Differential Expression of Human Peripheral Mononuclear Cells Phenotype Markers in Type 2 Diabetic Patients and Type 2 Diabetic Patients on Metformin

Dubayee, Mohammed S. Al; Alayed, Hind; Almansour, Rana; Alqaoud, Nora; Alnamlah, Rahaf; Obeid, Dana; Alshahrani, Ali; Zahra, Mahmoud; Al-Bawab, Ahmad; Aljada, Ahmad

doi:10.3389/fendo.2018.00537

Cited by 31 publications

(28 citation statements)

References 67 publications

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“…18 However, the ability of NAMPT to trigger IL-6/STAT3 cell survival pathway did not depend on the presence of nicotinamide and was not blocked by the NAMPT enzyme inhibitor FK866. 18 Thus, inhibition of NAMPT expression in PBMC and the higher expression levels of IL-6 previously reported 19 in our study support the notion that these pathways are regulated independently. Endothelial dysfunction is a characteristic of agingrelated vascular disease and is worsened during diabetes.…”

Section: Discussionsupporting

confidence: 89%

“…Interestingly, an accumulation of the nonclassical monocytes, in conjunction with higher levels of plasma TNFα and interleukin-8 (IL-8), has been observed in the elderly. 32 Our previous study has shown that PBMC from T2DM subjects have increased expression of IL-6, inducible nitric oxide synthase (iNOS), TNFα, CD36, and CD206 and reduced expression of CD11b, CD11c, CD169, and CD163 (19). Other studies have demonstrated an increased inflammatory state in obesity and T2DM.…”

Section: Discussionmentioning

confidence: 97%

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<p>Differential Expression of Human N-Alpha-Acetyltransferase 40 (hNAA40), Nicotinamide Phosphoribosyltransferase (NAMPT) and Sirtuin-1 (SIRT-1) Pathway in Obesity and T2DM: Modulation by Metformin and Macronutrient Intake</p>

Alshahrani

Al-Dubayee

Zahra

et al. 2019

DMSO

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Background: Interactions between environmental factors, such as diet and lifestyle, and metabolic pathways are pivotal in understanding aging mechanisms. hNAA40, Nicotinamide phosphoribosyltransferase (NAMPT), and NAD-dependent protein deacetylase sirtuin-1 (SIRT-1) have been shown to exert important biological processes, including stress response and aging. Methods: hNAA40, NAMPT, and SIRT-1 mRNA expression in peripheral blood mononuclear cells (PBMC) were quantitated in 30 lean adult volunteers of normal weight, 30 obese, 20 drugnaïve obese Type 2 diabetes mellitus (T2DM), and 30 obese T2DM on Metformin. Similarly, hNAA40, NAMPT, and SIRT-1 expression in PBMC were quantitated in 36 normal healthy adults randomly assigned to three different groups (Glucose or Whey proteins or lipids; 300 kcal). Blood samples were obtained at 1, 2, and 3 hrs after the macronutrient intake. Results: There was an increase in hNAA40 and a decrease in NAMPT and SIRT-1 expression in PBMC from T2DM. Metformin treatment reverted hNAA40, NAMPT, and SIRT-1 expression levels to normal levels. Glucose intake resulted in a significant increase in expression of hNAA40 at 1 hr and decreased significantly at 3 hrs post intake. Lipid intake resulted in an increase in expression of hNAA40 at 2 hr post intake and returned to normal levels at 3 hrs. Neither glucose nor lipid intake resulted in a significant change in NAMPT or SIRT-1 expression. Whey proteins resulted in significantly lower expression of NAMPT at 3 hrs and did not alter the expression levels of SIRT-1 significantly. Conclusion: hNAA40, NAMPT, and SIRT-1 pathway could play a role in the determination of the healthy lifespan. Metformin modulates this pathway.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 97%

<p>Differential Expression of Human N-Alpha-Acetyltransferase 40 (hNAA40), Nicotinamide Phosphoribosyltransferase (NAMPT) and Sirtuin-1 (SIRT-1) Pathway in Obesity and T2DM: Modulation by Metformin and Macronutrient Intake</p>

Alshahrani

Al-Dubayee

Zahra

et al. 2019

DMSO

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“…The phagocytic activity of MOs is the subject of several studies under normal and pathological conditions including breast cancer (53). In our study, we observed that pretreatment with MET downregulated the phagocytic capacity of MOs, which is of interest, knowing that high phagocytic capacity is associated with MOs that promote survival and extravasation of cancer cells, and characterizes the so-called 'classical MOs' in humans (54,55).…”

Section: Discussionmentioning

confidence: 64%

Phenotypic functional activities of monocyte change during crosstalk with breast cancer cell and enhancing effect of metformin of IFN-γ-associated antitumor cytokine production

Dahmani

Addou-Klouche

Gizard

et al. 2020

Preprint

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Background: Immune activities of monocytes (MOs) can be altered within the microenvironment of solid malignancies, including breast cancer. Metformin (1,1dimethylbiguanide hydrochloride, MET), has been shown to decrease tumor cell proliferation, but its effects have yet to be explored with respect to the crosstalk between monocytes and breast cancer cells. Here, we investigated the effects of MET on overall phenotypic functional activities of autologous MOs during the interplay with primary breast cancer cells. Methods:Human primary breast cancer cells were either cultured alone or co-cultured with autologous MOs before treatment with MET.Results: MET downregulated both breast cancer cell proliferation and the ratio of phosphorylated Akt (p-Akt)-to-Akt in breast cancer cells. Additionally, we observed that, in the absence of MET treatment, the levels of LDH-based cytotoxicity, catalase, intracellular free calcium ions (i fCa 2+ ), IL-10 and arginase activity were significantly reduced in co-cultures compared to those of MOs cultivated alone whereas levels of iNOS were significantly increased (for all comparisons, p < 0.05). In contrast, MET upregulated breast cancer cell LDH-based cytotoxicity levels when co-cultured with MO. MET also induced upregulation of both the inducible enzymatic activity of nitric oxide synthase (iNOS) and arginase activity in MO cells and co-culture systems, although these differences did not reach significant levels for iNOS activity (p > 0.05). MET greatly decreased phagocytic activity in isolated MOs while inducing a robust increase of catalase activity in co-culture systems and of superoxide dismutase (SOD) activity in MOs, but not in MOs co-cultured with breast cancer cells. MET strongly upregulated the levels of ifCa 2+ in co-culture systems and IFN-γ production in both isolated MOs and co-culture systems. Moreover, MET treatment markedly downregulated IL-10 production in MOs, while inducing a slight increase in co-cultures (p > 0.05). Conclusions: Our results show that the phenotypic functional activities of MOs change when co-cultured with primary human breast cancer cells. Furthermore, treatment with MET induced enhancing effects on the production of antitumor cytokine IFN-γ and ifCa 2+ , as well as cytotoxicity during breast cancer cell-MO crosstalk. Keywords: Akt activation; metformin; monocyte/primary human breast cancer cell crosstalk; monocyte phenotypic functional activity changes; primary breast cancer cell proliferation and viability; MO IFN-γ-associated anti-tumor activity

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“…The phagocytic activity of MOs is the subject of several studies under normal and pathological conditions, including breast cancer [ 51 ]. In our study, we observed that pretreatment with MET downregulated the phagocytic capacity of MOs, which is of interest, knowing that high phagocytic capacity is associated with MOs that promote survival and extravasation of cancer cells, and characterizes the so-called ’classical MOs’ in humans [ 52 , 53 ].…”

Section: Discussionmentioning

confidence: 99%

Metformin partially reverses the inhibitory effect of co-culture with ER-/PR-/HER2+ breast cancer cells on biomarkers of monocyte antitumor activity

et al. 2020

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Background Immune activities of monocytes (MOs) can be altered within the microenvironment of solid malignancies, including breast cancer. Metformin (1,1-dimethylbiguanide hydrochloride, MET), has been shown to decrease tumor cell proliferation, but its effects have yet to be explored with respect to MOs (monocytes) activity during their crosstalk with breast cancer cells. Here, we investigated the effects of MET on overall phenotypic functional activities, including cellular immunometabolism and protective redox signaling based-biomarkers, intracellular free calcium ions ( if Ca 2+ ), phagocytosis and co-operative cytokines (IFN-γ and IL-10) of autologous MOs before and during their interplay with primary ER - /PR - /HER2 + breast cancer cells. Methods Human primary breast cancer cells were either cultured alone or co-cultured with autologous MOs before treatment with MET. Results MET downregulated breast cancer cell proliferation and phagocytosis, while having no significant effect on the ratio of phosphorylated Akt (p-Akt) to total Akt. Additionally, we observed that, in the absence of MET treatment, the levels of lactate dehydrogenase (LDH)-based cytotoxicity, catalase, if Ca 2+ , IL-10 and arginase activity were significantly reduced in co-cultures compared to levels in MOs cultured alone whereas levels of inducible nitric oxide synthase (iNOS) activity were significantly increased. In contrast, MET treatment reduced the effects measured in co-culture on the levels of LDH-based cytotoxicity, arginase activity, catalase, if Ca 2+ , and IFN-γ. MET also induced upregulation of both iNOS and arginase in MO cells, although the increase did not reach significant difference for iNOS activity. Moreover, MET induced a robust increase of superoxide dismutase (SOD) activity in MOs, but not in MOs co-cultured with breast cancer cells. Furthermore, MET markedly upregulated the levels of IFN-γ production and downregulated those of IL-10 in isolated MOs, while inducing a slight opposing up-regulation of IL-10 production in co-cultures. Conclusions Our results show that the biomarkers of phenotypic functional activities of MOs are modified after co-culturing with primary human breast cancer cells. Treatment of co-cultures with MET resulted in increased release of antitumor cytokine IFN-γ and if Ca 2+ , and increased cell necrosis during breast cancer cells-MOs crosstalk.

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Differential Expression of Human Peripheral Mononuclear Cells Phenotype Markers in Type 2 Diabetic Patients and Type 2 Diabetic Patients on Metformin

Cited by 31 publications

References 67 publications

<p>Differential Expression of Human N-Alpha-Acetyltransferase 40 (hNAA40), Nicotinamide Phosphoribosyltransferase (NAMPT) and Sirtuin-1 (SIRT-1) Pathway in Obesity and T2DM: Modulation by Metformin and Macronutrient Intake</p>

<p>Differential Expression of Human N-Alpha-Acetyltransferase 40 (hNAA40), Nicotinamide Phosphoribosyltransferase (NAMPT) and Sirtuin-1 (SIRT-1) Pathway in Obesity and T2DM: Modulation by Metformin and Macronutrient Intake</p>

Phenotypic functional activities of monocyte change during crosstalk with breast cancer cell and enhancing effect of metformin of IFN-γ-associated antitumor cytokine production

Metformin partially reverses the inhibitory effect of co-culture with ER-/PR-/HER2+ breast cancer cells on biomarkers of monocyte antitumor activity

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