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BMC Cancer Nov 2023Colorectal cancer is a common malignant tumour. Invasive growth and distant metastasis are the main characteristics of its malignant biological behaviour, and they are...
BACKGROUND
Colorectal cancer is a common malignant tumour. Invasive growth and distant metastasis are the main characteristics of its malignant biological behaviour, and they are also the primary factors leading to death in colon cancer patients. Atovaquone is an antimalarial drug, and its anticancer effect has recently been demonstrated in several cancer models in vitro and in vivo, but it has not been examined in the treatment of colorectal cancer.
METHODS
To elucidate the effect of atovaquone on colorectal cancer. We used RNA transcriptome sequencing, RT‒PCR and Western blot experiments to examine the expression of NF-κB (p-P65), EMT-related proteins and related inflammatory factors (IL1B, IL6, CCL20, CCL2, CXCL8, CXCL6, IL6ST, FAS, IL10 and IL1A). The effect of atovaquone on colorectal cancer metastasis was validated using an animal model of lung metastases. We further used transcriptome sequencing, the GCBI bioinformatics database and the STRING database to predict relevant target proteins. Furthermore, pathological sections were collected from relevant cases for immunohistochemical verification.
RESULTS
This study showed that atovaquone could inhibit colorectal cancer metastasis and invasion in vivo and in vitro, inhibit the expression of E-cadherin protein, and promote the protein expression of N-cadherin, vimentin, ZEB1, Snail and Slug. Atovaquone could inhibit EMT by inhibiting NF-κB (p-P65) and related inflammatory factors. Further bioinformatics analysis and verification showed that PDGFRβ was one of the targets of atovaquone.
CONCLUSION
In summary, atovaquone can inhibit the expression of NF-κB (p-P65) and related inflammatory factors by inhibiting the protein expression of p-PDGFRβ, thereby inhibiting colorectal cancer metastasis. Atovaquone may be a promising drug for the treatment of colorectal cancer metastasis.
Topics: Animals; Humans; NF-kappa B; Atovaquone; Cell Line, Tumor; Signal Transduction; Colorectal Neoplasms; Epithelial-Mesenchymal Transition; Cell Movement
PubMed: 37932661
DOI: 10.1186/s12885-023-11585-9 -
The Journal of Infectious Diseases Aug 2023Mpox virus (MPXV) is a zoonotic orthopoxvirus and caused an outbreak in 2022. Although tecovirimat and brincidofovir are approved as anti-smallpox drugs, their effects...
BACKGROUND
Mpox virus (MPXV) is a zoonotic orthopoxvirus and caused an outbreak in 2022. Although tecovirimat and brincidofovir are approved as anti-smallpox drugs, their effects in mpox patients have not been well documented. In this study, by a drug repurposing approach, we identified potential drug candidates for treating mpox and predicted their clinical impacts by mathematical modeling.
METHODS
We screened 132 approved drugs using an MPXV infection cell system. We quantified antiviral activities of potential drug candidates by measuring intracellular viral DNA and analyzed the modes of action by time-of-addition assay and electron microscopic analysis. We further predicted the efficacy of drugs under clinical concentrations by mathematical simulation and examined combination treatment.
RESULTS
Atovaquone, mefloquine, and molnupiravir exhibited anti-MPXV activity, with 50% inhibitory concentrations of 0.51-5.2 μM, which was more potent than cidofovir. Whereas mefloquine was suggested to inhibit viral entry, atovaquone and molnupiravir targeted postentry processes. Atovaquone was suggested to exert its activity through inhibiting dihydroorotate dehydrogenase. Combining atovaquone with tecovirimat enhanced the anti-MPXV effect of tecovirimat. Quantitative mathematical simulations predicted that atovaquone can promote viral clearance in patients by 7 days at clinically relevant drug concentrations.
CONCLUSIONS
These data suggest that atovaquone would be a potential candidate for treating mpox.
Topics: Humans; Atovaquone; Mefloquine; Monkeypox virus
PubMed: 36892247
DOI: 10.1093/infdis/jiad058 -
Frontiers in Pharmacology 2023
PubMed: 37767402
DOI: 10.3389/fphar.2023.1282233 -
Viruses Aug 2023The emergence of SARS-CoV-1 in 2003 followed by MERS-CoV and now SARS-CoV-2 has proven the latent threat these viruses pose to humanity. While the SARS-CoV-2 pandemic...
The emergence of SARS-CoV-1 in 2003 followed by MERS-CoV and now SARS-CoV-2 has proven the latent threat these viruses pose to humanity. While the SARS-CoV-2 pandemic has shifted to a stage of endemicity, the threat of new coronaviruses emerging from animal reservoirs remains. To address this issue, the global community must develop small molecule drugs targeting highly conserved structures in the coronavirus proteome. Here, we characterized existing drugs for their ability to inhibit the endoribonuclease activity of the SARS-CoV-2 non-structural protein 15 (nsp15) via in silico, in vitro, and in vivo techniques. We have identified nsp15 inhibition by the drugs pibrentasvir and atovaquone which effectively inhibit SARS-CoV-2 and HCoV-OC43 at low micromolar concentrations in cell cultures. Furthermore, atovaquone, but not pibrentasvir, is observed to modulate HCoV-OC43 dsRNA and infection in a manner consistent with nsp15 inhibition. Although neither pibrentasvir nor atovaquone translate to clinical efficacy in a murine prophylaxis model of SARS-CoV-2 infection, atovaquone may serve as a basis for the design of future nsp15 inhibitors.
Topics: Animals; Mice; SARS-CoV-2; COVID-19; Atovaquone; Endoribonucleases; Coronavirus OC43, Human
PubMed: 37766247
DOI: 10.3390/v15091841 -
Nature Communications Oct 2023Long-acting injectable medications, such as atovaquone, offer the prospect of a "chemical vaccine" for malaria, combining drug efficacy with vaccine durability. However,...
Long-acting injectable medications, such as atovaquone, offer the prospect of a "chemical vaccine" for malaria, combining drug efficacy with vaccine durability. However, selection and transmission of drug-resistant parasites is of concern. Laboratory studies have indicated that atovaquone resistance disadvantages parasites in mosquitoes, but lack of data on clinically relevant Plasmodium falciparum has hampered integration of these variable findings into drug development decisions. Here we generate atovaquone-resistant parasites that differ from wild type parent by only a Y268S mutation in cytochrome b, a modification associated with atovaquone treatment failure in humans. Relative to wild type, Y268S parasites evidence multiple defects, most marked in their development in mosquitoes, whether from Southeast Asia (Anopheles stephensi) or Africa (An. gambiae). Growth of asexual Y268S P. falciparum in human red cells is impaired, but parasite loss in the mosquito is progressive, from reduced gametocyte exflagellation, to smaller number and size of oocysts, and finally to absence of sporozoites. The Y268S mutant fails to transmit from mosquitoes to mice engrafted with human liver cells and erythrocytes. The severe-to-lethal fitness cost of clinically relevant atovaquone resistance to P. falciparum in the mosquito substantially lessens the likelihood of its transmission in the field.
Topics: Humans; Animals; Mice; Atovaquone; Parasites; Antimalarials; Malaria; Malaria, Falciparum; Plasmodium falciparum; Anopheles; Antiparasitic Agents; Vaccines
PubMed: 37828012
DOI: 10.1038/s41467-023-42030-x -
Heliyon Jun 2023Babesiosis is a protozoal disease affect livestock and pet animals such as cattle, buffaloes, sheep, goats, horses, donkeys, mules, dogs, and cats. It causes severe... (Review)
Review
Babesiosis is a protozoal disease affect livestock and pet animals such as cattle, buffaloes, sheep, goats, horses, donkeys, mules, dogs, and cats. It causes severe economic losses in livestock as well as in pet animals. A large number of dairy animals are imported in order to fulfill the demands of milk, milk, meat and its products. In addition, different pet animals are transported from Pakistan to various parts of the world, therefore, it is important to identify the current status and distribution of babesiosis throughout Pakistan in order to control the disease and draw attention for future research, diagnosis, treatment and control of this diseases. No work has been done on a complete review on up-to-date on blood protozoal disease burden in Pakistan. This article will provide about the complete background of babesiosis in ruminants, equines and pet animals, its current status, distribution, vectors in Pakistan and allopathic and ethnoveterinary treatments used against babesiosis. Babesiosis may be subclinical (apparently normal) and may be clinical with acute to chronic disease and sometimes fatal. Babesia is found and develops inside the erythrocytes (red blood cells). Clinically, it causes fever, fatigue, lethargy, pallor mucus membranes, malaise, cachexia, respiratory distress, jaundice, icterus, hemolytic anemia, hemoglobinuria, lymphadenopathy, chollangocytitis, hepatomegaly, and splenomegaly. Chemotherapy for babesiosis includes Imidocarb dipropionate, Diaminazine aceturate Atovaquone and Bupravaquone, Azithromycin, Quinuronium sulfate and Amicarbalidesio-thionate are most widely used. Supportive therapy includes multivitamins, fluid therapy, antipyretics intravenous fluids, and blood transfusions are used if necessary. In addition, there are certain ethnoveterinary (homeopathic) ingredients which having anti-babesial activity. As the resistance against these drugs is developing every day. New more specific long-lasting drugs should be developed for the treatment of Babesiosis. Further studies should be done on disease genome of different species of for vaccine development like malarial parasites.
PubMed: 37441378
DOI: 10.1016/j.heliyon.2023.e17172 -
Antimicrobial Agents and Chemotherapy Jul 2023Ivermectin is an endectocide used widely to treat a variety of internal and external parasites. Field trials of ivermectin mass drug administration for malaria...
Ivermectin is an endectocide used widely to treat a variety of internal and external parasites. Field trials of ivermectin mass drug administration for malaria transmission control have demonstrated a reduction of mosquito survival and human malaria incidence. Ivermectin will mostly be deployed together with artemisinin-based combination therapies (ACT), the first-line treatment of falciparum malaria. It has not been well established if ivermectin has activity against asexual stage Plasmodium falciparum or if it interacts with the parasiticidal activity of other antimalarial drugs. This study evaluated antimalarial activity of ivermectin and its metabolites in artemisinin-sensitive and artemisinin-resistant P. falciparum isolates and assessed drug-drug interaction with artemisinins and its partner drugs. The concentration of ivermectin causing half of the maximum inhibitory activity (IC) on parasite survival was 0.81 μM with no significant difference between artemisinin-sensitive and artemisinin-resistant isolates ( = 0.574). The ivermectin metabolites were 2-fold to 4-fold less active than the ivermectin parent compound ( < 0.001). Potential pharmacodynamic drug-drug interactions of ivermectin with artemisinins, ACT-partner drugs, and atovaquone were studied using mixture assays providing isobolograms and derived fractional inhibitory concentrations. There were no synergistic or antagonistic pharmacodynamic interactions when combining ivermectin and antimalarial drugs. In conclusion, ivermectin does not have clinically relevant activity against the asexual blood stages of P. falciparum. It also does not affect the antimalarial activity of artemisinins or ACT-partner drugs against asexual blood stages of P. falciparum.
Topics: Animals; Humans; Antimalarials; Plasmodium falciparum; Ivermectin; Artemisinins; Malaria, Falciparum; Malaria; Drug Combinations; Drug Resistance
PubMed: 37338381
DOI: 10.1128/aac.01730-22 -
Ticks and Tick-borne Diseases Jul 2023In the present study, the effect of a combination therapy consisting of diminazene aceturate (DA) and imidocarb dipropionate (ID) on the in vitro growth of several...
In the present study, the effect of a combination therapy consisting of diminazene aceturate (DA) and imidocarb dipropionate (ID) on the in vitro growth of several parasitic piroplasmids, and on Babesia microti in BALB/c mice was evaluated using a fluorescence-based SYBR Green I test. We evaluated the structural similarities between the regularly used antibabesial medications, DA and ID, and the recently found antibabesial drugs, pyronaridine tetraphosphate, atovaquone, and clofazimine, using atom pair fingerprints (APfp). The Chou-Talalay approach was used to determine the interactions between the two drugs. A Celltac MEK-6450 computerized hematology analyzer was used to detect hemolytic anemia every 96 hours in mice infected with B. microti and in those treated with either mono- or combination therapy. According to the APfp results, DA and ID have the most structural similarities (MSS). DA and ID had synergistic and additive interactions against the in vitro growth of Babesia bigemina and Babesia bovis, respectively. Low dosages of DA (6.25 mg kg) and ID (8.5 mg kg) in conjunction with each other inhibited B. microti growth by 16.5 %, 32 %, and 4.5 % more than 25 mg kg DA, 6.25 mg kg DA, and 8.5 mg kg ID monotherapies, respectively. In the blood, kidney, heart, and lung tissues of mice treated with DA/ID, the B. microti small subunit rRNA gene was not detected. The obtained findings suggest that DA/ID could be a promising combination therapy for treating bovine babesiosis. Also, such combination may overcome the potential problems of Babesia resistance and host toxicity induced by utilizing full doses of DA and ID.
Topics: Animals; Mice; Babesiosis; Theileria; Babesia; Imidocarb
PubMed: 37011497
DOI: 10.1016/j.ttbdis.2023.102145 -
MBio Oct 2023parasites rely on a functional electron transport chain (ETC) within their mitochondrion for proliferation, and compounds targeting mitochondrial functions are...
parasites rely on a functional electron transport chain (ETC) within their mitochondrion for proliferation, and compounds targeting mitochondrial functions are validated antimalarials. Here, we localize patatin-like phospholipase 2 (PNPLA2, PF3D7_1358000) to the mitochondrion and reveal that disruption of the PNPLA2 gene impairs asexual replication. PNPLA2-null parasites are hypersensitive to proguanil and inhibitors of the mitochondrial ETC, including atovaquone. In addition, PNPLA2-deficient parasites show reduced mitochondrial respiration and reduced mitochondrial membrane potential, indicating that disruption of PNPLA2 leads to a defect in the parasite ETC. Lipidomic analysis of the mitochondrial phospholipid cardiolipin (CL) reveals that loss of PNPLA2 is associated with a moderate shift toward shorter-chained and more saturated CL species, implying a contribution of PNPLA2 to CL remodeling. PNPLA2-deficient parasites display profound defects in gametocytogenesis, underlining the importance of a functional mitochondrial ETC during both the asexual and sexual development of the parasite. IMPORTANCE For their proliferation within red blood cells, malaria parasites depend on a functional electron transport chain (ETC) within their mitochondrion, which is the target of several antimalarial drugs. Here, we have used gene disruption to identify a patatin-like phospholipase, PNPLA2, as important for parasite replication and mitochondrial function in . Parasites lacking PNPLA2 show defects in their ETC and become hypersensitive to mitochondrion-targeting drugs. Furthermore, PNPLA2-deficient parasites show differences in the composition of their cardiolipins, a unique class of phospholipids with key roles in mitochondrial functions. Finally, we demonstrate that parasites devoid of PNPLA2 have a defect in gametocyte maturation, underlining the importance of a functional ETC for parasite transmission to the mosquito vector.
PubMed: 37882543
DOI: 10.1128/mbio.01718-23 -
Microbiology Spectrum Jun 2023The human malaria parasite undergoes a noncanonical cell division, namely, endoreduplication, where several rounds of nuclear, mitochondrial, and apicoplast replication...
The human malaria parasite undergoes a noncanonical cell division, namely, endoreduplication, where several rounds of nuclear, mitochondrial, and apicoplast replication occur without cytoplasmic division. Despite its importance in biology, the topoisomerases essential for decatenation of replicated chromosome during endoreduplication remain elusive. We hypothesize that the topoisomerase VI complex, containing Plasmodium falciparum topiosomerase VIB (PfTopoVIB) and catalytic P. falciparum Spo11 (PfSpo11), might be involved in the segregation of the mitochondrial genome. Here, we demonstrate that the putative PfSpo11 is the functional ortholog of yeast Spo11 that can complement the sporulation defects of the yeast Δ strain, and the catalytic mutant Pfspo11Y65F cannot complement such defects. PfTopoVIB and PfSpo11 display a distinct expression pattern compared to the other type II topoisomerases of and are induced specifically at the late schizont stage of the parasite, when the mitochondrial genome segregation occurs. Furthermore, PfTopoVIB and PfSpo11 are physically associated with each other at the late schizont stage, and both subunits are localized in the mitochondria. Using PfTopoVIB- and PfSpo11-specific antibodies, we immunoprecipitated the chromatin of tightly synchronous early, mid-, and late schizont stage-specific parasites and found that both the subunits are associated with the mitochondrial genome during the late schizont stage of the parasite. Furthermore, PfTopoVIB inhibitor radicicol and atovaquone show synergistic interaction. Accordingly, atovaquone-mediated disruption of mitochondrial membrane potential reduces the import and recruitment of both subunits of PfTopoVI to mitochondrial DNA (mtDNA) in a dose-dependent manner. The structural differences between PfTopoVIB and human TopoVIB-like protein could be exploited for development of a novel antimalarial agent. This study demonstrates a likely role of topoisomerase VI in the mitochondrial genome segregation of Plasmodium falciparum during endoreduplication. We show that PfTopoVIB and PfSpo11 remain associated and form the functional holoenzyme within the parasite. The spatiotemporal expression of both subunits of PfTopoVI correlates well with their recruitment to the mitochondrial DNA at the late schizont stage of the parasite. Additionally, the synergistic interaction between PfTopoVI inhibitor and the disruptor of mitochondrial membrane potential, atovaquone, supports that topoisomerase VI is the mitochondrial topoisomerase of the malaria parasite. We propose that topoisomerase VI may act as a novel target against malaria.
Topics: Animals; Humans; Parasites; Atovaquone; Saccharomyces cerevisiae; Plasmodium falciparum; Malaria, Falciparum; Malaria; DNA, Mitochondrial; Protozoan Proteins; Endodeoxyribonucleases; Saccharomyces cerevisiae Proteins
PubMed: 37212694
DOI: 10.1128/spectrum.04980-22