Cysteine proteases play key roles in the biology of Plasmodium parasites and are recognized as antimalarial drug targets. Because these enzymes are involved in diverse biological functions, precise regulation is required to prevent unnecessary damage to both parasites and hosts. In this study, we identified an endogenous inhibitor of cysteine protease of Plasmodium vivax (PvICP) and characterized its biochemical properties. PvICP was found to share highly similar structural characteristics with orthologous proteins from other Plasmodium species. Recombinant PvICP (rPvICP) expressed in Escherichia coli showed a broad range of inhibitory activity against falcipain family cysteine proteases, including vivapain-3, vivapain-4, falcipain-3, malapain-2, and malapain-4, with more potent inhibitory activity against vivapain-3 and vivapain-4. rPvICP’s inhibitory activity was not significantly affected by pH, suggesting its broad biological functions. These findings provide new insights into PvICP and lay the groundwork for future studies exploring its biological significance and potential as a therapeutic target in malaria research.
Plasmodium vivax variant interspersed repeats (vir) refer to the key protein used for escaping the host immune system. Knowledge in the genetic variation of vir genes can be used for the development of vaccines or diagnostic methods. Therefore, we evaluated the genetic diversity of the vir genes of P. vivax populations of several Asian countries, including Pakistan, which is a malaria-endemic country experiencing a significant rise in malaria cases in recent years. We analyzed the genetic diversity and population structure of 4 vir genes (vir 4, vir 12, vir 21, and vir 27) in the Pakistan P. vivax population and compared these features to those of the corresponding vir genes in other Asian countries. In Pakistan, vir 4 (S=198, H=9, Hd=0.889, Tajima’s D value=1.12321) was the most genetically heterogenous, while the features of vir 21 (S=8, H=7, Hd=0.664, Tajima’s D value =-0.63763) and vir 27 (S =25, H =11, Hd =0.682, Tajima’s D value=-2.10836) were relatively conserved. Additionally, vir 4 was the most genetically diverse among Asian P. vivax populations, although within population diversity was low. Meanwhile, vir 21 and vir 27 among all Asian populations were closely related genetically. Our findings on the genetic diversity of vir genes and its relationships between populations in diverse geographical locations contribute toward a better understanding of the genetic characteristics of vir. The high level of genetic diversity of vir 4 suggests that this gene can be a useful genetic marker for understanding the P. vivax population structure. Longitudinal genetic diversity studies of vir genes in P. vivax isolates obtained from more diverse geographical areas are needed to better understand the function of vir genes and their use for the development of malaria control measures, such as vaccines.
Citations
Citations to this article as recorded by
Genetic polymorphisms of merozoite surface protein-3α in Plasmodium vivax isolates from Pakistan Kim Oanh Nguyễn, Jung-Mi Kang, Tuấn Cường Võ, Hương Giang Lê, Seemab Akhtar, Thu Hằng Nguyễn, Đăng Thùy Dương Nguyễn, Minkyoung Cho, Sahib Gul Afridi, Byoung-Kuk Na Acta Tropica.2025; 272: 107904. CrossRef
Genetic polymorphism of Duffy binding protein in Pakistan Plasmodium vivax isolates Đăng Thùy Dương Nguyễn, Tuấn Cường Võ, Kim Oanh Nguyễn, Hương Giang Lê, Jung-Mi Kang, Thu Hằng Nguyễn, Minkyoung Cho, Sahib Gul Afridi, Byoung-Kuk Na Acta Tropica.2024; 260: 107421. CrossRef
Plasmodium falciparum apical membrane antigen-1 (PfAMA-1) is a major candidate for the blood-stage malaria vaccine. Genetic polymorphisms of global pfama-1suggest that the genetic diversity of the gene can disturb effective vaccine development targeting this antigen. This study was conducted to explore the genetic diversity and gene structure of pfama-1 among P. falciparum isolates collected in the Khyber Pakhtunkhwa (KP) province of Pakistan. A total of 19 full-length pfama-1 sequences were obtained from KP-Pakistan P. falciparum isolates, and genetic polymorphism and natural selection were investigated. KP-Pakistan pfama-1 exhibited genetic diversity, wherein 58 amino acid changes were identified, most of which were located in ectodomains, and domains I, II, and III. The amino acid changes commonly found in the ectodomain of global pfama-1 were also detected in KP-Pakistan pfama-1. Interestingly, 13 novel amino acid changes not reported in the global population were identified in KP-Pakistan pfama-1. KP-Pakistan pfama-1 shared similar levels of genetic diversity with global pfama-1. Evidence of natural selection and recombination events were also detected in KP-Pakistan pfama-1.
Citations
Citations to this article as recorded by
Genetic diversity and natural selection of cell-traversal protein for ookinetes and sporozoites (CelTOS) in Plasmodium falciparum isolates from Vietnam Tuấn Cường Võ, Hương Giang Lê, Jung-Mi Kang, Nguyen Thi Minh Trinh, Minkyoung Cho, Youn-Kyoung Goo, Huynh Hong Quang, Byoung-Kuk Na Gene.2025; 968: 149731. CrossRef
Genetic polymorphism of Duffy binding protein in Pakistan Plasmodium vivax isolates Đăng Thùy Dương Nguyễn, Tuấn Cường Võ, Kim Oanh Nguyễn, Hương Giang Lê, Jung-Mi Kang, Thu Hằng Nguyễn, Minkyoung Cho, Sahib Gul Afridi, Byoung-Kuk Na Acta Tropica.2024; 260: 107421. CrossRef
Naegleria fowleri invades the brain and causes a fatal primary amoebic meningoencephalitis (PAM). Despite its high mortality rate of approximately 97%, an effective therapeutic drug for PAM has not been developed. Approaches with miltefosine, amphotericin B, and other antimicrobials have been clinically attempted to treat PAM, but their therapeutic efficacy remains unclear. The development of an effective and safe therapeutic drug for PAM is urgently needed. In this study, we investigated the anti-amoebic activity of Pinus densiflora leaf extract (PLE) against N. fowleri. PLE induced significant morphological changes in N. fowleri trophozoites, resulting in the death of the amoeba. The IC50 of PLE on N. fowleri was 62.3±0.95 μg/ml. Alternatively, PLE did not significantly affect the viability of the rat glial cell line C6. Transcriptome analysis revealed differentially expressed genes (DEGs) between PLE-treated and non-treated amoebae. A total of 5,846 DEGs were identified, of which 2,189 were upregulated, and 3,657 were downregulated in the PLE-treated amoebae. The DEGs were categorized into biological process (1,742 genes), cellular component (1,237 genes), and molecular function (846 genes) based on the gene ontology analysis, indicating that PLE may have dramatically altered the biological and cellular functions of the amoeba and contributed to their death. These results suggest that PLE has anti-N. fowleri activity and may be considered as a potential candidate for the development of therapeutic drugs for PAM. It may also be used as a supplement compound to enhance the therapeutic efficacy of drugs currently used to treat PAM.
Citations
Citations to this article as recorded by
A xanthone O-glucoside isolated from Iris setosa Pall. ex Link exhibits promising anti-amoebic activity against the brain-eating amoeba Naegleria fowleri Hương Giang Lê, Buyng Su Hwang, Ji-Su Choi, Yong Tae Jeong, Tuấn Cường Võ, Minkyoung Cho, Yeonchul Hong, Jeong Ho Kim, Young Taek Oh, Byoung-Kuk Na Phytomedicine.2025; 147: 157199. CrossRef
From nose to neurons: The lethal journey of the brain-eating amoeba Naegleria fowleri Arindam Mitra, Débora Brito Goulart The Microbe.2025; 8: 100537. CrossRef
Free-living amoebae (FLA) rarely cause human infections but can invoke fatal infections in the central nervous system (CNS). No consensus treatment has been established for FLA infections of the CNS, emphasizing the urgent need to discover or develop safe and effective drugs. Flavonoids, natural compounds from plants and plant-derived products, are known to have antiprotozoan activities against several pathogenic protozoa parasites. The anti-FLA activity of flavonoids has also been proposed, while their antiamoebic activity for FLA needs to be emperically determined. We herein evaluated the antiamoebic activities of 18 flavonoids against Naegleria fowleri and Acanthamoeba species which included A. castellanii and A. polyphaga. These flavonoids showed different profiles of antiamoebic activity against N. fowleri and Acanthamoeba species. Demethoxycurcumin, kaempferol, resveratrol, and silybin (A+B) showed in vitro antiamoebic activity against both N. fowleri and Acanthamoeba species. Apigenin, costunolide, (‒)-epicatechin, (‒)-epigallocatechin, rosmarinic acid, and (‒)-trans-caryophyllene showed selective antiamoebic activity for Acanthamoeba species. Luteolin was more effective for N. fowleri. However, afzelin, berberine, (±)-catechin, chelerythrine, genistein, (+)-pinostrobin, and quercetin did not exhibit antiamoebic activity against the amoeba species. They neither showed selective antiamoebic activity with significant cytotoxicity to C6 glial cells. Our results provide a basis for the anti-FLA activity of flavonoids, which can be applied to develope alternative or supplemental therapeutic agents for FLA infections of the CNS.
Citations
Citations to this article as recorded by
Effectiveness of phytoproducts against pathogenic free-living amoebae - A scoping and critical review paving the way toward plant-based pharmaceuticals Beni Jequicene Mussengue Chaúque, Thaisla Cristiane Borella da Silva, Eduardo Brittes Rott, Felipe Brittes Rott, Ana Paula Marçal Copetti Leite, Guilherme Brittes Benitez, Neuana Fernando Neuana, José Roberto Goldim, Marilise Brittes Rott, Régis Adriel Za Fitoterapia.2025; 182: 106404. CrossRef
Unveiling phenolic content, antibacterial, and antibiofilm potential of sacha inchi (Plukenetia volubilis L.) seed shell extracts against Staphylococcus aureus Gadah A. Al-Hamoud, Musarat Amina, Reem Hamoud Alrashoudi, Ayesha Mateen, Farah Maqsood, Hanan M. Al-Yousef PeerJ.2025; 13: e19524. CrossRef
A xanthone O-glucoside isolated from Iris setosa Pall. ex Link exhibits promising anti-amoebic activity against the brain-eating amoeba Naegleria fowleri Hương Giang Lê, Buyng Su Hwang, Ji-Su Choi, Yong Tae Jeong, Tuấn Cường Võ, Minkyoung Cho, Yeonchul Hong, Jeong Ho Kim, Young Taek Oh, Byoung-Kuk Na Phytomedicine.2025; 147: 157199. CrossRef
From nose to neurons: The lethal journey of the brain-eating amoeba Naegleria fowleri Arindam Mitra, Débora Brito Goulart The Microbe.2025; 8: 100537. CrossRef
(‒)-Epicatechin reveals amoebicidal activity against Acanthamoeba castellanii by activating the programmed cell death pathway Hương Giang Lê, Jung-Mi Kang, Tuấn Cường Võ, Won Gi Yoo, Yeonchul Hong, Byoung-Kuk Na Phytomedicine.2024; 125: 155389. CrossRef
The potential of nanocomposites (patuletin-conjugated with gallic acid-coated zinc oxide) against free-living amoebae pathogens Ruqaiyyah Siddiqui, Bushra Khatoon, Muhammad Kawish, Sreedevi Sajeev, Shaheen Faizi, Muhammad Raza Shah, Ahmad M. Alharbi, Naveed Ahmed Khan International Microbiology.2024; 28(5): 929. CrossRef
A Comprehensive Review on the Antibacterial, Antifungal, Antiviral, and Antiparasitic Potential of Silybin José Lima Pereira-Filho, Amanda Graziela Gonçalves Mendes, Carmem Duarte Lima Campos, Israel Viegas Moreira, Cinara Regina Aragão Vieira Monteiro, Suzany Hellen da Silva Soczek, Elizabeth Soares Fernandes, Rafael Cardoso Carvalho, Valério Monteiro-Neto Antibiotics.2024; 13(11): 1091. CrossRef
Heliminthic paramyosin is a multifunctional protein that not only acts as a structural protein in muscle layers but as an immune-modulatory molecule interacting with the host immune system. Previously, we found that paramyosin from Clonorchis sinensis (CsPmy) is bound to human complement C9 protein (C9). To analyze the C9 binding region on CsPmy, overlapping recombinant fragments of CsPmy were produced and their binding activity to human C9 was investigated. The fragmental expression of CsPmy and C9 binding assays revealed that the C9 binding region was located at the C-terminus of CsPmy. Further analysis of the C-terminus of CsPmy to narrow the C9 binding region on CsPmy indicated that the region flanking731Leu–780 Leu was a potent C9 binding region. The CsPmy fragments corresponding to the region effectively inhibited human C9 polymerization. These results provide a precise molecular basis for CsPmy as a potent immunomodulator to evade host immune defenses by inhibiting complement attack.
Citations
Citations to this article as recorded by
Transmission-Blocking Vaccines against Schistosomiasis Japonica Chika P. Zumuk, Malcolm K. Jones, Severine Navarro, Darren J. Gray, Hong You International Journal of Molecular Sciences.2024; 25(3): 1707. CrossRef
What about the Cytoskeletal and Related Proteins of Tapeworms in the Host’s Immune Response? An Integrative Overview Diana G. Ríos-Valencia, Javier Ambrosio, Rocío Tirado-Mendoza, Julio César Carrero, Juan Pedro Laclette Pathogens.2023; 12(6): 840. CrossRef
Knockdown resistance (kdr) mutations in the voltage-gated sodium channel (VGSC) of mosquitoes confer resistance to insecticides. Although insecticide resistance has been suspected to be widespread in the natural population of Aedes aegypti in Myanmar, only limited information is currently available. The overall prevalence and distribution of kdr mutations was analyzed in Ae. aegypti from Mandalay areas, Myanmar. Sequence analysis of the VGSC in Ae. aegypti from Myanmar revealed amino acid mutations at 13 and 11 positions in domains II and III of VGSC, respectively. High frequencies of S989P (68.6%), V1016G (73.5%), and F1534C (40.1%) were found in domains II and III. T1520I was also found, but the frequency was low (8.1%). The frequency of S989P/V1016G was high (55.0%), and the frequencies of V1016G/F1534C and S989P/V1016G/F1534C were also high at 30.1% and 23.5%, respectively. Novel mutations in domain II (L963Q, M976I, V977A, M994T, L995F, V996M/A, D998N, V999A, N1013D, and F1020S) and domain III (K1514R, Y1523H, V1529A, F1534L, F1537S, V1546A, F1551S, G1581D, and K1584R) were also identified. These results collectively suggest that high frequencies of kdr mutations were identified in Myanmar Ae. aegypti, indicating a high level of insecticide resistance.
Citations
Citations to this article as recorded by
Monitoring insecticide resistance and target-site mutations in field populations of Spodoptera frugiperda (Lepidoptera: Noctuidae) in China Baojuan Zeng, Jianghao Ding, Yajuan Xiao, Shilong Wang, Jie Zhong, Yueru Ye, Huiru Zhou, Jing Song, Wenxin Zhao, Shutang Zhou, Huidong Wang, Raul Narciso Guedes Journal of Economic Entomology.2025; 118(2): 868. CrossRef
Knockdown-resistance (kdr) mutations in Indian Aedes aegypti populations: Lack of recombination among haplotypes bearing V1016G, F1534C, and F1534L kdr alleles Taranjeet Kaur, Rajababu S. Kushwah, Sabyasachi Pradhan, Manoj K. Das, Madhavinadha P. Kona, Anushrita, Radhika Mittal, David Weetman, Rajnikant Dixit, Om P. Singh, Jean-philippe David PLOS Neglected Tropical Diseases.2025; 19(6): e0013126. CrossRef
Pyrethroid resistance in Aedes aegypti: genetic mechanisms worldwide, and recommendations for effective vector control Jonathan Rene Hernandez, Patricia Victoria Pietrantonio Parasites & Vectors.2025;[Epub] CrossRef
Detection of Putative Mutation I873S in the Sodium Channel of Megalurothrips usitatus (Bagnall) Which May Be Associated with Pyrethroid Resistance Ruibo Gao, Rongcai Lu, Xinyao Qiu, Likui Wang, Kun Zhang, Shaoying Wu Insects.2023; 14(4): 388. CrossRef
Knockdown Resistance Mutations in the Voltage-Gated Sodium Channel of Aedes aegypti (Diptera: Culicidae) in Myanmar Haung Naw, Tuấn Cường Võ, Hương Giang Lê, Jung-Mi Kang, Yi Yi Mya, Moe Kyaw Myint, Tong-Soo Kim, Ho-Joon Shin, Byoung-Kuk Na Insects.2022; 13(4): 322. CrossRef
Detection of pyrethroid resistance mutations and intron variants in the voltage‐gated sodium channel of Aedes (Stegomyia) aegypti and Aedes (Stegomyia) albopictus mosquitoes from Lao People's Democratic Republic Sebastien Marcombe, Katherine Shimell, Rachel Savage, Edward Howlett, Phonesavanh Luangamath, Somphat Nilaxay, Vacky Vungkyly, Anne Baby, Mathew King, Josie Clarke, Chloe Jeffries, Josna Jojo, Emily Lacey, Farris Bhatty, Dadirayi Mabika, Andrea Dela Cruz, Medical and Veterinary Entomology.2022; 36(4): 424. CrossRef
First
Prev
