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Updated: May 9, 2025
Deciphering the Molecular Mechanism and Function of Pore-Forming Toxins Using Leishmania major
Published on: October 28, 2022
The developing role of NRF2 and HMOX1 in treatment response of cutaneous leishmaniasis
Niloofar Mehrolhasani1, Mahsa Faramarzpour1,2, Ehsan Salarkia2
1Pathology and Stem Cell Research center, Kerman University of Medical Sciences, Medical University Campus, Haft-Bagh Highway, Kerman, Iran.
Abstract:
Anthroponotic cutaneous leishmaniasis (ACL), a neglected parasitic disease, created significant treatment challenges due to rising antimonial resistance, particularly in endemic regions like Iran. This study aimed to investigate the mechanisms behind treatment unresponsiveness in ACL patients. Demographic and clinical characteristics of 21 unresponsive and 10 responsive patients were randomly collected. Leishmania isolates were genotyped using nested polymerase chain reaction (PCR). Real-time PCR assessed the expression levels of two key genes related to treatment unresponsiveness: nuclear factor erythroid 2-related factor 2 (NRF2) and heme oxygenase 1 (HMOX1), along with their associated microRNAs, mir-24a-3p and mir-27b-3p. Gene expression and immunohistochemistry (IHC) assays measured apoptosis activation. Unresponsive patients revealed decreased expression of apoptosis-related genes (Bax, caspase-3, caspase-8) and increased expression of B-cell lymphoma 2 (Bcl2). Furthermore, HMOX1 and NRF2 expression, significant mir-27b-3p upregulation, and mir-24a-3p downregulation were observed in the unresponsive group. These results suggest diminished apoptosis and/or possible potential for chronic progression of Leishmania (L.) tropica infection in unresponsive patients. The increased levels of NRF2 and HMOX1 demonstrate their probable role in drug unresponsiveness. Also, the opposing effects of mir-24a-3p and mir-27b-3p on mentioned genes highlight the necessity for targeted molecular studies to modulate microRNAs expression effectively.
Insights
Drug resistance in Anthroponotic Cutaneous Leishmaniasis (ACL) is a growing concern. This study reveals that reduced apoptosis and altered gene expression, including NRF2 and HMOX1, contribute to treatment unresponsiveness in ACL patients.
Area of Science:
- * Molecular biology
- * Parasitology
- * Dermatology
Background:
- * Anthroponotic cutaneous leishmaniasis (ACL) presents significant treatment challenges, particularly in Iran, due to increasing antimonial drug resistance.
- * Understanding the molecular mechanisms underlying treatment unresponsiveness is crucial for developing effective therapeutic strategies.
Purpose of the Study:
- * To investigate the molecular mechanisms associated with treatment unresponsiveness in Anthroponotic Cutaneous Leishmaniasis (ACL).
- * To analyze the expression of key genes (NRF2, HMOX1) and microRNAs (mir-24a-3p, mir-27b-3p) in responsive versus unresponsive ACL patients.
- * To assess the role of apoptosis-related genes in ACL treatment failure.
Main Methods:
- * Collection of demographic and clinical data from 21 unresponsive and 10 responsive ACL patients.
- * Genotyping of Leishmania isolates using nested polymerase chain reaction (PCR).
- * Real-time PCR and immunohistochemistry (IHC) to quantify gene expression (NRF2, HMOX1, apoptosis markers) and microRNA levels.
Main Results:
- * Unresponsive ACL patients exhibited decreased expression of pro-apoptotic genes (Bax, caspase-3, caspase-8) and increased expression of anti-apoptotic gene (Bcl2).
- * Elevated expression of nuclear factor erythroid 2-related factor 2 (NRF2) and heme oxygenase 1 (HMOX1) was observed in the unresponsive group.
- * Significant upregulation of mir-27b-3p and downregulation of mir-24a-3p were detected in patients unresponsive to treatment.
Conclusions:
- * Diminished apoptosis and potential for chronic Leishmania (L.) tropica infection progression are indicated in treatment-unresponsive ACL.
- * Increased NRF2 and HMOX1 expression likely contributes to drug unresponsiveness in ACL.
- * The opposing roles of mir-24a-3p and mir-27b-3p necessitate targeted microRNA modulation studies for effective ACL treatment.
