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Immunity, Inflammation and Disease Apr 2024Chronic obstructive pulmonary disease (COPD) is a globally prevalent respiratory disease, and programmed cell death plays a pivotal role in the development of COPD....
BACKGROUND
Chronic obstructive pulmonary disease (COPD) is a globally prevalent respiratory disease, and programmed cell death plays a pivotal role in the development of COPD. Disulfidptosis is a newly discovered type of cell death that may be associated with the progression of COPD. However, the expression and role of disulfidptosis-related genes (DRGs) in COPD remain unclear.
METHODS
The expression of DRGs was identified by analyzing RNA sequencing (RNA-seq) data in COPD. Further, COPD patients were classified into two subtypes by unsupervised cluster analysis to reveal their differences in gene expression and immune infiltration. Meanwhile, hub genes associated with disulfidptosis were screened by weighted gene co-expression network analysis. Subsequently, the hub genes were validated experimentally in cells and animals. In addition, we screened potential therapeutic drugs through the hub genes.
RESULTS
We identified two distinct molecular clusters and observed significant differences in immune cell populations between them. In addition, we screened nine hub genes, and experimental validation showed that CDC71, DOHH, PDAP1, and SLC25A39 were significantly upregulated in cigarette smoke-induced COPD mouse lung tissues and bronchial epithelial cells (BEAS-2B) treated with cigarette smoke extract. Finally, we predicted 10 potential small molecule drugs such as Atovaquone, Taurocholic acid, Latamoxef, and Methotrexate.
CONCLUSION
We highlighted the strong association between COPD and disulfidptosis, with DRGs demonstrating a discriminative capacity for COPD. Additionally, the expression of certain novel genes, including CDC71, DOHH, PDAP1, and SLC25A39, is linked to COPD and may aid in the diagnosis and assessment of this condition.
Topics: Humans; Animals; Mice; Pulmonary Disease, Chronic Obstructive; Apoptosis; Atovaquone; Cluster Analysis; Epithelial Cells; Intercellular Signaling Peptides and Proteins
PubMed: 38578019
DOI: 10.1002/iid3.1231 -
Pharmaceutics Jan 2024Onchocerciasis treatment and control relies mainly on the use of ivermectin which has high activity against the microfilarial stage of but limited activity against the...
Onchocerciasis treatment and control relies mainly on the use of ivermectin which has high activity against the microfilarial stage of but limited activity against the long-lived, tissue dwelling adult nematodes. As this neglected tropical disease has now been targeted for elimination, there is an urgent need for new drugs to combat these parasites, ideally with macrofilaricidal activity. In this study, we have examined the anti- activity of a range of existing FDA-approved drugs with a view to repurposing, which can lead to rapid and relatively inexpensive development. From the Pharmakon-1600 library, 106 drugs were selected and tested against adult male parasites using a concentration of 1.25 × 10 M in an in vitro 5-day standard assay to assess motility and viability (using MTT/formazan colorimetry). The findings revealed that 44 drugs produced marginal/moderate activity (50-99% motility and/or MTT reductions) including cefuroxime sodium, methenamine, primaquine phosphate and rivastigmine tartrate, while 23 drugs produced good activity (100% motility reductions and significant MTT reductions), including atovaquone, isradipine, losartan, rifaximin, cefaclor and pyrantel pamoate. Although this study represents only a first step, some of the identified hits indicate there are potential anti- drug candidates worthy of further investigation.
PubMed: 38399264
DOI: 10.3390/pharmaceutics16020210 -
CEN Case Reports Feb 2024A 50-year-old man who had undergone a living-donor kidney transplant 12 years prior for chronic renal failure due to autosomal dominant polycystic kidney disease...
A 50-year-old man who had undergone a living-donor kidney transplant 12 years prior for chronic renal failure due to autosomal dominant polycystic kidney disease contracted coronavirus disease 19 (COVID-19). He had a positive antigen test, mild symptoms, sore throat, and fever of 37.9 ℃. The patient was treated with molnupiravir for 5 days, and the symptoms disappeared 5 days after onset. However, 10 days after onset, he developed a fever of approximately 37 ℃ and a non-productive cough; 27 days after onset, the patient was hospitalized for anorexia and a worsening respiratory condition. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigen test results on admission were negative, and no antiviral medications were administered against SARS-CoV-2. Computed tomography revealed extensive ground-glass opacities in both lung fields. The patient was treated with steroid pulse therapy, ceftriaxone, atovaquone, azithromycin, and respiratory management using a high-flow nasal cannula. The combined therapies were successful, and the patient was managed with a nasal oxygen cannula after 3 days. Oxygen administration was discontinued after 6 days of hospitalization, and the patient was discharged after 14 days. Based on the laboratory findings, bacterial, interstitial, and Pneumocystis pneumonia were unlikely. The success of the steroid pulse therapy suggested that respiratory failure was caused by pneumonia due to the immune response after COVID-19 infection.
PubMed: 38367183
DOI: 10.1007/s13730-023-00849-9 -
Cancer Immunology, Immunotherapy : CII Feb 2024T-cell receptor (TCR) engineered T-cell therapy has recently emerged as a promising adoptive immunotherapy approach for tumor treatment, yet hindered by tumor immune...
T-cell receptor (TCR) engineered T-cell therapy has recently emerged as a promising adoptive immunotherapy approach for tumor treatment, yet hindered by tumor immune evasion resulting in poor therapeutic efficacy. The introduction of ferroptosis-targeted inducers offers a potential solution, as they empower T cells to induce ferroptosis and exert influence over the tumor microenvironment. Atovaquone (ATO) stands as a prospective pharmaceutical candidate with the potential to target ferroptosis, effectively provoking an excessive generation and accumulation of reactive oxygen species (ROS). In this study, we evaluated the effectiveness of a combination therapy comprising ATO and TCR-T cells against hepatocellular carcinoma (HCC), both in vitro and in vivo. The results of lactate dehydrogenase and cytokine assays demonstrated that ATO enhanced cytotoxicity mediated by AFP-specific TCR-T cells and promoted the release of IFN-γ in vitro. Additionally, in an established HCC xenograft mouse model, the combined therapy with low-dose ATO and TCR-T cells exhibited heightened efficacy in suppressing tumor growth, with no apparent adverse effects, comparable to the results achieved through monotherapy. The RNA-seq data unveiled a significant activation of the ferroptosis-related pathway in the combination therapy group in comparison to the TCR-T cells group. Mechanistically, the synergy between ATO and TCR-T cells augmented the release of IFN-γ by TCR-T cells, while concurrently elevating the intracellular and mitochondrial levels of ROS, expanding the labile iron pool, and impairing the integrity of the mitochondrial membrane in HepG2 cells. This multifaceted interaction culminated in the potentiation of ferroptosis within the tumor, primarily induced by an excess of ROS. In summary, the co-administration of ATO and TCR-T cells in HCC exhibited heightened vulnerability to ferroptosis. This heightened susceptibility led to the inhibition of tumor growth and the stimulation of an anti-tumor immune response. These findings suggest that repurposing atovaquone for adoptive cell therapy combination therapy holds the potential to enhance treatment outcomes in HCC.
Topics: Humans; Animals; Mice; Carcinoma, Hepatocellular; Atovaquone; Reactive Oxygen Species; Ferroptosis; Prospective Studies; Liver Neoplasms; Receptors, Antigen, T-Cell; Disease Models, Animal; Tumor Microenvironment
PubMed: 38349553
DOI: 10.1007/s00262-024-03628-2 -
Ticks and Tick-borne Diseases May 2024Canine babesiosis has been increasingly diagnosed in various regions of Germany such as north-eastern Germany in recent years. A dog with several relapses of Babesia...
Canine babesiosis has been increasingly diagnosed in various regions of Germany such as north-eastern Germany in recent years. A dog with several relapses of Babesia canis infection after treatment with imidocarb is described. A 9-year-old male Magyar Viszla with B. canis infection was referred after two treatments with imidocarb (dosage 2.1 mg/kg SC) because of lethargy, fever and pancytopenia (additional treatments with prednisolone and doxycycline). Merozoites were detected in the blood smear and imidocarb treatment was repeated. Clinical signs, pancytopenia and a positive B. canis PCR occurred after the 3rd (6 mg/kg SC), 4th (7.7 mg/kg SC) and 5th (7.5 mg/kg SC and doxycycline for 4 weeks in addition) imidocarb injection and thorough tick prevention with isoxazoline and permethrin products. 12 days after the 5th injection, the PCR was negative for the first time. The dog was again presented with fever 35 days after the 5th injection. The B. canis PCR was positive and laboratory examination revealed pancytopenia. Treatment with atovaquone/azithromycin for 18 days was performed and no further relapse occurred for 32 weeks. In the case of suspected imidocarb resistance in B. canis infection, treatment with atovaquone/azithromycin can be an alternative.
Topics: Male; Dogs; Animals; Imidocarb; Babesia; Antiprotozoal Agents; Atovaquone; Doxycycline; Azithromycin; Pancytopenia; Babesiosis; Germany; Treatment Failure; Dog Diseases
PubMed: 38301344
DOI: 10.1016/j.ttbdis.2024.102315 -
Cureus Dec 2023Malaria is a highly infectious disease transmitted through the bite of the Anopheles mosquito carrying the parasite of the Plasmodium genus; it presents with cyclical...
Malaria is a highly infectious disease transmitted through the bite of the Anopheles mosquito carrying the parasite of the Plasmodium genus; it presents with cyclical fevers, myalgias, and headaches. In the United States, the vast majority of malaria cases are reported in people who travel abroad, mainly to Africa.These cases are predominantly linked to Plasmodium falciparum or ovale and can be medically treated with artemisinin, chloroquine, or atovaquone-proguanil. We discuss a case of a 38-year-old female immigrant from Venezuela living at an immigration facility who presented to a hospital located on the United States-Mexico border with a two-day history of watery diarrhea, headache, and subjective fever. She had experienced mosquito bites and likely contracted the illness in Chiapas, Mexico during her trek from Peru to the United States. Her case was unique as she tested positive for dengue fever antibodies acquired from a previous infection and also contracted rhinovirus during her clinical course. Her diagnosis of malaria was confirmed with a peripheral blood smear that revealed ring forms with no gametocytes. This in tandem with her route of travel suggested infection with Plasmodium vivax. She was treated with chloroquine while the malaria culture was pending and continued to spike fevers every 24-36 hours while on medication. Once the culture was confirmed, she was treated with atovaquone-proguanil as maintenance therapy. She was subsequently discharged on primaquine for 14 days to prevent relapse.
PubMed: 38293001
DOI: 10.7759/cureus.51400 -
The World Allergy Organization Journal Jan 2024Trimethoprim-sulfamethoxazole (TMP-SMX) is a broad spectrum antibiotic in use for more than 50 years. It has an important indication as first line agent in the... (Review)
Review
Trimethoprim-sulfamethoxazole (TMP-SMX) is a broad spectrum antibiotic in use for more than 50 years. It has an important indication as first line agent in the prophylaxis of opportunistic infections, particularly pneumonia (PJP), in immunosuppressed patients. For those who have a history of allergy or severe intolerance to TMP-SMX, pentamidine, dapsone or atovaquone may be substituted; however there is evidence that TMP-SMX offers superior coverage for PJP, toxoplasmosis, and nocardiosis. Compared to pentamidine, it has the added benefit of cost-effectiveness and self-administration as opposed to required hospital attendance for administration. Many patients who report a history of allergy or adverse reaction to TMP-SMX (or "sulfur allergy") will be found not to be allergic; and even those who are allergic may be able to be desensitized. The evaluation and, where appropriate, removal of TMP-SMX allergy label enables the use of TMP-SMX for prophylaxis against opportunistic infections. This is a cost-effective intervention to optimize antimicrobial prescribing and reduce the risk of opportunistic infections in immunosuppressed patients.
PubMed: 38235260
DOI: 10.1016/j.waojou.2023.100856 -
Cell Death & Disease Jan 2024Immune checkpoint blockade (ICB) provides effective and durable responses for several tumour types by unleashing an immune response directed against cancer cells....
Immune checkpoint blockade (ICB) provides effective and durable responses for several tumour types by unleashing an immune response directed against cancer cells. However, a substantial number of patients treated with ICB develop relapse or do not respond, which has been partly attributed to the immune-suppressive effect of tumour hypoxia. We have previously demonstrated that the mitochondrial complex III inhibitor atovaquone alleviates tumour hypoxia both in human xenografts and in cancer patients by decreasing oxygen consumption and consequently increasing oxygen availability in the tumour. Here, we show that atovaquone alleviates hypoxia and synergises with the ICB antibody anti-PD-L1, significantly improving the rates of tumour eradication in the syngeneic CT26 model of colorectal cancer. The synergistic effect between atovaquone and anti-PD-L1 relied on CD8+ T cells, resulted in the establishment of a tumour-specific memory immune response, and was not associated with any toxicity. We also tested atovaquone in combination with anti-PD-L1 in the LLC (lung) and MC38 (colorectal) cancer syngeneic models but, despite causing a considerable reduction in tumour hypoxia, atovaquone did not add any therapeutic benefit to ICB in these models. These results suggest that atovaquone has the potential to improve the outcomes of patients treated with ICB, but predictive biomarkers are required to identify individuals likely to benefit from this intervention.
Topics: Humans; Animals; Mice; Atovaquone; Electron Transport Complex III; Neoplasms; CD8-Positive T-Lymphocytes; Immunotherapy; B7-H1 Antigen; Tumor Microenvironment
PubMed: 38212297
DOI: 10.1038/s41419-023-06405-8 -
Nanoscale Advances Nov 2023Inherent barrier properties of the skin impose significant challenges to the transdermal delivery of drugs to systemic circulation. Here, the transdermal permeation and...
Inherent barrier properties of the skin impose significant challenges to the transdermal delivery of drugs to systemic circulation. Here, the transdermal permeation and deposition of an anti-malarial prophylactic atovaquone solid drug nanoformulation is radiometrically evaluated following application of a solid microneedle format.
PubMed: 38024306
DOI: 10.1039/d3na00454f -
Microbiology Spectrum Jan 2024This study is the first of its kind that suggests exosomes as a nano-carrier loaded with atovaquone (ATQ), which could be considered as a new strategy for improving the...
This study is the first of its kind that suggests exosomes as a nano-carrier loaded with atovaquone (ATQ), which could be considered as a new strategy for improving the effectiveness of ATQ against acute and chronic phases of .
Topics: Atovaquone; Toxoplasma; Exosomes; Macrophages
PubMed: 38014940
DOI: 10.1128/spectrum.03080-23