Systemic immune-inflammation index mediates the association between metabolic dysfunction-associated fatty liver disease and sub-clinical carotid atherosclerosis: a mediation analysis.

Background: Limited research has been conducted to quantitatively assess the impact of systemic inflammation in metabolic dysfunction-associated fatty liver disease (MAFLD) and sub-clinical carotid atherosclerosis (SCAS). The systemic immune-inflammation index (SII), which integrates inflammatory cells, has emerged as a reliable measure of local immune response and systemic inflammation Therefore, this study aims to assess the mediating role of SII in the association between MAFLD and SCAS in type 2 diabetes mellitus (T2DM). Method: This study prospectively recruited 830 participants with T2DM from two centers. Unenhanced abdominal CT scans were conducted to evaluate MAFLD, while B-mode carotid ultrasonography was performed to assess SCAS. Weighted binomial logistic regression analysis and restricted cubic splines (RCS) analyses were employed to analyze the association between the SII and the risk of MAFLD and SCAS. Mediation analysis was further carried out to explore the potential mediating effect of the SII on the association between MAFLD and SCAS. Results: The prevalence of both MAFLD and SCAS significantly increased as the SII quartiles increased (P<0.05). MAFLD emerged as an independent factor for SCAS risk across three adjusted models, exhibiting odds ratios of 2.15 (95%CI: 1.31-3.53, P < 0.001). Additionally, increased SII quartiles and Ln (SII) displayed positive associations with the risk of MAFLD and SCAS (P < 0.05). Furthermore, a significant dose-response relationship was observed (P for trend <0.001). The RCS analyses revealed a linear correlation of Ln (SII) with SCAS and MAFLD risk (P for nonlinearity<0.05). Importantly, SII and ln (SII) acted as the mediators in the association between MAFLD and SCAS following adjustments for shared risk factors, demonstrating a proportion-mediated effect of 7.8% and 10.9%. Conclusion: SII was independently correlated with MAFLD and SCAS risk, while also acting as a mediator in the relationship between MAFLD and SCAS.

Research on plasma modified fly ash denitration.

The effects of reactor parameters and process parameters on the denitration rate of modified fly ash in different gas atmospheres were studied by using a dielectric barrier plasma reactor and using orthogonal experiments. The characteristics of modified fly ash were analyzed using scanning electron microscope, specific surface area analyzer, X-ray diffraction, Boehm titration and Fourier transform infrared spectroscopy. The experimental data were processed by variance analysis and linear regression to induce the denitration mechanism. R2 of the linear regression analysis model is 0.789, which means that the adsorption pore size, acid groups and basic group can explain 78.9% of the change in denitration rate. The basic group will have a significant positive impact on the denitration rate, and the adsorption pore size and acidic group will have a significant negative impact on the denitration rate. Through variance analysis of the experimental data, it was found that the input power and discharge gap have a significant effect on the denitration rate, but the ionization time and discharge length have no significant effect. The input power affects the denitration rate by impacting the basic group, and the discharge gap affects the denitration rate by influencing the adsorption pore size. There are three denitration mechanisms on the surface of fly ash: physical adsorption, chemical adsorption and absorption process. Among them, chemical adsorption is the main mechanism of action, accounting for approximately 60.86%.

Perirenal fat thickness as a superior obesity-related marker of subclinical carotid atherosclerosis in type 2 diabetes mellitus.

Objective: Emerging evidence highlighted that perirenal adipose tissue might regulate the cardiovascular and metabolism system through several pathways. This study aimed to assess the association between perirenal fat thickness (PrFT) and subclinical carotid atherosclerosis (SCCA) in type 2 diabetes mellitus (T2DM). Method: A total of 670 participants with complete data were included in this study. The trained reviewer collected demographic and anthropometric information. Laboratory assessments were determined by standard methods. PrFT and SCCA were evaluated by computed tomography and ultrasound. Binomial logistic regression analysis was conducted to assess the association between PrFT and SCCA. Receiver operating characteristic (ROC) curve analysis was conducted to evaluate the identifying value of PrFT for SCCA. Results: Overall, the prevalence of SCCA was 61.8% in T2DM. PrFT was significantly increased in the SCCA group. Growing trends were observed in the prevalence of hypertension, carotid intima-media thickness (cIMT) > 1, plaque, and SCCA across the PrFT quartiles. Spearman correlation analysis revealed that PrFT was positively associated with cIMT (r = 0.401, p < 0.001). This correlation remained significant after adjustment for visceral fat area (VFA), subcutaneous fat area (SFA), and traditional metabolic risk factors (ß = 0.184, p < 0.001). Meanwhile, PrFT was independently correlated with plaque, cIMT > 1 mm, and SCCA. The ORs (95% CI) were 1.072 (1.014-1.135), 1.319 (1.195-1.455), and 1.216 (1.119-1.322). Furthermore, PrFT remained correlated considerably with SCCA in subgroup analysis after stratification for age, sex, smoking, hypertension, and body mass index. From the ROC curve analysis, the AUCs (95% CI) of PrFT, VFA, and SFA identifying SCCA were 0.794 (0.760-0.828), 0.760 (0.724-0.796), and 0.697 (0.656-0.737), respectively. The AUC of PrFT was significantly higher than VFA (p = 0.028) and SFA (p < 0.001). The optimal cutoff values of PrFT were 14.0 mm, with a sensitivity of 66.7% and a specificity of 76.2%. Conclusion: PrFT was independently associated with cIMT, plaque, cIMT > 1 mm, and SCCA as a superior obesity-related marker of SCCA in T2DM. Clinical trial registration: Clinical Trials.Gov, identifier ChiCTR2100052032.

Apolipoprotein A1 is associated with osteocalcin and bone mineral density rather than high-density lipoprotein cholesterol in Chinese postmenopausal women with type 2 diabetes mellitus.

Objective: Disturbances in high-density lipoprotein cholesterol (HDL-c) metabolic pathways can affect bone metabolism, which may rely on the particle function of apolipoprotein rather than HDL-c levels. This study aimed to evaluate the correlation of serum HDL-c and apolipoprotein A1 (APOA1) with bone metabolism in Chinese postmenopausal women with type 2 diabetes mellitus (T2DM). Method: A total of 1,053 participants with complete data were enrolled and separated into three groups based on the HDL-c and APOA1 tertiles. The trained reviewer collected demographic and anthropometric information. Bone turnover markers (BTMs) were determined by standard methods. Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry. Results: Overall, the prevalence of osteoporosis was 29.7%. Groups with higher APOA1 have a remarkably more elevated level of osteocalcin (OC), L1-L4 BMD, and T-score across the APOA1 tertiles. APOA1 presented a positive correlation with OC (r = 0.194, p < 0.001), L1-L4 BMD (r = 0.165, p < 0.001), and T-score (r = 0.153, p < 0.001) rather than HDL-c. Meanwhile, APOA1 remained independently associated with OC (ß = 0.126, p < 0.001), L1-L4 BMD (ß = 0.181, p < 0.001), and T-score (ß = 0.180, p < 0.001) after adjustment for confounding factors. APOA1 is also shown to be independently correlated with osteoporosis after adjustment for confounding factors, and the OR (95%CI) was 0.851 (0.784-0.924). In contrast, there was no significant association between HDL-c and osteoporosis. Furthermore, APOA1 seemed to have the largest areas under the curve (AUC) for osteoporosis. The AUC (95% CI) of APOA1 identifying osteoporosis was 0.615 (0.577-0.652). The optimal cut-off value of APOA1 was 0.89 g/L (sensitivity: 56.5%, specificity: 67.9%). Conclusion: APOA1 is independently associated with OC, L1-L4 BMD, and osteoporosis rather than HDL-c in Chinese postmenopausal women with T2DM.

Perirenal Fat Thickness is Associated with Metabolic Dysfunction-Associated Fatty Liver Disease in Type 2 Diabetes Mellitus.

Objective: Recent advances in perirenal adipose tissue (PAT) highlighted that PAT might involve in the pathogenesis of chronic inflammatory and dysfunctional metabolic diseases. This study assessed the association between perirenal fat thickness (PrFT) and metabolic dysfunction-associated fatty liver disease (MALFD) in type 2 diabetes mellitus (T2DM). Methods: This study comprised 867 eligible participants with T2DM. Trained reviewers collected anthropometric and biochemical measurements. The diagnosis of MAFLD was based on the latest international expert consensus statement. PrFT and fatty liver were evaluated by computed tomography. The visceral fat area (VFA) and subcutaneous fat area (SFA) were measured by bioelectrical impedance analysis. The non-alcoholic fatty liver disease fibrosis score (NFS) and fibrosis-4 (FIB-4) index were used to assess progressive liver fibrosis in MAFLD. Results: Overall, the prevalence of MAFLD was 62.3% in T2DM. The PrFT in the MAFLD group was statistically increased than in the non-MAFLD group (P < 0.05). Correlation analysis showed that PrFT was significantly correlated with dysfunctional metabolic factors like body mass index, waist circumference, triglycerides, high-density lipoprotein cholesterol, systolic blood pressure, diastolic blood pressure, uric acid, and insulin resistance. Multiple regression analysis revealed that PrFT was positively correlated with NFS (ß=0.146, P<0.001) and FIB-4 (ß=0.082, P=0.025) in the MAFLD. In contrast, PrFT was negatively correlated with CTL-S (ß=-0.188, P<0.001). Furthermore, PrFT was also significantly associated with MAFLD independent of VFA and SFA, the OR (95% CI) was 1.279 (1.191-1.374). Meanwhile, PrFT also had a good identifying value for MAFLD as VFA. The area under the curve (95% CI) value of PrFT identifying MAFLD was 0.782 (0.751-0.812). The optimal cut-off value of PrFT was 12.6mm, with a sensitivity of 77.8% and specificity of 70.8%. Conclusion: PrFT was independently associated with MAFLD, NFS, and FIB-4 and showed a similar identifying value for MAFLD as VFA, which suggested that PrFT can be used as an alternative index to VFA.

Circulating galectin-3 promotes tumor-endothelium-adhesion by upregulating ICAM-1 in endothelium-derived extracellular vesicles.

The adhesion of tumor cells to vascular endothelial cells is an important process of tumor metastasis. Studies have shown that tumor could educate vascular endothelial cells to promote tumor metastasis through many ways. However, the effect of tumor cells on the functions of vascular endothelial cells-derived extracellular vesicles (H-EVs) and the mechanisms underlying their effects in tumor-endothelium adhesion in metastasis remain mysterious. In this study, we found that H-EVs promoted the adhesion of triple negative breast cancer cell to endothelial cells and cirGal-3 enhanced the adhesion-promoting effects of H-EVs. The underlying mechanism was related to the upregulation of glycolysis in endothelial cells induced by cirGal-3 which led to the increase of the ICAM-1 expression and its transmission to MDA-MB-231 cells by H-EVs. Targeting of cirGal-3 or glycolysis of vascular endothelium in breast cancer therefore represents a promising therapeutic strategy to reduce metastasis.

Perirenalfat thickness is associated with bone turnover markers and bone mineral density in postmenopausal women with type 2 diabetes mellitus.

Objectives: Emerging evidence demonstrated that perirenal fat may modulate bone metabolism through several pathological pathways. This study was aimed to assess the associations between perirenal fat thickness (PrFT) and bone turnover markers (BTMs) and bone mineral density (BMD) in postmenopausal women with type 2 diabetes mellitus (T2DM) and further explore the correlation between PrFT and osteoporosis. Methods: In this cross-sectional study, a total of 626 participants with complete data were enrolled in this study. Demographic and anthropometric information was collected. Biochemical parameters and BTMs were determined. PrFT and BMD were measured by computed tomography and dual-energy x-ray absorptiometry, respectively. Correlation analysis and regression models were used to assess the associations between PrFT and BTMs and BMD. The multiple binomial logistic regression model was used to estimate the independent variables of PrFT for osteoporosis. Results: Overall, the prevalence of osteoporosis was 38.7%. PrFT was negatively correlated with ß-cross-linked C-telopeptide of type I collagen (ß-CTX) (r = -0.216,< 0.001), L1-L4 BMD (r = -0.351, < 0.001), and T-score (r = -0.396, < 0.001). PrFT also remained significantly correlated with ß-CTX (ß = -0.291, P< 0.001), L1-L4 BMD (ß = -0.109, P= 0.027), and L1-L4 T-score (ß = -0.149, P= 0.001) after adjustment for other confounding factors. Furthermore, PrFT was also independently associated with osteoporosis after adjustment for other confounding factors; the OR (95% CI) was 1.13 (1.04-1.23). PrFT also seems to have a relatively good identifying value for osteoporosis. The area under the curve (AUC) value of PrFT in identifying osteoporosis was 0.766 (95% CI: 0.705-0.826, P < 0.001). The optimal cutoff value of PrFT was 15.2 mm (sensitivity: 72.5%, specificity: 79.8%). Conclusions: PrFT was significantly associated with ß-CTX, BMD, and osteoporosis. These findings indicate that perirenal fat may play an important role in bone metabolism. Clinical Trial Registration: http://www.chictr.org.cn/, identifier (ChiCTR2100052032).

DSC2 Suppresses the Metastasis of Gastric Cancer through Inhibiting the BRD4/Snail Signaling Pathway and the Transcriptional Activity of ß-Catenin.

Downregulated DSC2 involved in the metastasis of cancers. Unfortunately, its role on the development of gastric cancer (GC) and the potential mechanisms remain unclear. Bioinformatics analysis, Western blot, qRT-PCR, and immunohistochemistry were performed to detect the DSC2 levels of human GC and normal stomach tissues. The role of DSC2 and the downstream signaling in gastric carcinogenesis were explored by using GC specimens, GC cells with different DSC2 expression, inhibitors, and mouse metastasis models. We found that the level of DSC2 decreased significantly in GC tissues and cells. Recovered DSC2 inhibited the invasion and migration of GC cells both in culture and in xenografts. Mechanistically, DSC2 could not only decrease Snail level and nuclear BRD4 level by forming DSC2/BRD4, but also inhibit nuclear translocation of ß-catenin. We concluded that DSC2 inhibited the metastasis of GC, and the underlying mechanisms were closely related to the regulation on nuclear translocation of BRD4 and ß-catenin. Our results suggest that DSC2 may serve as a novel therapeutic target for GC.

Monocyte to High-Density lipoprotein and Apolipoprotein A1 Ratios: Novel Indicators for Metabolic Syndrome in Chinese Newly Diagnosed Type 2 Diabetes.

Objective: Increasing evidence highlighted that chronic inflammation involved in the development of metabolic syndrome (MetS) and Type 2 diabetes mellitus (T2DM). This prospective study was aimed to assess the association between MetS and novel pro-inflammatory indicators like monocyte-to-high-density lipoprotein and monocyte-to-apolipoprotein A1 ratios (MHR and MAR) in Chinese newly diagnosed T2DM. Method: A total of 605 Chinese newly diagnosed T2DM with complete and available data were enrolled in this study. Demographic and anthropometric information were collected. Laboratory assessments were determined by standard methods. MetS was based on the Chinese Diabetes Society definition. Multiple binomial logistic regression model was used to estimate the independent variables of MHR and MAR for MetS. Receiver operating characteristic (ROC) curve was conducted to assess the optimal cutoff value of MHR and MAR in identifying MetS. Results: Overall, the prevalence of MetS was 60.2%. The correlation analysis showed that MHR and MAR were closely correlated with metabolic risk factors like body mass index, waist circumference, triglycerides, high-density lipoprotein cholesterol, systolic blood pressure, diastolic blood pressure, uric acid, and insulin resistance. MHR and MAR were also significantly associated with higher odds of MetS after adjustment for other confounders, the odds ratios (ORs) (95%CI) were 1.50 (1.14-1.97) and 2.26(1.79-2.87) respectively. Furthermore, MHR and MAR were also seemed to have higher area under the curve (AUC) for MetS than ApoA1 and monocyte alone from the ROC curve analysis (P < 0.05). The AUCs of MHR and MAR identifying MetS were 0.804 (95% CI: 0.768-0.839) and 0.840 (95% CI: 0.806-0.873) respectively (P < 0.001). The optimal cutoff values of MHR and MAR were 3.57 × 108/mmol (sensitivity: 76.1%, specificity: 73.4%) and 3.95 × 108/g (sensitivity: 79.7%, specificity: 84.6%), respectively. Conclusions: MHR and MAR were significantly associated with MetS. These two novel pro-inflammatory indicators may be useful markers for MetS in Chinese newly diagnosed T2DM.

Perirenal Fat Thickness: A Surrogate Marker for Metabolic Syndrome in Chinese Newly Diagnosed Type 2 Diabetes.

Objective: Increasing evidence suggested that perirenal fat thickness (PrFT) was associated with metabolic risk factors. This study aimed to assess the association between PrFT and metabolic syndrome (MetS) in Chinese newly diagnosed type 2 diabetes (T2DM), further evaluating the ability of PrFT in identifying MetS. Method: A total of 445 Chinese newly diagnosed T2DM were enrolled in this study from January to June 2021. Demographic and anthropometric information were collected. PrFT was evaluated by CT scan on Revolution VCT 256. MetS was based on the Chinese Diabetes Society definition. Receiver operating characteristic (ROC) curve was conducted to assess the optimal cutoff value of PrFT in identifying MetS. Results: Overall, the prevalence of MetS was 57.5% (95% CI: 54.0-64.0%) in men and 58.9% (95% CI: 52.3-65.5%) in women separately. The correlation analysis showed that PrFT was significantly correlated with metabolic risk factors like body mass index, waist circumference, triglycerides, high-density lipoprotein cholesterol, systolic blood pressure, diastolic blood pressure, uric acid, and insulin resistance. PrFT was also shown to be independently associated with MetS after adjustment for other confounders. The odds ratios (ORs, 95% CI) were 1.15 (1.03-1.38) in men and 1.31 (1.08-1.96) in women (P < 0.05). The ROC curves showed a good predictive value of PrFT for MetS. The areas under the curve of PrFT identifying MetS were 0.895 (95% CI: 0.852-0.939) in men and 0.910 (95% CI: 0.876-0.953) in women (P < 0.001). The optimal cutoff values of PrFT were 14.6 mm (sensitivity: 83.8%, specificity: 89.6%) for men and 13.1 mm (sensitivity: 87.6%, specificity: 91.1%) for women. Conclusions: PrFT was significantly associated with MetS and showed a powerful predictive value for it, which suggested that PrFT can be an applicable surrogate marker for MetS in Chinese newly diagnosed T2DM. Clinical Trial Registration: This study was registered in clinicaltrials.gov (ChiCTR2100052032).

Modified citrus pectin inhibits breast cancer development in mice by targeting tumor-associated macrophage survival and polarization in hypoxic microenvironment.

Large amounts of tumor-associated macrophages (TAM), which are predominately localized in hypoxia area of the tumor tissue, are associated with the malignant progression of the tumor. In the present study, we investigated the inhibitory effects of modified citrus pectin (MCP), a natural dietary polysaccharide, on the survival and polarization of TAM in relation to its inhibition on the growth and migration of breast cancer. M2 macrophages polarized from human monocyte THP-1 were chosen as a model for TAM. We showed that MCP (0.06%-1%) concentration-dependently suppressed the survival of TAM through inhibiting glucose uptake with a greater extent in hypoxia than in normoxia. Furthermore, MCP treatment decreased ROS level in TAM through its reducibility and inhibiting galectin-3 expression, leading to inhibition of glucose transporter-1 expression and glucose uptake. In addition, MCP suppressed M2-like polarization via inhibiting STAT3 phosphorylation. Moreover, the tumor-promoting effect of TAM could be restrained by MCP treatment as shown in human breast cancer MDA-MB-231 cells in vitro and in mouse breast cancer 4T1-luc orthotopic and metastasis models. In both tumor tissue and lung tissue of the mouse tumor models, the number of TAM was significantly decreased after MCP treatment. Taken together, MCP may be a promising agent for targeting TAM in tumor hypoxic microenvironment for breast cancer treatment.

Potential Therapeutic Strategies for Targeting Y-Box-Binding Protein 1 in Cancers.

As one of the most conservative proteins in evolution, Y-box-binding protein 1 (YB-1) has long been considered as a potential cancer target. YB-1 is usually poorly expressed in normal cells and exerts cellular physiological functions such as DNA repair, pre-mRNA splicing and mRNA stabilizing. In cancer cells, the expression of YB-1 is up-regulated and undergoes nuclear translocation and contributes to tumorigenesis, angiogenesis, tumor proliferation, invasion, migration and chemotherapy drug resistance. During the past decades, a variety of pharmacological tools such as siRNA, shRNA, microRNA, circular RNA, lncRNA and various compounds have been developed to target YB-1 for cancer therapy. In this review, we describe the physiological characteristics of YB-1 in detail, highlight the role of YB-1 in tumors and summarize the current therapeutic methods for targeting YB-1 in cancer.

Pantoprazole ameliorates liver fibrosis and suppresses hepatic stellate cell activation in bile duct ligation rats by promoting YAP degradation.

Liver fibrosis is one of the most severe pathologic consequences of chronic liver diseases, and effective therapeutic strategies are urgently needed. Proton pump inhibitors (PPIs) are H+/K+-ATPase inhibitors and currently used to treat acid-related diseases such as gastric ulcers, which have shown other therapeutic effects in addition to inhibiting acid secretion. However, few studies have focused on PPIs from the perspective of inhibiting hepatic fibrosis. In the present study, we investigated the effects of pantoprazole (PPZ), a PPI, against liver fibrosis in a bile duct ligation (BDL) rat model, human hepatic stellate cell (HSC) line LX-2 and mouse primary HSCs (pHSCs), and explored the potential mechanisms underlying the effects of PPZ in vitro and in vivo. In BDL rats, administration of PPZ (150 mg· kg-1· d-1, i.p. for 14 d) significantly attenuated liver histopathological injury, collagen accumulation, and inflammatory responses, and suppressed fibrogenesis-associated gene expression including Col1a1, Acta2, Tgfß1, and Mmp-2. In LX-2 cells and mouse pHSCs, PPZ (100-300 µM) dose-dependently suppressed the levels of fibrogenic markers. We conducted transcriptome analysis and subsequent validation in PPZ-treated LX-2 cells, and revealed that PPZ inhibited the expression of Yes-associated protein (YAP) and its downstream targets such as CTGF, ID1, survivin, CYR61, and GLI2. Using YAP overexpression and silencing, we demonstrated that PPZ downregulated hepatic fibrogenic gene expression via YAP. Furthermore, we showed that PPZ promoted the proteasome-dependent degradation and ubiquitination of YAP, thus inhibiting HSC activation. Additionally, we showed that PPZ destabilized YAP by disrupting the interaction between a deubiquitinating enzyme OTUB2 and YAP, and subsequently blocked the progression of hepatic fibrosis.

Downregulation of Renal MRPs Transporters in Acute Lymphoblastic Leukemia Mediated by the IL-6/STAT3/PXR Signaling Pathway.

PURPOSE: Considering prior investigations on reductions of renal multidrug resistance-associated protein (MRP) 2 and 4 transporters in mice with acute lymphoblastic leukemia (ALL), we sought to characterize the underlying mechanisms responsible for IL-6/STAT3/PXR-mediated changes in the expression of MRP2 and MRP4 in ALL. SUBJECTS AND METHODS: ALL xenograft models were established and intravenously injected with methotrexate (MTX) of MRPs substrate in NOD/SCID mice. Protein expression of MRPs and associated mechanisms were detected by Western blotting and immunocytochemistry. Plasma concentrations of MTX were determined using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). RESULTS: Plasma IL-6 levels in patients with newly diagnosed ALL were increased compared to children with pneumonia. Similarly, plasma IL-6 levels in ALL, ALL-tocilizumab (TCZ, an IL-6 receptor inhibitor) and ALL-S3I-201 (a selective inhibitor of STAT3) mice were increased compared to the control group. The MRP2, MRP4, and PXR expression in HK-2 cells treated with IL-6 were decreased, whereas the p-STAT3 expression was significantly increased compared to the control group results. These results are consistent with clearance of MRPs-mediated MTX in the ALL group. These effects were attenuated by blocking IL-6/STAT3/PXR signaling pathway. CONCLUSION: Inflammation-mediated changes in pharmacokinetics are thought to be executed through pathways IL-6-activated pathways, which can facilitate a better understanding of the potential for the use of IL-6 to predict the severity of adverse outcomes and the major implications on potential ALL treatments.

Microglial NLRP3 inflammasome activation-mediated inflammation promotes prolactinoma development.

Prolactinomas have harmful effects on human health, and the pathogenesis is still unknown. Furthermore, 25% of prolactinoma patients do not respond to the therapy of dopamine receptor agonist in the clinic. Thus, it is important to reveal the pathogenesis and develop new therapeutic methods for prolactinomas. Herein, two animal models of prolactinomas, namely oestrogen-treated rats and transgenic D2 dopamine receptor-deficient mice, were used. PET/CT imaging detection showed that translocator protein-mediated microglia activation and inflammation significantly increased in the pituitary glands of prolactinomas rats. Messenger RNA microarrays were used to analyze and compare the differential gene and signal pathways of the pituitary glands between control and prolactinomas rats. Statistical results pertaining to gene enrichment showed that the innate immune response genes were upregulated in the pituitary glands of prolactinoma rats. This suggested that the innate immune response was activated. We analyzed the NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome that is one of the most important members of the innate immune system in mammals and found that the expressions of NLRP3, Caspase-1, apoptosis-associated speck-like, interleukin 1B (IL1B) and IL18 proteins of pituitary glands in prolactinomas rats were increased considerably compared with those in control rats. This suggested the activation of the NLRP3 inflammasome during the emergence and evolution of prolactinomas. Immunohistochemistry results also confirmed that the NLRP3 expression was elevated in human prolactinoma tissues, and the microglia marker-ionised calcium binding adaptor molecule-1 was co-located with the NLRP3 protein in prolactinomas by immunofluorescence assay. Finally, compared with the WT mice, NLRP3-/- mice had smaller pituitary glands (weight/body weight) and diminished prolactin (PRL) expressions and secretions. These findings were associated with a reduction in the caspase-1 activation and maturation of IL1B. Furthermore, MCC950 decreased the PRL expression and secretion following the inhibition of NLRP3 inflammasome activation in GH3 cells stimulated with lipopolysaccharide and nigericin. And MCC950 inhibited the pituitary tumor overgrowth and PRL expression and secretion in prolactinoma rats. These data confirm that the microglial NLRP3 inflammasome activation upregulates the inflammatory cytokines IL1/IL18 in the pituitary glands and induces prolactinomas. Our findings showed that microglial NLRP3 inflammasome activation-mediated IL1B-related inflammation promoted the development of prolactinomas and identified the inflammasome as a new therapeutic target for prolactinomas.

Targeting galectins in T cell-based immunotherapy within tumor microenvironment.

Over the past few years, tumor immunotherapy has emerged as an innovative tumor treatment and owned incomparable advantages over other tumor therapy. With unique complexity and uncertainty, immunotherapy still need helper to apply in the clinic. Galectins, modulated in tumor microenvironment, can regulate the disorders of innate and adaptive immune system resisting tumor growth. Considering the role of galectins in tumor immunosuppression, combination therapy of targeted anti-galectins and immunotherapy may be a promising tumor treatment. This brief review summarizes the expression and immune functions of different galectins in tumor microenvironment and discusses the potential value of anti-galectins in combination with checkpoint inhibitors in tumor immunotherapy.

Combination treatment strategies with a focus on rosiglitazone and adriamycin for insulin resistant liver cancer.

Insulin resistance promotes the occurrence of liver cancer and decreases its chemosensitivity. Rosiglitazone (ROSI), a thiazolidinedione insulin sensitiser, could be used for diabetes with insulin resistance and has been reported to show anticancer effects on human malignant cells. In this paper, we investigated the combination of ROSI and chemotherapeutics on the growth and metastasis of insulin-resistant hepatoma. In vitro assay, ROSI significantly enhanced the inhibitory effects of adriamycin (ADR) on the proliferation, autophagy and migration of insulin-resistant hepatoma HepG2/IR cells via downregulation of EGFR/ERK and AKT/mTOR signalling pathway. In addition, ROSI promoted the apoptosis of HepG2/IR cells induced by ADR. In vivo assay, high fat and glucose diet and streptozotocin (STZ) induced insulin resistance in mice by increasing the body weight, fasting blood glucose (FBG) level, oral glucose tolerance, fasting insulin level and insulin resistance index. Both the growth of mouse liver cancer hepatoma H22 cells and serum FBG level in insulin resistant mice were significantly inhibited by combination of ROSI and ADR. Thus, ROSI and ADR in combination showed a stronger anti-tumour effect in insulin resistant hepatoma cells accompanying with glucose reduction and might represent an effective therapeutic strategy for liver cancer accompanied with insulin resistant diabetes.

Drug Elimination Alteration in Acute Lymphoblastic Leukemia Mediated by Renal Transporters and Glomerular Filtration.

PURPOSE: Drug elimination alteration has been well reported in acute lymphoblastic leukemia (ALL). Considering that transporters and glomerular filtration influence, to different extents, the drug disposition, and possible side effects, we evaluated the effects of ALL on major renal transporters and glomerular filtration mediated pharmacokinetic changes, as well as expression of renal drug transporters. METHODS: ALL xenograft models were established and intravenously injected with substrates of renal transporters and glomerular filtration separately in NOD/SCID mice. The plasma concentrations of substrates, after single doses, were determined using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). RESULTS: With the development of ALL, protein expression of MDR1, OAT3 and OCT2 were increased by 2.62-fold, 1.70-fold, and 1.45-fold, respectively, whereas expression of MRP2 and MRP4 were significantly decreased by 30.98% and 45.28% in the kidney of ALL groups compared with control groups. Clearance of MDR1-mediated digoxin, OAT3-mediated furosemide, and OCT2-mediated metformin increased by 3.04-fold, 1.47-fold, and 1.26-fold, respectively. However, clearance of MRPs-mediated methotrexate was reduced by 39.5%. These results are consistent with mRNA expression. Clearance of vancomycin and amikacin, as markers of glomerular filtration rate, had a 2.14 and 1.64-fold increase in ALL mice, respectively. CONCLUSIONS: The specific alteration of renal transporters and glomerular filtration in kidneys provide a rational explanation for changes in pharmacokinetics for ALL.

Galectin-3 expression and secretion by tumor-associated macrophages in hypoxia promotes breast cancer progression.

Tumor-associated macrophages (TAMs) have been shown to be associated with poor prognosis of cancer and are predominately localized in the hypoxia regions of tumor. We demonstrated in this study that hypoxia increases the synthesis and secretion of galectin-3 by TAMs. The increased expression of galectin-3 in TAMs was seen to be associated with nucleation of transcription factor NF-κB through generation and activation of ROS and promoted tumor growth and metastasis in vitro and in mice through multiple molecular mechanisms. It was found that the TAMs-mediated promotion of tumor growth and metastasis in hypoxia was inhibited by administration of macrophage-depletion agent clodronate liposomal (CL) or galectin-3 inhibitor modified citric pectin (MCP) in orthotopic syngeneic mammary adenocarcinoma model and metastasis model. Co-administration of anti-angiogenesis agent sorafenib or bevacizumab with CL and MCP showed to cause stronger inhibition of tumor growth and metastasis than administration of each agent alone. These results indicate that hypoxia-induced galectin-3 expression and secretion from TAMs promotes tumor growth and metastasis. Targeting the actions of galectin-3 in hypoxia may be a potential therapeutic strategy for cancer treatment.