The composition, pharmacological effects, related mechanisms and drug delivery of alkaloids from Corydalis yanhusuo.

Corydalis yanhusuo W. T. Wang, also known as yanhusuo, yuanhu, yanhu and xuanhu, is one of the herb components of many Chinese Traditional Medicine prescriptions such as Jin Ling Zi San and Yuanhu-Zhitong priscription. C. yanhusuo was traditionally used to relieve pain and motivate blood and Qi circulation. Now there has been growing interest in pharmacological effects of alkaloids, the main bioactive components of C. yanhusuo. Eighty-four alkaloids isolated from C. yanhusuo are its important bioactive components and can be characterized into protoberberine alkaloids, aporphine alkaloids, opiate alkaloids and others and proper extraction or co-administration methods modulate their contents and efficacy. Alkaloids from C. yanhusuo have various pharmacological effects on the nervous system, cardiovascular system, cancer and others through multiple molecular mechanisms such as modulating neurotransmitters, ion channels, gut microbiota, HPA axis and signaling pathways and are potential treatments for many diseases. Plenty of novel drug delivery methods such as autologous red blood cells, self-microemulsifying drug delivery systems, nanoparticles and others have also been investigated to better exert the effects of alkaloids from C. yanhusuo. This review summarized the alkaloid components of C. yanhusuo, their pharmacological effects and mechanisms, and methods of drug delivery to lay a foundation for future investigations.

Three new chromones from the whole plants of Chamaecrista rotundifolia and their anti-rotavirus activities.

Chamaecrista rotundifolia (C. rotundifolia) is a perennial herb of leguminosae, which increasingly being grown as a forage in China. In our search for original bioactive metabolites from Cassia plants, the phytochemical reinvestigation of the C. rotundifolia was carried out, which led to the isolation of three new (1-3) and six known (4-9) chromones. Their structures were confirmed by spectroscopic methods, including extensive 1D and 2D NMR techniques. Compounds 1-9 were evaluated for their anti-rotavirus activities, and the results revealed that compounds 1-9 exhibited potential anti-rotavirus activities with therapeutic index (TI) valves in the range of 12.0 ∼ 20.2, respectively.

Circular RNA PVT1 Regulates Cell Proliferation, Migration, and Apoptosis by Stabilizing c-Myc and Downstream Target CXCR4 Expression in Acute Myeloid Leukemia

Objective: This study aimed to investigate the role and mechanism of circular RNA PVT1 (circPVT1) in patients with acute myeloid leukemia (AML). Materials and Methods: The expression of circPVT1 in 23 patients with de novo AML (not acute promyelocytic leukemia, not APL) and cell lines were detected by RT-qPCR. Loss of function assays were carried out to explore the influence of silenced circPVT1 on the proliferation, migration, and apoptosis in the THP-1 cell line. CCK-8 assays, trans-well assays, and annexin V/PI staining assays were performed to assess proliferation, migration, and apoptosis, respectively. Results: CircPVT1 was highly expressed in AML patients and myeloid cell lines compared to healthy controls. Higher expression of circPVT1 was related to shorter overall survival (OS) and relapse-free survival (RFS) in AML patients. Cell viability and migration were inhibited and apoptosis was increased when circPVT1 was knocked down in THP-1 cells. Knockdown of circPVT1 resulted in marked suppression of c-Myc protein with no significant change in mRNA levels. We also found that circPVT1 knockdown markedly increased the phosphorylation of c-Myc Thr-58, which was responsible for c-Myc degradation. Silencing of c-Myc caused a significant decrease in CXCR4 mRNA and protein expression, whereas the overexpression of c-Myc caused the opposite result, suggesting that CXCR4 is a target molecule of c-Myc. Finally, we found that overexpression of c-Myc could partially reverse circPVT1 knockdown-induced anti-tumor effects on THP-1 cells in vitro. Conclusion: Our findings showed that circPVT1 was highly expressed in AML patients and was related to shorter OS and RFS. CircPVT1 may exert an oncogenic effect in THP-1 cells by stabilizing c-Myc protein expression and downstream target CXCR4 expression. These data indicate that circPVT1 may be a promising therapeutic target for AML.

Manipulating PP2Acα-ASK-JNK signaling to favor apoptotic over necroptotic hepatocyte fate reduces the extent of necrosis and fibrosis upon acute liver injury.

In the widely used Carbon tetrachloride (CCl4)-induced acute liver injury (ALI) mouse model, hepatocytes are known to die from programmed cell death (PCD) processes including apoptosis and necroptosis. Both in vivo and in vitro experiments showed that CCl4 treatment could induce both apoptosis and necroptosis. Treatment of mice with the apoptosis inducer SMAC mimetic reduced necroptosis, led to less pronounced liver damage, and improved overall liver function. By LC-MS/MS, we found that PP2Acα expression was increased in ALI mice liver, and we confirmed its high expression in subacute hepatitis patients. We observed that ALI severity (including aggravated fibrogenesis) was significantly alleviated in hepatocyte-specific PP2Acα conditional knockout (PP2Acα cKO) mice. Furthermore, the relative extent of apoptosis over necroptosis was increased in the PP2Acα cKO ALI mice. Pursuing the idea that biasing the type of PCD towards apoptosis may reduce liver damage, we found that treatment of PP2Acα cKO ALI mice with the apoptosis inhibitor z-Vad-fmk increased the extent of necroptosis and caused severer damage. Mechanistically, disruption of PP2Acα prevents the dephosphorylation of pASK1(Ser967), thereby preventing the sustained activation of JNK. Inhibition of PP2Acα prevents CCl4-induced liver injury and fibrogenesis by disrupting ASK/JNK pathway mediated PCD signaling, ultimately improving liver function by biasing hepatocytes towards an apoptotic rather than necroptotic cell fate. Thus, targeting PP2A and/or ASK1 to favor apoptotic over necroptotic hepatocyte fate may represent an attractive therapeutic strategy for treating ALI.

Necroptosis-associated long noncoding RNAs can predict prognosis and differentiate between cold and hot tumors in ovarian cancer.

Objective: The mortality rate of ovarian cancer (OC) is the highest among all gynecologic cancers. To predict the prognosis and the efficacy of immunotherapy, we identified new biomarkers. Methods: The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression Project (GTEx) databases were used to extract ovarian cancer transcriptomes. By performing the co-expression analysis, we identified necroptosis-associated long noncoding RNAs (lncRNAs). We used the least absolute shrinkage and selection operator (LASSO) to build the risk model. The qRT-PCR assay was conducted to confirm the differential expression of lncRNAs in the ovarian cancer cell line SK-OV-3. Gene Set Enrichment Analysis, Kaplan-Meier analysis, and the nomogram were used to determine the lncRNAs model. Additionally, the risk model was estimated to evaluate the efficacy of immunotherapy and chemotherapy. We classified necroptosis-associated IncRNAs into two clusters to distinguish between cold and hot tumors. Results: The model was constructed using six necroptosis-associated lncRNAs. The calibration plots from the model showed good consistency with the prognostic predictions. The overall survival of one, three, and five-year areas under the ROC curve (AUC) was 0.691, 0.678, and 0.691, respectively. There were significant differences in the IC50 between the risk groups, which could serve as a guide to systemic treatment. The results of the qRT-PCR assay showed that AL928654.1, AL133371.2, AC007991.4, and LINC00996 were significantly higher in the SK-OV-3 cell line than in the Iose-80 cell line (P < 0.05). The clusters could be applied to differentiate between cold and hot tumors more accurately and assist in accurate mediation. Cluster 2 was more vulnerable to immunotherapies and was identified as the hot tumor. Conclusion: Necroptosis-associated lncRNAs are reliable predictors of prognosis and can provide a treatment strategy by screening for hot tumors.

Defects in a liver-bone axis contribute to hepatic osteodystrophy disease progression.

Hepatic osteodystrophy (HOD) is a metabolic bone disease that is often associated with chronic liver disease and is marked by bone loss. Here, we demonstrate that hepatic expression of the phosphatase PP2Acα is upregulated during HOD, leading to the downregulation of expression of the hepatokine lecithin-cholesterol acyltransferase (LCAT). Loss of LCAT function markedly exacerbates the bone loss phenotype of HOD in mice. In addition, we found that alterations in cholesterol levels are involved in the regulation of osteoblast and osteoclast activities. We also found that LCAT improves liver function and relieves liver fibrosis in the mouse HOD model by promoting reversal of cholesterol transport from the bone to the liver. In summary, defects in a liver-bone axis occur during HOD that can be targeted to ameliorate disease progression.

Egr1 deficiency disrupts dynamic equilibrium of chondrocyte extracellular matrix through PPARγ/RUNX2 signaling pathways.

BACKGROUND: This study is to investigate the effect of Egr1 on the mineralization and accumulation of chondrocyte extracellular matrix. METHODS: The femoral heads of patients of various heights were collected. Egr1 knockout mice were used. Their limb lengtha nd body weight were assessed. The bone characteristics were detected by micro-CT scan and histological staining. Immature murine articular chondrocytes (iMACs) were isolated. Gross morphology was observed by histological staining. Relevant mRNA and protein expression were detected by qRT-PCR and Western blot, respectively. the related proteins were observed by immunohistochemical staining and immunofluorescence assay. Chromatin immunoprecipitation and reporter gene assay were also used. TUNEL was used to detect apoptosis. RESULTS: It was found that shorter patients had reduced Egr1 expression levels in the hypertrophic cartilage zone of the femoral head. In addition, Egr1 knockout mice exhibited reduced body size. Micro-CT analysis showed that these mice also had reduced bone volume. Safranin-O staining showed that the extracellular matrix of these mice exhibited a relatively limited degree of mineralization, and TUNEL staining showed reduced cell apoptosis levels. After transfecting the iMACs with dominant-negative Egr1 adenoviruses to inhibit Egr1, the enzymes of Adamst4, Adamst5, Mmp3 and Mmp13 were significantly upregulated. ChIP and luciferase assays revealed that Egr1 might regulate the chondrocyte extracellular matrix by the PPARγ/RUNX2 signaling pathways. CONCLUSION: Egr1 has an important regulatory effect on the dynamic equilibrium of the chondrocyte extracellular matrix, which may be achieved through the PPARγ/RUNX2 signaling pathways.

DCA increases the antitumor effects of capecitabine in a mouse B16 melanoma allograft and a human non-small cell lung cancer A549 xenograft.

PURPOSE: Capecitabine is one of the few chemotherapy drugs with high oral availability. Recently, sodium dichloroacetate (DCA) has shown great potential as an anticancer agent. In the present study, we assessed the anticancer effect of DCA in combination with capecitabine for cancers that modestly expressed TP. METHODS: A mouse B16 melanoma allograft and a human non-small cell lung cancer A549 xenograft were used to assess the effect of DCA and capecitabine combined treatment. Histology and immunohistochemistry were used to detect the apoptosis and proliferation of cancer cells. Real-time PCR and Western blot were carried out to detect the expression of TP and caspases, respectively. RESULTS: For the first time, we report that DCA increased the antitumor effects of capecitabine in a mouse B16 allograft and a human A549 xenograft by promoting apoptosis of tumor cells. DCA has little effect on the expression of TP. CONCLUSIONS: Our finding suggests that DCA in combination with capecitabine might be potential as a new therapeutic regimen against some cancers.

Sinomenine decreases MyD88 expression and improves inflammation-induced joint damage progression and symptoms in rat adjuvant-induced arthritis.

Sinomenine (SIN) is the active principle of the Chinese medical plant Sinomenium acutum which is widely used for the treatment of rheumatoid arthritis (RA) in China. Recently, several groups indicated that myeloid differentiation primary response protein 88 (MyD88) might be associated with disease progression of RA. Here, we observed the effect of SIN on MyD88 expression and showed its therapeutic role in RA. First, immunohistochemical staining in clinical specimens showed that MyD88 was mainly located in characteristic pathological structures of RA synovial tissues. Second, we found that MyD88 was overexpressed in the synovial tissues of the rats with adjuvant-induced arthritis (AIA). Treatment with SIN markedly decreased the expression of MyD88 in AIA rats. Finally, we provided evidences that SIN suppressed inflammation response and inflammation-induced joint destructive progression and arthritis symptoms in AIA rats. Therefore, SIN is an effective therapeutic agent for RA. Targeting MyD88 signaling may provide new methods for the treatment of RA.

[Relationship between lupus headache and headache due to internal injury in traditional Chinese medicine].

In 1999, the nomenclature and case definitions for neuropsychiatric lupus syndromes were published by American College of Rheumatology (ACR), and the cognition of neuropsychiatric damage of systemic lupus erythematosus (SLE) was gradually unified and standardized. Lupus headache is an intractable problem in SLE, especially in SLE patients complicated with multiple organ injury. In general, vascular headache is common in most SLE patients, and a small number of SLE patients complicated with nervous headache are found in clinic. Moreover, its pathophysiological mechanism is far from being understood. Although early diagnosis is essential for good outcomes, the diagnosis method is rather confused in the world. There still exist some limitations in the proposal of clinical classification of headache from ACR and International Headache Society (IHS), and the proposal does not mention the classification of headache related to psychiatric damage. Current therapeutic regimens are almost exclusively based on empirical evidence. Treatment approaches include symptomatic treatment, immunosuppressive, anticoagulant and anti-aggregant therapies. It provides enormous and hopeful space in research of combined therapy strategy, especially in the field of traditional Chinese medicine. The authors discussed the relationship between lupus headache and headache due to internal injury in the view of integrated traditional Chinese and Western medicine, and suggested that the treatment strategy for lupus headache should be made in argument with the headache due to internal injury. Syndrome differentiation treatment according to deficiency in the root and excess in the branch and the therapy for activating blood to dredge collaterals maybe have great advantages in treatment of the headache in SLE.

[Assessment and explorations on the mechanism of neuroprotection of patients in ischemic stroke by traditional Chinese medicine].

Ischemic stroke is a common clinical emergency, with thrombolysis and neuroprotection as its cardinal treatment, and nowadays the latter is more and more stressed by stroke researchers. On the basis of pathophysiology and ischemic cascade of ischemic stroke, we now try to analyze the conceivable mechanism of intervention by tradition Chinese medicine (TCM) and hopefully provide experience for experimental and clinical research in the future.