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Background: Acute gouty arthritis (AGA) is classified as 'arthritis' in traditional Chinese medicine (TCM) theory. Shirebi granules (SGs), derived from the classic prescription SiMiaoWan, exerts satisfying therapeutic efficacy in ameliorating AGA clinically. However, the underlying mechanisms of SGs against AGA remain unclarified. Methods: AGA-related biological processes, signal pathways and biomarker genes were mined from the GEO database through bioinformatics. SGs components were systematically recognized using the UPLC-Q-TOF–MS/MS. A correlation network was established based on the biomarker genes and the chemical components, from which the signal pathway used for further study was selected. Finally, we established an AGA model using SD rats injected with monosodium urate (MSU) in the ankle joint for experimental validation. A combination of behavioral tests, H&E, safranin O- fast green, western blotting, and immunofluorescence were employed to reveal the mechanism of action of SGs on AGA. Results: The deterioration of AGA was significantly related to the imbalance between immunity and inflammation, neutrophil chemotaxis and inflammatory factor activation. HDAC5, PRKCB, NFκB1, MPO, PRKCA, PIK3CA were identified to be the candidate targets of SGs against AGA, associated with neutrophil extracellular traps (NETs) signal pathway. Animal experiments demonstrated that SGs effectively repaired cartilage damage, blocked TLR4 activation, and inhibited the expression of NETs indicators and inflammatory factors. In addition, SGs prominently alleviated joint redness and swelling, improved joint dysfunction, inhibited inflammatory infiltration of AGA rats. Conclusion: Our data reveal that SGs may effectively alleviate the disease severity of AGA by suppressing NETs-promoted imbalance between immunity and inflammation. [ABSTRACT FROM AUTHOR]

Background: Osteoking has been used for fracture therapy with a satisfying clinical efficacy. However, its therapeutic properties and the underlying mechanisms remain elusive. Method: A bone defect rat model was established to evaluate the pharmacological effects of Osteoking by the dynamic observation of X-ray, micro-CT and histopathologic examination. Transcriptome profiling was performed to identify bone defect-related genes and Osteoking effective targets. Then, a "disease-related gene–drug target" interaction network was constructed and a list of key network targets were screened, which were experimentally verified. Results: Osteoking effectively promoted bone defect repair in rats by accelerating the repair of cortical bone and the growth of trabeculae. Histopathologically, the bone defect rats displayed lower histopathologic scores in cortical bone, cancellous bone and bone connection than normal controls. In contrast, Osteoking exerted a favorable effect with a dose-dependent manner. The abnormal serum levels of bone turnover markers, bone growth factors and bone metabolism-related biochemical indexes in bone defect rats were also reversed by Osteoking treatment. Following the transcriptome-based network investigation, we hypothesized that osteoking might attenuate the levels of ZBP1–STAT1–PKR–MLKL-mediated necroptosis involved into bone defect. Experimentally, the expression levels of ZBP1, STAT1, PKR and the hallmark inflammatory cytokines for the end of necroptosis were distinctly elevated in bone defect rats, but were all effectively reversed by Osteoking treatment, which were also suppressed the activities of RIPK1, RIPK3 and MLKL in bone tissue supernatants. Conclusions: Osteoking may promote bone formation and bone defect repair by regulating ZBP1–STAT1–PKR axis, leading to inhibit RIPK1/RIPK3/MLKL activation-mediated necroptosis. [ABSTRACT FROM AUTHOR]

Background: Cold-dampness Syndrome (RA-Cold) and Hot-dampness Syndrome (RA-Hot) are two distinct groups of rheumatoid arthritis (RA) patients with different clinical symptoms based on traditional Chinese medicine (TCM) theories and clinical empirical knowledge. However, the biological basis of the two syndromes has not been fully elucidated, which may restrict the development of personalized medicine and drug discovery for RA diagnosis and therapy. Methods: An integrative strategy combining clinical transcriptomics, phenomics, and metabolomics data based on clinical cohorts and adjuvant-induced arthritis rat models was performed to identify novel candidate biomarkers and to investigate the biological basis of RA-Cold and RA-Hot. Results: The main clinical symptoms of RA-Cold patients are joint swelling, pain, and contracture, which may be associated with the dysregulation of T cell-mediated immunity, osteoblast differentiation, and subsequent disorders of steroid biosynthesis and phenylalanine metabolism. In contrast, the main clinical symptoms of RA-Hot patients are fever, irritability, and vertigo, which may be associated with various signals regulating angiogenesis, adrenocorticotropic hormone release, and NLRP3 inflammasome activation, leading to disorders of steroid biosynthesis, nicotinamide, and sphingolipid metabolism. IL17F, 5-HT, and IL4I1 were identified as candidate biomarkers of RA-Cold, while S1P and GLNS were identified as candidate biomarkers of RA-Hot. Conclusions: The current study presents the most comprehensive metabonomic and transcriptomic profiling of serum, urine, synovial fluid, and synovial tissue samples obtained from RA-Cold and RA-Hot patients and experimental animal models to date. Through the integration of multi-omics data and clinical independent validation, a list of novel candidate biomarkers of RA-Cold and RA-Hot syndromes were identified, that may be useful in improving RA diagnosis and therapy. [ABSTRACT FROM AUTHOR]

Background: Baihu-Guizhi decoction (BHGZD) is a well-documented traditional Chinese Medicine (TCM) prescription that has been extensively applied to treating rheumatoid arthritis. Despite of its beneficial outcomes, the chemical constituents of BHGZD have not been fully portrayed and the in vivo absorption, distribution, metabolism, and excretion (ADME) patterns of absorbed components have never been described. Methods: Characterization of absorbed components and in vivo biotransformation profiling of these feature compounds were based on the ultra-fast liquid chromatography-quadrupole-time-of-flight tandem mass spectrometry (UFLC-Q-TOF-MS/MS). Furthermore, the ultra-high-performance liquid chromatography tandem ion trap quadrupole mass spectrometry (UHPLC-Q-TRAP-MS/MS) system were performed to investigate the pharmacokinetics of active ingredients from BHGZD. Results: In this study, we have identified and tentatively characterized 18 feature absorbed prototype and 15 metabolites of BHGZD in rat serum and the in vivo transformation pathways of these absorbed constituents were proposed. Besides, we have established novel quantitative methodology of five crucial components of BHGZD and have monitored the pharmacokinetic behaviors of these constituents spontaneously in rat serum after BHGZD gavage. After rats received two ways of BHGZD gavage, the pharmacokinetic behaviors of each compound exhibited relatively similar behaviors, as evidenced by similar curve track as well as relatively close time to reach maximum concentration (Tmax) and half washout time (T1/2). Whereas the maximum plasma concentration (Cmax) and area under the plasma concentration–time curve (AUC) values of five analytes with multiple dosage were a bit higher than single dosage. Conclusion: This study added knowledge into the material basis and bio-transformation patterns of BHGZD in vivo, which would be of great value for exploring pharmacological effects and mechanism of BHGZD. [ABSTRACT FROM AUTHOR]

Background: Growing clinical evidences show the potentials of Colquhounia root tablet (CRT) in alleviating diabetic kidney disease (DKD). However, its pharmacological properties and underlying mechanisms remain unclear. Methods: 'Drug target-Disease gene' interaction network was constructed and the candidate network targets were screened through evaluating node genes' topological importance. Then, a DKD rat model induced by high-fat diet/streptozotocin was established and used to determine pharmacological effects and network regulatory mechanisms of CRT against DKD, which were also verified using HK2 cell model induced by high glucose. Results: The candidate network targets of CRT against DKD were involved into various type II diabetes-related and nephropathy-related pathways. Due to the topological importance of the candidate network targets and the important role of the imbalance between immunity and inflammation in the pathogenesis of DKD, PI3K/AKT/NF-кB signaling-mediated immune-modulatory and anti-inflammatory actions of CRT were selected to be experimentally verified. On the basis of high-fat diet (HFD) / streptozotocin (STZ)-induced DKD rat model, CRT effectively reduced the elevated level of blood glucose, decreased the accumulation of renal lipid, suppressed inflammation and the generation of ECM proteins, and ameliorated kidney function and the renal histopathology through inhibiting the activation of PI3K, AKT and NF-кB proteins, reducing the nuclear accumulation of NF-кB protein and the serum levels of downstream cytokines, which were in line with the in vitro findings. Conclusions: Our data suggest that CRT may be the promising candidate drug for treating DKD via reversing the imbalance of immune-inflammation system mediated by the PI3K/AKT/NF-кB/IL-1β/TNF-α signaling. [ABSTRACT FROM AUTHOR]

We investigated the therapeutic role of the herbal combination Euphorbia kansui (GS) and Glycyrrhiza (GC) in ascites during hepatocellular carcinoma (HCC). The AVPR2 and AQP2 expression in kidney tissues of ascites mice in different groups was determined by immunohistochemistry, Western blot, and real-time PCR analyses. When the dose of GS was less than 0.70 g/kg at a ratio of GC : GS not exceeding 0.4 : 1, the combination of GS and GC exhibited synergistic effects on HCC ascites and significantly elevated the expression levels of AVPR2 and AQP2 (all P<0.05). On the contrary, when GS ≥ 0.93 g/kg and GC ≥ 1.03 g/kg with the GC-to-GS ratio exceeding 1.11 : 1, the combination of GS and GC displayed antagonistic effects on HCC ascites and dramatically reduced the expression levels of AVPR2 and AQP2 (all P<0.05). Furthermore, the administration of herbal pair GS and GC at different ratios did not exacerbate the pathological changes in liver and kidney tissues of HCC ascites mice. The different combinations of GS and GC exerted synergistic or antagonistic effects on HCC ascites, partially by regulating the expression of AVPR2 and AQP2. [ABSTRACT FROM AUTHOR]

Yuanhu Zhitong Prescription (YZP) is a well-known traditional Chinese medicine (TCM) formula for neuropathic pain (NP) therapy with a satisfying clinical efficacy. However, the underlying pharmacological mechanism and its compatibility principle remain unclear. This study aims to investigate the analgesic and compatibility mechanisms of YZP on neuropathic pain (NP) at the gene and biological process levels. The chronic constriction injury (CCI) rats were intragastrically administrated with extracts of YZP, YH and BZ separately, and then mechanical hypersensitivity were measured to evaluate the analgesic effects between YH and BZ before and after compatibility. Then, RNA-seq and bioinformatics analyses were performed to elucidate the potential mechanisms underlying YZP's analgesia and compatibility. Finally, the expression levels and significant differences of key genes were analyzed. Behaviorally, both YZP and YH effectively alleviated mechanical allodynia in CCI rats, with YZP being superior to YH. In contrast, we did not observe an analgesic effect of BZ. Genetically, YZP, YH, and BZ reversed the expression levels of 52, 34, and 42 aberrant genes in the spinal cord of CCI rats, respectively. Mechanically, YZP was revealed to alleviate NP mainly by modulating the inflammatory response and neuropeptide signaling pathway, which are the dominant effective processes of YH. Interestingly, the effective targets of YZP were especially enriched in leukocyte activation and cytokine-mediated signaling pathways. Moreover, BZ was found to exert an adjunctive effect in enhancing the analgesic effect of YH by promoting skeletal muscle tissue regeneration and modulating calcium ion transport. YH, as the monarch drug, plays a dominant role in the analgesic effect of YZP that effectively relieves NP by inhibiting the spinal inflammation and neuropeptide signaling pathway. BZ, as the minister drug, not only synergistically enhances analgesic processes of YH but also helps to alleviate the accompanying symptoms of NP. Consequently, YZP exerted a more potent analgesic effect than YH and BZ alone. In conclusion, our findings offer new insights into understanding the pharmacological mechanism and compatibility principle of YZP, which may support its clinical application in NP therapy. [Display omitted] • The analgesic effect of YZP is more efficient than that of YH and BZ alone. YH plays a dominant role in the analgesic effect of YZP. • YZP ameliorates NP by inhibiting the inflammatory response and regulating neuropeptide signaling. • BZ alleviates skeletal muscle atrophy, which facilitates the analgesic effects of YH. • Ucn, Gal, and Ptgs2 may be pivotal targets associated with YZP analgesia as well as YH-BZ synergism. [ABSTRACT FROM AUTHOR]

A Chinese patent medicine derived from a classical traditional Chinese medicine formula, Yu-Xue-Bi tablet (YXB) is widely used in the clinic to treat rheumatoid arthritis (RA). During the progression of RA, angiogenesis plays a central role in fostering the production of inflammatory cells, leading to synovial hyperplasia and bone destruction. However, whether YXB attenuates the angiogenesis during RA progression remains to be defined. We aimed to evaluate the anti-angiogenic activity of YXB and explore its mechanism of action in collagen-induced arthritis (CIA) rats and VEGF-induced HUVECs. Transcriptional regulatory network analysis and a network pharmacology approach were employed to explore mechanism of YXB in RA angiogenesis. The antiarthritic effect of YXB was evaluated by determining the arthritis incidence, and score, and by micro-CT analysis. The anti-angiogenic effect of YXB in vivo was assessed by histological and immunohistochemical analyses. The anti-angiogenic effect of YXB in vitro was assessed by wound healing, Transwell migration, Transwell invasion, and tube formation assays. Western-blotting and immunohistochemical analysis were employed to explore the molecular mechanisms of YXB. YXB reduced disease severity and ameliorated pathological features in CIA rats. YXB markedly decreased bone destruction and synovial angiogenesis. Consistently, we also demonstrated that YXB effectively suppressed angiogenesis marker CD31 and VEGF expression. In vitro , YXB effectively inhibited HUVEC migration, invasion, and tube formation. Following the identification of transcriptional expression profiles, "YXB putative targets–known RA-related genes–genes associated with the therapeutic effect of YXB" interaction network was constructed and analyzed. After that, the LOX/Ras/Raf-1 signaling axis, which is involved in RA angiogenesis, was identified as one of the candidate mechanisms of YXB against RA. Experimentally, YXB dose-dependently decreased the expression levels of LOX, Ras, and Raf-1, as well as the phosphorylation of MEK and ERK in CIA rats, and these effects were better than the inhibitory effects of methotrexate (MTX), an FDA approved drug used for some autoimmune diseases such as RA. In addition, YXB may function as a potent angiogenesis inhibitor and significantly suppress the VEGF-induced activation of LOX/Ras/Raf-1 signaling in vitro. We provide evidence that YXB may decrease the disease severity of RA and reduce bone erosion by suppressing angiogenesis via inhibition of LOX/Ras/Raf-1 signaling. [Display omitted] • YXB might attenuate the severity of rheumatoid arthritis by blocking angiogenesis. • YXB might suppress RA synovial angiogenesis via suppressing the LOX/Ras/Raf-1 signaling pathway. • YXB may represent a promising antiangiogenic candidate drug for the treatment of RA in the future. [ABSTRACT FROM AUTHOR]