-
Animals : An Open Access Journal From... Nov 2023Avian malaria is a re-emerging threat to avian species worldwide. It is sustained by several protozoan species belonging to the genus , mainly . The even wider diffusion...
Avian malaria is a re-emerging threat to avian species worldwide. It is sustained by several protozoan species belonging to the genus , mainly . The even wider diffusion of the disease, probably because of the increase in the areas covered by their mosquito vectors, may pose new risks for avian species lacking natural resistance (especially those from artic or sub-artic environments) or those hosted in structures like zoos and wildlife rescue centers. With that premise, this study describes the efficacy and safety of a therapeutic protocol to treat avian malaria in three snowy owls () hosted in a wildlife rescue center in Apulia, south of Italy, and affected by avian malaria by . The protocol consisted of administering 10/4 mg/kg atovaquone/proguanil per os once a day for three consecutive days, repeating this seven days later. Seven days after the end of the treatment, was not detected in the birds' blood and no adverse effects were observed during the 60 days of monitoring after the end of the treatment. Therefore, a therapeutic regimen of 10/4 mg/kg/day may be considered safe and effective in a valuable and endangered species such as .
PubMed: 38003076
DOI: 10.3390/ani13223457 -
Ticks and Tick-borne Diseases Jan 2024Canine babesiosis is an important protozoan tick-borne disease associated with anemia and thrombocytopenia and caused by several different Babesia spp. Babesia negevi...
Canine babesiosis is an important protozoan tick-borne disease associated with anemia and thrombocytopenia and caused by several different Babesia spp. Babesia negevi was first reported to infect dogs in the Middle East in 2020. This study describes the presentation, clinical signs, parasitemia levels quantified by molecular techniques, laboratory findings and treatment of dogs infected with B. negevi following the first description of this species. Clinical findings in the infected dogs, a 3-year old female and two 8-week old male and female pups, included extreme lethargy and pale mucous membranes, anemia and thrombocytopenia found in all three animals. Fever was present in the older female and icterus in the female pup. Babesia parasites resembling B. negevi were detected by microscopy of blood smears from the dogs. PCR of blood targeting the 18S rRNA and cox1 genes confirmed that babesiosis was caused by B. negevi and PCR targeting the Borrelia flagellin gene indicated co-infection with Borrelia persica in two dogs. Treatment of the dogs with imidocarb dipropionate resulted in clinical improvement and initial decrease in the B. negevi parasite load as detected by quantitative PCR in two dogs, however the female pup continued to deteriorate and died. The parasite load in the 3-year old female decreased from 43,451 parasites/µl blood pre-imidocarb dipropionate treatment to 803 parasites/µl within two weeks. In the surviving pup, it decreased from 3,293,538 parasites/µl pre-treatment to 20,092 parasites/µl after two weeks. Babesia negevi DNA was still recovered from blood samples by PCR despite repeated treatment with imidocarb dipropionate one-month post-treatment in the surviving pup and up to seven months post-treatment in the 3-year old female. Only treatment with atovaquone and azithromycin for ten days eliminated B. negevi in both dogs as confirmed by negative PCR two weeks later. In conclusion, treatment with imidocarb dipropionate was helpful for recovery from clinical disease but did not facilitate parasite elimination, and it is therefore recommended to treat canine B. negevi infection with the combination of atovaquone and azithromycin.
Topics: Dogs; Animals; Male; Female; Babesiosis; Atovaquone; Antiprotozoal Agents; Azithromycin; Babesia; Thrombocytopenia; Anemia; Dog Diseases
PubMed: 37989015
DOI: 10.1016/j.ttbdis.2023.102282 -
Clinical and Translational Radiation... Jan 2024Neoadjuvant radiotherapy is successfully used in rectal cancer to improve overall survival. However, treatment response is both unpredictable and variable. There is...
INTRODUCTION
Neoadjuvant radiotherapy is successfully used in rectal cancer to improve overall survival. However, treatment response is both unpredictable and variable. There is strong evidence to show that the phenomenon of tumour hypoxia is associated with radioresistance, however the mechanism(s) behind this are poorly understood. Consequently, there have only been a small number of studies evaluating methods targeting hypoxia-induced radioresistance. The purpose of this systematic review is to evaluate the potential effectiveness of targeting hypoxia-induced radioresistance in rectal cancer and provide recommendations for future research in this area.
METHODS
A comprehensive literature search was performed following the PRISMA guidelines. This study was registered on the Prospero database (CRD42023441983).
RESULTS
Eight articles met the inclusion criteria. All studies identified were or studies, there were no clinical trials. Of the 8 studies identified, 5 assessed the efficacy of drugs which directly or indirectly targeted hypoxia and three that identified potential targets. There was conflicting evidence for the use of metformin to overcome hypoxia induced radioresistance. Vorinostat, atovaquone, and evofosfamide showed promising preclinical evidence that they can overcome hypoxia-induced radioresistance.
DISCUSSION
The importance of investigating hypoxia-induced radioresistance in rectal cancer is crucial. However, to date, only a small number of preclinical studies exist evaluating this phenomenon. This systematic review highlights the importance of further research to fully understand the mechanism behind this radioresistance. There are promising targets identified in this systematic review however, substantially more pre-clinical and clinical research as a priority for future research is needed.
PubMed: 37961749
DOI: 10.1016/j.ctro.2023.100695 -
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 -
Cancer Communications (London, England) Mar 2024
Topics: Humans; Atovaquone; Tumor Microenvironment; Energy Metabolism; Mitochondria; Lung Neoplasms
PubMed: 37930151
DOI: 10.1002/cac2.12500 -
Case Reports in Infectious Diseases 2023
PubMed: 37908307
DOI: 10.1155/2023/9793264 -
Chemical Science Oct 2023Photodynamic therapy (PDT) has emerged as an invasive and promising antitumour treatment, however, the hypoxia in deep tumour tissues and the poor water-solubility of...
Photodynamic therapy (PDT) has emerged as an invasive and promising antitumour treatment, however, the hypoxia in deep tumour tissues and the poor water-solubility of photosensitizers as bottlenecks greatly hinder PDT efficiency. Herein, a tumour microenvironment (TME) activated supramolecular nanoplatform consisting of the pillar[5]arene-based amphiphilic polymer POPD, the phototherapeutic agent Cy7-CN, respiratory medication atovaquone (ATO) and chemotherapeutic drug pyridinyl camptothecin (CPT-Py) was constructed for imaging-guided hypoxia-ameliorated phototherapies. Owing to host-guest interaction, the photochemical and photophysical properties of cyanine were improved exceedingly due to the suppression of π-π stacking. Triggered by the acidic microenvironment in tumour sites, the supramolecular nanoplatform would dissociate and release CPT-Py and ATO which inhibits mitochondria-associated oxidative phosphorylation (OXPHOS) and encourages more oxygen to be used in enhanced PDT. and studies verified that the rational combination of ATO-enhanced PDT and PTT overcame the disadvantages of single phototherapy and formed mutual promotion, and simultaneously sensitized chemotherapeutic drugs, which resulted in high tumour inhibition. It is hoped that the supramolecular nanoplatform could shed light on the development of phototherapeutic agents.
PubMed: 37886080
DOI: 10.1039/d3sc03797e -
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 -
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 -
Materials Today. Bio Dec 2023Radiation therapy (RT) has emerged as one of the most promising anti-tumor strategies for neuroblastoma. Nevertheless, the special tumor microenvironment (TME),...
Radiation therapy (RT) has emerged as one of the most promising anti-tumor strategies for neuroblastoma. Nevertheless, the special tumor microenvironment (TME), including hypoxic and GSH-overexpressed TME, often greatly restricts the RT outcome. In this study, we demonstrated a dual-channel parallel radicals nanoamplifier (ATO@PAE-PEG-AS1411/Fe). The nanoamplifier was shaped into a bilayer shell-core structure, in which atovaquone-loaded poly (β-amino esters)-poly (ethylene glycol) (ATO@PAE-PEG) served as the core while Fe-absorbed AS1411 aptamer (AS1411/Fe) served as the shell. Taking advantage of the targeting ability of AS1411, ATO@PAE-PEG-AS1411/Fe specifically accumulated in tumor cells, and then released ATO as well as Fe in response to the acidic TME. The released ATO dramatically inhibited the mitochondrial respiration of tumor cells, thus sparing vast amounts of oxygen for the generation of free radicals during RT process, which was the first free radicals-amplifying pathway Meanwhile, the released Fe could consume the tumor-overexpressed GSH through the redox reaction, thus effectively preserving the generated free radicals in RT process, which was the second free radicals-amplifying pathway. Taken together, our study demonstrates a dual-channel parallel free radicals-amplifying RT strategy, and it is expected this work will promote the clinical application prospects of RT treatment against neuroblastoma.
PubMed: 37822451
DOI: 10.1016/j.mtbio.2023.100828