0 to D7, the mice concomitantly received diosmetin (25, 50 mg · kg-1 · d-1) from D1 to D7. During the experiments, body weight and disease activity index (DAI) were assessed daily. After the mice were sacrificed, colon tissue and feces samples were collected, and colon length was measured. We showed that in both models, diosmetin administration significantly decreased DAI score and ameliorated microscopic colon tissue damage; increased the expression of tight junction proteins (occludin, claudin-1, and zonula occludens-1), and reduced the secretion of proinflammatory cytokines IL-1ß, IL-6, TNF-α, and Cox-2 in colon tissue. We found that diosmetin administration remarkably inhibited colon oxidative damage by adjusting the levels of intracellular and mitochondrial reactive oxygen species, GSH-Px, SOD, MDA and GSH in colon tissue. The protection of diosmetin against intestinal epithelial barrier damage and oxidative stress were also observed in LPS-treated Caco-2 and IEC-6 cells in vitro. Furthermore, we demonstrated that diosmetin markedly increased the expression of Nrf2 and HO-1 and reduced the ratio of acetylated NF-κB and NF-κB by activating the circ-Sirt1/Sirt1 axis, which inhibited oxidative stress and inflammation in vivo and in vitro. Diosmetin reversed the effects of si-circSirt1 and si-Sirt1 in LPS-treated Caco-2 and IEC-6 cells. When the gut microbiota was analyzed in the mouse model of colitis, we found that diosmetin administration modulated the abundance of Bacteroidetes, Actinobacteria, Cyanobacteria and Firmicutes, which were crucial for inflammatory bowel disease. Our results have linked colitis to the circ-Sirt1/Sirt1 signaling pathway, which is activated by diosmetin. The results imply that diosmetin may be a novel candidate to alleviate DSS-induced colitis and can be a lead compound for future optimization and modification.