Although a critical role of adaptive immune system has been confirmed in driving local and systemic inflammation in type 2 diabetes and promoting insulin resistance, the underlying mechanism is not completely understood. Inflammatory regulation has been focused on innate immunity especially macrophage for a long time, while increasing evidence suggests T cells are crucial for the development of metabolic inflammation and insulin resistance since 2009. There was growing evidence supporting the critical implication of T cells in the pathogenesis of type 2 diabetes. We will discuss the available effect of T cells subsets in adaptive immune system associated with the procession of T2DM, which may unveil several potential strategies that could provide successful therapies in the future.

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Role of T Lymphocytes in Type 2 Diabetes and Diabetes-Associated Inflammation

Glucosinolates (GSL) are naturally occurring β-d-thioglucosides found across the cruciferous vegetables. Core structure formation and side-chain modifications lead to the synthesis of more than 200 types of GSLs in Brassicaceae. Isothiocyanates (ITCs) are chemoprotectives produced as the hydrolyzed product of GSLs by enzyme myrosinase. Benzyl isothiocyanate (BITC), phenethyl isothiocyanate (PEITC) and sulforaphane ([1-isothioyanato-4-(methyl-sulfinyl) butane], SFN) are potential ITCs with efficient therapeutic properties. Beneficial role of BITC, PEITC and SFN was widely studied against various cancers such as breast, brain, blood, bone, colon, gastric, liver, lung, oral, pancreatic, prostate and so forth. Nuclear factor-erythroid 2-related factor-2 (Nrf2) is a key transcription factor limits the tumor progression. Induction of ARE (antioxidant responsive element) and ROS (reactive oxygen species) mediated pathway by Nrf2 controls the activity of nuclear factor-kappaB (NF-κB). NF-κB has a double edged role in the immune system. NF-κB induced during inflammatory is essential for an acute immune process. Meanwhile, hyper activation of NF-κB transcription factors was witnessed in the tumor cells. Antagonistic activity of BITC, PEITC and SFN against cancer was related with the direct/indirect interaction with Nrf2 and NF-κB protein. All three ITCs able to disrupts Nrf2-Keap1 complex and translocate Nrf2 into the nucleus. BITC have the affinity to inhibit the NF-κB than SFN due to the presence of additional benzyl structure. This review will give the overview on chemo preventive of ITCs against several types of cancer cell lines. We have also discussed the molecular interaction(s) of the antagonistic effect of BITC, PEITC and SFN with Nrf2 and NF-κB to prevent cancer.

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Anti-Carcinogenic Glucosinolates in Cruciferous Vegetables and Their Antagonistic Effects on Prevention of Cancers

The cardiac microvascular reperfusion injury is characterized by the microvascular endothelial cells (CMECs) oxidative damage which is responsible for the progression of cardiac dysfunction. However, few strategies are available to reverse such pathologies. This study aimed to explore the mechanism by which oxidative stress induced CMECs death and the beneficial actions of melatonin on CMECs survival, with a special focused on IP3R-[Ca2+]c/VDAC-[Ca2+]m damage axis and the MAPK/ERK survival signaling. We found that oxidative stress induced by H2O2 significantly activated cAMP response element binding protein (CREB) that enhanced IP3R and VDAC transcription and expression, leading to [Ca2+]c and [Ca2+]m overload. High concentration of [Ca2+]m suppressed ΔΨm, opened mPTP, and released cyt-c into cytoplasm where it activated mitochondria-dependent death pathway. However, melatonin could protect CMECs against oxidative stress injury via stimulation of MAPK/ERK that inactivated CREB and therefore blocked IP3R/VDAC upregulation and [Ca2+]c/[Ca2+]m overload, sustaining mitochondrial structural and function integrity and ultimately blockading mitochondrial-mediated cellular death. In summary, these findings confirmed the mechanisms by which oxidative injury induced CMECs mitochondrial-involved death and provided an attractive and effective way to enhance CMECs survival.

/pdf/melatonin-protected-cardiac-microvascular-endothelial-cells-3eecxyscq5.pdf

Melatonin protected cardiac microvascular endothelial cells against oxidative stress injury via suppression of IP3R-[Ca 2+ ]c/VDAC-[Ca 2+ ]m axis by activation of MAPK/ERK signaling pathway

Understanding the Molecular Mechanisms Underpinning Gene by Environment Interactions in Psychiatric Disorders: The FKBP5 Model.

Hypoxia-inducible factor (HIF)-1α is the regulatory subunit of HIF-1 that is stabilized under hypoxic conditions Under different circumstances, HIF-1α may promote both tumorigenesis and apoptosis There is conflicting data on the importance of HIF-1α as a prognostic factor This study evaluated HIF-1α expression in 172 consecutive patients with stage I-IIIA non small cell lung cancer (NSCLC) using standard immunohistochemical techniques The extent of HIF-1α nuclear immunostaining was determined using light microscopy and the results were analyzed using the median (5%) as a low cut-point and 60% as a high positive cut-point Using the low cut-point, positive associations were found with epidermal growth factor receptor (EGFR; p = 001), matrix metalloproteinase (MMP)-9 (p = 0003), membranous (p < 0001) and perinuclear (p = 0004) carbonic anhydrase (CA) IX, pS3 (p = 0008), T-stage (p = 0042), tumor necrosis (TN; p < 0001) and squamous histology (p < 0001) No significant association was found with Bcl-2 or either N- or overall TMN stage or prognosis When the high positive cut-point was used, HIF-1α was associated with a poor prognosis (p = 0034) In conclusion, the associations with EGFR, MMP-9, p53 and CA IX suggest that these factors may either regulate or be regulated by HIF-1α The association with TN and squamous-type histology, which is relatively more necrotic than other NSCLC types, reflects the role of hypoxia in the regulation of HIF-1α The prognostic data may reflect a change in the behavior of HIF-1α in increasingly hypoxic environments © 2004 Wiley-Liss, Inc

Hypoxia-inducible factor-1α in non small cell lung cancer: Relation to growth factor, protease and apoptosis pathways

The generic mitogen-activated protein kinases (MAPK) signaling pathway is shared by four distinct cascades, including the extracellular signal-related kinases (ERK1/2), Jun amino-terminal kinases (JNK1/2/3), p38-MAPK and ERK5. Mitogen-activated protein kinases/extracellular signal-regulated kinase (MAPK/ERK) pathway is reported to be associated with the cell proliferation, differentiation, migration, senescence and apoptosis. The literatures were searched extensively and this review was performed to review the role of MAPK/ERK signaling pathway in cell proliferation, differentiation, migration, senescence and apoptosis.

Signaling pathway of MAPK/ERK in cell proliferation, differentiation, migration, senescence and apoptosis

Background and aim: Many reported studies have been conducted to investigate the association of angiotensin II type 1 receptor (AT1R) A1166C gene polymorphism with myocardial infarction (MI) susceptibility. However, the results from those reports are still conflicting. This meta-analysis was performed to study the relationship between AT1R A1166C gene polymorphism and MI risk. Method: The databases of PubMed, Embase, and Cochrane Library were searched as of 1 March 2012, and eligible investigations were recruited into this meta-analysis. Results: Eighteen investigations were identified for the analysis of association between AT1R A1166C gene polymorphism and MI risk, 11 in Caucasians, three in Asians, two in Africans, one in the population of Brazil and one in the population of Durban, South Africa . There was a marked association between AT1R C allele and MI susceptibility for overall populations (odds ratio (OR)=1.12, 95% confidence interval (CI): 1.01–1.25, p=0.03), and AT1R AA genotype was associated with a lower risk of MI in overall populations (OR=0.87, 95% CI: 0.78–0.98, p=0.02). However, AT1R A1166C gene polymorphism was not associated with MI risk in the sub-groups of Caucasians, Asians, Africans, Brazil and Durban populations. Conclusions: C allele is a risk factor for the MI susceptibility in overall populations, and AA genotype might be a protective factor against the MI risk in overall populations. However, more case-control association investigations on larger, stratified populations are required in the future.

https://journals.sagepub.com/doi/pdf/10.1177/1470320312466927

A systematic review and meta-analysis of the association between angiotensin II type 1 receptor A1166C gene polymorphism and myocardial infarction susceptibility

Background B3GNT3 (β1, 3-N-acetylglucosaminyltransferase-3) belongs to the β3GlcNAcT family and is essential to form extended core 1 oligosaccharides. Previous studies revealed that B3GNT3 expression was dysregulated in multiple cancers. Here, we aimed to understand the expression profile and function of B3GNT3 in lung cancer. Materials and methods The expression of B3GNT3 was measured by immunohistochemistry and public database analysis. B3GNT3 was knocked down to evaluate the lung cancer cell proliferation, migration and invasion in in vitro and in vivo tumor formation experiments. miR-149-5p targeting B3GNT3 was identified with TargetScan analysis and confirmed with reporter assay. Overexpression of miR-149-5p was achieved using microRNA mimics and function of microRNA-149-5p/B3GNT3 axis was tested in vitro. Results B3GNT3 was upregulated in lung cancer, and B3GNT3 overexpression was associated with poor prognosis of lung cancer patients. High expression of B3GNT3 was associated with advanced TNM stages, larger tumor size, tumor metastasis and recurrence. Functionally, we demonstrated that knockdown of B3GNT3 suppressed lung cancer cell growth and invasion in vitro. Knockdown of B3GNT3 suppressed lung cancer development in a xenograft tumor model. Moreover, miR-149-5p was validated to negatively regulate B3GNT3 expression through directly targeting B3GNT3 3'-UTR. Overexpression of miR-149-5p could antagonize the tumorigenesis effect of B3GNT3 in vitro. Conclusion In summary, our study demonstrated that B3GNT3 overexpression was correlated with poor prognosis of lung cancer patient, indicating that B3GNT3 could be a promising prognostic biomarker for lung cancer. miR-149-5p negatively regulated B3GNT3 expression, which might be utilized for therapeutic target in lung cancer.

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B3GNT3, a Direct Target of miR-149-5p, Promotes Lung Cancer Development and Indicates Poor Prognosis of Lung Cancer.

The conclusions of the published reports on the relationship between glutathione S-transferase P1 (GSTP1) gene polymorphism and the risk of lung cancer are still debated. GSTP1 is one of the important mutant sites reported at present. This meta-analysis was performed to evaluate the association between GSTP1 and the risk of lung cancer. The association investigations were identified from PubMed and Cochrane Library, and eligible studies were included and synthesized using meta-analysis method. Forty-four reports were included into this meta-analysis for the association of GSTP1 A/G gene polymorphism and lung cancer susceptibility, consisting of 12,363 patients with lung cancer and 13,948 controls. The association between GSTPI G allele and lung cancer risk was found in this meta-analysis (OR 1.08, 95 % CI 1.02-1.15, P = 0.01). However, the GG genotype and AA genotype were not associated with the susceptibility of lung cancer. Furthermore, there was no association between GSTP1 A/G gene polymorphism and the risk of lung cancer in Caucasians, and East-Asians. In conclusion, GSTP1 G allele is associated with the lung cancer susceptibility. However, more studies on the relationship between GSTP1 A/G gene polymorphism and the risk of lung cancer should be performed in the future.

Association of glutathione S-transferase P1 gene polymorphism with the susceptibility of lung cancer

The relationship between glutathione S-transferase T1 (GSTT1) null/presence gene polymorphism and the risk of lung cancer from the published reports are still conflicting. This study was conducted to evaluate the relationship between GSTT1 null/presence gene polymorphism and the risk of lung cancer using meta-analysis method. The association studies were identified from PubMed, and Cochrane Library on July 1, 2012, and eligible investigations were included and synthesized using meta-analysis method. 51 reports were recruited into this meta-analysis for the association of null genotype of GSTT1 with lung cancer susceptibility, consisting of 15,140 patients with lung cancer and 16,662 controls. There was a marked association between GSTT1 null genotype and lung cancer risk in overall populations (OR = 1.15, 95 % CI 1.04–1.27, P = 0.007). Furthermore, GSTT1 null genotype was associated with the lung cancer risk in Asians (OR = 1.47, 95 % CI 1.23–1.76, P < 0.0001). However, GSTT1 null genotype was not associated with the risk of lung cancer in Caucasians, Brazilian population and Africans. In conclusion, GSTT1 null genotype is associated with the lung cancer in overall populations and in Asians.

A meta-analysis of the relationship between glutathione S-transferase T1 null/presence gene polymorphism and the risk of lung cancer including 31802 subjects

Hua-Fu Zhou

Papers

Signaling pathway of MAPK/ERK in cell proliferation, differentiation, migration, senescence and apoptosis

A systematic review and meta-analysis of the association between angiotensin II type 1 receptor A1166C gene polymorphism and myocardial infarction susceptibility

B3GNT3, a Direct Target of miR-149-5p, Promotes Lung Cancer Development and Indicates Poor Prognosis of Lung Cancer.

Association of glutathione S-transferase P1 gene polymorphism with the susceptibility of lung cancer

A meta-analysis of the relationship between glutathione S-transferase T1 null/presence gene polymorphism and the risk of lung cancer including 31802 subjects