Modular networks and genomic variation during progression from stable angina pectoris through ischemic cardiomyopathy to chronic heart failure.

BACKGROUND: Analyzing disease-disease relationships plays an important role for understanding etiology, disease classification, and drug repositioning. However, as cardiovascular diseases with causative links, the molecular relationship among stable angina pectoris (SAP), ischemic cardiomyopathy (ICM) and chronic heart failure (CHF) is not clear. METHODS: In this study, by integrating the multi-database data, we constructed paired disease progression modules (PDPMs) to identified relationship among SAP, ICM and CHF based on module reconstruction pairs (MRPs) of K-value calculation (a Euclidean distance optimization by integrating module topology parameters and their weights) methods. Finally, enrichment analysis, literature validation and structural variation (SV) were performed to verify the relationship between the three diseases in PDPMs. RESULTS: Total 16 PDPMs were found with K > 0.3777 among SAP, ICM and CHF, in which 6 pairs in SAP-ICM, 5 pairs for both ICM-CHF and SAP-CHF. SAP-ICM was the most closely related by having the smallest average K-value (K = 0.3899) while the maximum is SAP-CHF (K = 0.4006). According to the function of the validation gene, inflammatory response were through each stage of SAP-ICM-CHF, while SAP-ICM was uniquely involved in fibrosis, and genes were related in affecting the upstream of PI3K-Akt signaling pathway. 4 of the 11 genes (FLT1, KDR, ANGPT2 and PGF) in SAP-ICM-CHF related to angiogenesis in HIF-1 signaling pathway. Furthermore, we identified 62.96% SVs were protein deletion in SAP-ICM-CHF, and 53.85% SVs were defined as protein replication in SAP-ICM, while ICM-CHF genes were mainly affected by protein deletion. CONCLUSION: The PDPMs analysis approach combined with genomic structural variation provides a new avenue for determining target associations contributing to disease progression and reveals that inflammation and angiogenesis may be important links among SAP, ICM and CHF progression.

Pluripotent anti-inflammatory immunomodulatory effects of papaverine against cerebral ischemic-reperfusion injury.

The mechanism of the papaverine (PV) for the treatment of cerebral ischemia remains unclear. A total of 42 mice induced with focal cerebral ischemia were randomly divided into three groups: PV,baicalin (BA)and vehicle group. Both PV and BA could significantly reduce the ischemic infarct volume (P < 0.05). Pathway enrichment analysis was performed on MetaCore™ to search the molecular pathways associated with the gene expression profile of PV, compared with vehicle and BA. Compared with vehicle, we found that 60% of the top 10 pathways in PV group were related to immune response. The top 10 biological processes of the targeted pathways were mainly related to the multiple immunomodulatory process of neuro-vascular inflammation, including immune_Th17-deried cytokins, regulation of angiogenesis, cell adhesion_Leucocyte chemotaxis, antigen presentation, cell adhesion_synaptic contact, and inflammation related to Amphoterin signaling. Moreover, compared with BA, 17 pathways of PV were identified, and 58.82% (10/17) were also related to immune response, especially, half of the top 10 pathways with the lower p-value. In these top 10 pathways, 4 were the cytokine-mediated signaling pathways, which play key role in inflammation, like IL-17 signaling pathways with the activation of G-CSF,IL-23,RANKL, p38MAPK and NF-κB.These findings indicate that PV may be an efficacious pluripotent anti-inflammatory agent against cerebral ischemic-reperfusion injury by targeting on multiple immunomodulatory process of neuro-vascular inflammation.

The TGF-ß-induced up-regulation of NKG2DLs requires AKT/GSK-3ß-mediated stabilization of SP1.

Natural killer (NK) cells play an important role in preventing cancer development. NK group 2 member D (NKG2D) is an activating receptor expressed in the membrane of NK cells. Tumour cells expressing NKG2DL become susceptible to an immune-dependent rejection mainly mediated by NK cells. The paradoxical roles of transforming growth factor beta (TGF-ß) in regulation of NKG2DL are presented in many studies, but the mechanism is unclear. In this study, we showed that TGF-ß up-regulated the expression of NKG2DLs in both PC3 and HepG2 cells. The up-regulation of NKG2DLs was characterized by increasing the expression of UL16-binding proteins (ULBPs) 1 and 2. TGF-ß treatment also increased the expression of transcription factor SP1. Knockdown of SP1 significantly attenuated TGF-ß-induced up-regulation of NKG2DLs in PC3 and HepG2 cells, suggesting that SP1 plays a key role in TGF-ß-induced up-regulation of NKG2DLs. TGF-ß treatment rapidly increased SP1 protein expression while not mRNA level. It might be due to that TGF-ß can elevate SP1 stability by activating PI3K/AKT signalling pathway, subsequently inhibiting GSK-3ß activity and decreasing the association between SP1 and GSK-3ß. Knockdown of GSK-3ß further verified our findings. Taken together, these results revealed that AKT/GSK-3ß-mediated stabilization of SP1 is required for TGF-ß induced up-regulation of NKG2DLs. Our study provided valuable evidence for exploring the tumour immune modulation function of TGF-ß.

Histone deacetylase inhibitors deplete myeloid-derived suppressor cells induced by 4T1 mammary tumors in vivo and in vitro.

Myeloid-derived suppressor cells (MDSC) have been identified as a population of immature myeloid cells that suppress anti-tumor immunity. MDSC are increased in tumor-bearing hosts; thus, depletion of MDSC may enhance anti-tumor immunity. Histone deacetylase inhibitors (HDACi) are chemical agents that are primarily used against hematologic malignancies. The ability of these agents to modulate anticancer immunity has recently been extensively studied. However, the effect of HDACi on MDSC has remained largely unexplored. In the present study, we provide the first demonstration that HDACi treatment decreases MDSC accumulation in the spleen, blood and tumor bed but increases the proportion of T cells (particularly the frequency of IFN-γ- or perforin-producing CD8+ T cells) in BALB/C mice with 4T1 mammary tumors. In addition, HDACi exposure of bone marrow (BM) cells significantly eliminated the MDSC population induced by GM-CSF or the tumor burden in vitro, which was further demonstrated as functionally important to relieve the inhibitory effect of MDSC-enriched BM cells on T cell proliferation. Mechanistically, HDACi increased the apoptosis of Gr-1+ cells (almost MDSC) compared with that of Gr-1- cells, which was abrogated by the ROS scavenger N-acetylcysteine, suggesting that the HDACi-induced increase in MDSC apoptosis due to increased intracellular ROS might partially account for the observed depletion of MDSC. These findings suggest that the elimination of MDSC using an HDACi may contribute to the overall anti-tumor properties of these agents, highlighting a novel property of HDACi as potent MDSC-targeting agents, which may be used to enhance the efficacy of immunotherapeutic regimens.

Nodal signaling modulates the expression of Oct-4 via nuclear translocation of ß-catenin in lung and prostate cancer cells.

Nodal is a member of transforming growth factor beta (TGF-ß) superfamily. Nodal promotes the self-renewal of human cancer stem cells (CSCs) and triggers carcinogenesis of human cancers via an autocrine manner through Smad2/3 pathway. In our study, generation of Nodal-overexpressed cancer cells was constructed, and the effect of Nodal on the stem cell marker Oct-4 was evaluated by overexpression or blocked Nodal/ALKs signaling pathway in non-small cell lung cancer cells A549 and prostate cancer cells PC3. Functionally, Nodal also increased the proliferation via the ß-catenin nuclear translocation. This increase was attributed to GSK-3ß dephosphorylating, and activin receptor-like kinase 4/7 (ALK4/7) played a major role in human cancer cells. Our study provides a positive understanding of Nodal function in cancer cells and suggests a potential novel target for clinical therapeutic research.

[Study on antidepressant effect of kuanxinjieyutang combined aerobic exercise].

OBJECTIVE: To observe antidepressant effects of Kuanxinjieyutang (KXJYT), short-term aerobic exercise and their joint intervention and its possible mechanism. METHODS: Ninty-six SPF male KM mice were randomly divided into control group, imipramine, low dose (KXJYT 1.8 g crude drugs/kg bw/time/day), high dose (3.6 g crude drugs/kg bw/time/day), exercise group (swimming 30 min/times/day), joint group (low dose and swimming ), with 8 days intervention. The antidepressant effect was evaluated by forced swimming, tail suspension test and overhead cross maze test. After mice were killed, brain monoamine neurotransmitter levels of mice were detected by ELISA, and BDNF expression in brain was analyzed by Western blotting. RESULTS: High dose group showed antidepressant effect like imipramine while low dose didn't. Exercise group showed similar or better antidepressant effect than imipramine. Joint group showed better interaction antidepressant effect. Brain NE, DA of high dose group and brain NE, DA and 5-HT content of exercise group increased significantly, similar to imipramine. Brain NE,DA and 5-HT content of Joint group were significantly higher than those of imipramine. The protein expression of BDNF in brain was more in imipramine, high dose,exercise and joint groups than that of control group, sports group was higher than that of low dose and high dose group, joint group was obviously higher than other groups. CONCLUSION: Moderate KXJYT, short-term aerobic exercise and their joint intervention have obvious antidepressant effect on mild depression. Its mechanism may be related to increasing brain NE and 5-HT content, and inducing brain BDNF expression, which may affect the nerve regeneration and plasticity, improve cognitive function.

A serum metabolomics study of vascular cognitive impairment patients based on Traditional Chinese medicine syndrome differentiation.

Objective: Vascular cognitive impairment (VCI) accounts for approximately 50%-70% of all dementia cases and poses a significant burden on existing medical systems. Identifying an optimal strategy for preventing VCI and developing efficient symptomatic treatments remains a significant challenge. Syndrome differentiation represents a fundamental approach for personalized diagnosis and treatment in Traditional Chinese Medicine (TCM) and aligns with the principles of precision medicine. The objective of this study was to elucidate the metabolic characteristics of VCI based on TCM syndrome differentiation, thus providing novel insights into the diagnosis and treatment of VCI. Methods: A 2-year cross-sectional cognitive survey was conducted in four communities in Beijing between September 2020 and November 2022. The syndrome differentiation of participants was based on the Kidney-Yang Deficiency Syndrome Scale (KYDSS), which was originally developed by Delphi expert consultation. The identification of serum metabolites was performed by Ultra performance liquid chromatography (UPLC) analysis coupled with an electrospray ionization quadruple time-of-flight mass spectrometer (ESI-QTOF MS). Multivariate, univariate, and pathway analyses were used to investigate metabolic changes. Logistic regression models were also used to construct metabolite panels that were capable of discerning distinct groups. Phospholipase A2 (PLA2) levels were measured by a commercial ELISA kit. Results: A total of 2,337 residents completed the survey, and the prevalence of VCI was 9.84%. Of the patients with VCI, those with Kidney-Yang deficiency syndrome (VCIS) accounted for 70.87% of cases and exhibited more severe cognitive impairments. A total of 80 participants were included in metabolomics study, including 30 with VCIS, 20 without Kidney-Yang deficiency syndrome (VCINS), and 30 healthy control participants (C). Ultimately, 45 differential metabolites were identified when comparing the VCIS group with group C, 65 differential metabolites between the VCINS group and group C, and 27 differential metabolites between the VCIS group and the VCINS group. The downregulation of phosphatidylethanolamine (PE), and phosphatidylcholine (PC) along with the upregulation of lysophosphatidylethanolamine (LPE), lysophosphatidylcholine (LPC), phosphatidic acid (PA) and phospholipase A2 (PLA2) can be considered as the general metabolic characteristics associated with VCI. Dysfunction of glycerophospholipids, particularly LPEs and PCs, was identified as a key metabolic characteristic of VCIS. In particular Glycerophospho-N-Arachidonoyl Ethanolamine (GP-NArE) was discovered for the first time in VCI patients and is considered to represent a potential biomarker for VCIS. The upregulation of PLA2 expression was implicated in the induction of alterations in glycerophospholipid metabolism in both VCIS and VCINS. Moreover, robust diagnostic models were established based on these metabolites, achieving high AUC values of 0.9322, 0.9550, and 0.9450, respectively. Conclusion: These findings contribute valuable information relating to the intricate relationship between metabolic disorders in VCI, neurodegeneration and vascular/neuroinflammation. Our findings also provide a TCM perspective for the precise diagnosis and treatment of VCI in the context of precision medicine.

AP-1 confers resistance to anti-cancer therapy by activating XIAP.

The underlying cause of treatment failure in many cancer patients is intrinsic and acquired resistance to chemotherapy. Recently, histone deacetylase (HDAC) inhibitors have developed into a promising cancer treatment. However, resistance mechanism induced by HDAC inhibitors remains largely unknown. Here we report that a HDAC inhibitor, JNJ-2648158 induced transcription of XIAP by activating AP-1 expression, which conferring resistance to chemotherapeutics. Our results showed that high expression of c-Fos caused by HDAC inhibitor promoted AP-1 formation during acquired resistance towards chemo-drugs, indicating an extremely poor clinical outcome in breast cancers and liver cancers. Our study reveals a novel regulatory mechanism towards chemo-drug resistance, and suggests that XIAP may serve as a potential therapeutic target in those chemo-resistant cancer cells.

CCL21 Facilitates Chemoresistance and Cancer Stem Cell-Like Properties of Colorectal Cancer Cells through AKT/GSK-3ß/Snail Signals.

Some evidence indicated that chemoresistance associates with the acquisition of cancer stem-like properties. Recent studies suggested that chemokines can promote the chemoresistance and stem cell properties in various cancer cells, while the underling mechanism is still not completely illustrated. In our study, we found that CCL21 can upregulate the expression of P-glycoprotein (P-gp) and stem cell property markers such as Bmi-1, Nanog, and OCT-4 in colorectal cancer (CRC) HCT116 cells and then improve the cell survival rate and mammosphere formation. Our results suggested that Snail was crucial for CCL21-mediated chemoresistance and cancer stem cell property in CRC cells. Further, we observed that CCL21 treatment increased the protein but not mRNA levels of Snail, which suggested that CCL21 upregulates Snail via posttranscriptional ways. The downstream signals AKT/GSK-3ß mediated CCL21 induced the upregulation of Snail due to the fact that CCL21 treatment can obviously phosphorylate both AKT and GSK-3ß. The inhibitor of PI3K/Akt, LY294002 significantly abolished CCL21 induced chemoresistance and mammosphere formation of HCT116 cells. Collectively, our results in the present study revealed that CCL21 can facilitate chemoresistance and stem cell property of CRC cells via the upregulation of P-gp, Bmi-1, Nanog, and OCT-4 through AKT/GSK-3ß/Snail signals, which suggested a potential therapeutic approach to CRC patients.

[Clinical investigation of different routes of administration of dexamethasone on sudden deafness].

OBJECTIVE: To investigate the therapeutic effects of conventional treatment with different routes of administration of dexamethasone on sudden deafness. METHOD: Eighty-four patients with sudden deafness were included in this prospective randomized study. Twenty one patients (group 1) were treated with taking dexamethasone orally combined with conventional methods. Another 21 patients (group 2) were treated with intravenous dexamethasone injection combined with conventional methods. Group 3 (21 patients) were treated with intratympanic dexamethasone injection by the way of external ear combined with conventional methods. The other 21 patients (group 4) were treated with intratympanic dexamethasone injection by the way of pharyngotympanic tube combined with conventional methods. The hearing gains at 0.5, 1.0, 2.0, 4.0 kHz and the mean values were compared among four groups. RESULTS: The average hearing gains of 1, 2, 3 and 4 group was 21.3 dB, 27.5 dB, 43.2 dB and 48.1 dB respectively. Group 3 and group 4 had statistical difference compared with group 1 and group 2 in the average hearing gains. There was no obviously statistical difference between group 1 and group 2 and between group 3 and group 4. In patients with PTA < or = 70 dB, the average hearing gains at 0.5, 1.0, 2.0, 4.0 kHz had no obvious difference (P > 0.05) among four groups. However, in patients with PTA > 70 dB, there was statistical difference between group 1, 2 and group 3, 4 (P < 0.05), the hearing gains of group 3. 4 were apparently higher than that of group 1, 2. However, there was no significant difference of hearing gains between group 1 and group 2 (P > 0.05) and between group 3 and group 4 (P > 0.05). CONCLUSION: The conventional drug treatment with taking dexamethasone orally or intravenous dexamethasone injection had no obvious effect on sudden deafness with PTA > 70 dB, but the conventional drug treatment with intratympanic dexamethasone injection is a useful treatment for sudden deafness. Comparison with whole body administration, intratympanic dexamethasone injection is more convenient to use in clinic, and with less prohibitions and complications. Patients with PTA > 70 dB should take intratympanic dexamethasone injection in early days.