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- Majhi, RK, et al.
(författare)
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Metformin strengthens uroepithelial immunity against E. coli infection
- 2021
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1, s. 19263-
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Tidskriftsartikel (refereegranskat)abstract
- Urinary tract infection frequently caused by E. coli is one of the most common bacterial infections. Increasing antibiotic resistance jeopardizes successful treatment and alternative treatment strategies are therefore mandatory. Metformin, an oral antidiabetic drug, has been shown to activate macrophages in the protection against certain infecting microorganisms. Since epithelial cells often form the first line of defense, we here investigated the effect on uroepithelial cells during E. coli infection. Metformin upregulated the human antimicrobial peptides cathelicidin LL-37 and RNase7 via modulation of the TRPA1 channel and AMPK pathway. Interestingly, metformin stimulation enriched both LL-37 and TRPA1 in lysosomes. In addition, metformin specifically increased nitric oxide and mitochondrial, but not cytosolic ROS. Moreover, metformin also triggered mRNA expression of the proinflammatory cytokines IL1B, CXCL8 and growth factor GDF15 in human uroepithelial cells. The GDF15 peptide stimulated macrophages increased LL-37 expression, with increased bacterial killing. In conclusion, metformin stimulation strengthened the innate immunity of uroepithelial cells inducing enhanced extracellular and intracellular bacterial killing suggesting a favorable role of metformin in the host defense.
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- Swain, N, et al.
(författare)
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TRPV1 channel in spermatozoa is a molecular target for ROS-mediated sperm dysfunction and differentially expressed in both natural and ART pregnancy failure
- 2022
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Ingår i: Frontiers in cell and developmental biology. - : Frontiers Media SA. - 2296-634X. ; 10, s. 867057-
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Tidskriftsartikel (refereegranskat)abstract
- Bi-directional crosstalk between Ca2+ signaling and ROS modulates physiological processes as a part of a regulatory circuit including sperm function. The role of transient receptor potential vanilloid 1 (TRPV1) in this regard cannot be undermined. This is the first report demonstrating the Ca2+-sensitive TRPV1 channel to be under-expressed in spermatozoa of subfertile men, idiopathic infertile men, and normozoospermic infertile males with high ROS (idiopathic infertility and unilateral varicocele). To study the effect of TRPV1 in determining the fertility outcome, we compared the expression profile of TRPV1 in spermatozoa of male partners who achieved pregnancy by natural conception (NC+, n = 10), IVF (IVF+, n = 23), or ICSI (ICSI +, n = 9) and their respective counterparts with failed pregnancy NC (n = 7), IVF (n = 23), or ICSI (n = 10), by both immunocytochemistry and flow-cytometry. Reduced expression of TRPV1 in sperm of IVF ± and ICSI ± men with respect to that NC+ men imply its role in mediating successful fertilization. Unsuccessful pregnancy outcome with an underexpression of TRPV1 in sperm of NC-/IVF-/ICSI-men suggests its role in conception and maintenance of pregnancy. Since ROS is regarded as one of the major contributors to sperm dysfunction, the effect of H2O2 +/- TRPV1 modulators (RTX/iRTX) on acrosomal reaction and calcium influx was evaluated to confirm TRPV1 as a redox sensor in human sperm. A significant increment in the percentage of acrosome reacted spermatozoa along with augmented Ca2+-influx was observed after H2O2 treatment, both in the presence or absence of TRPV1 agonist resiniferatoxin (RTX). The effect was attenuated by the TRPV1 antagonist iodoresiniferatoxin (iRTX), indicating the involvement of TRPV1 in mediating H2O2 response. Enhancement of motility and triggering of acrosomal reaction post TRPV1 activation suggested that disruption of these signaling cascades in vivo, possibly due to down-regulation of TRPV1 in these subfertile males. Bioinformatic analysis of the crosstalk between TRPV1 with fertility candidate proteins (reported to influence IVF outcome) revealed cell death and survival, cellular compromise, and embryonic development to be the primary networks affected by anomalous TRPV1 expression. We therefore postulate that TRPV1 can act as a redox sensor, and its expression in spermatozoa may serve as a fertility marker.
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