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High concentrations of Maraviroc do not alter immunological and metabolic parameters of CD4 T cells.Scientific Reports Jun 2024Maraviroc (MVC) is an antiretroviral drug capable of binding to CCR5 receptors and block HIV entry into target cells. Moreover, MVC can activate NF-kB pathway and induce...
Maraviroc (MVC) is an antiretroviral drug capable of binding to CCR5 receptors and block HIV entry into target cells. Moreover, MVC can activate NF-kB pathway and induce viral transcription in HIV-infected cells, being proposed as a latency reversal agent (LRA) in HIV cure strategies. However, the evaluation of immunological and metabolic parameters induced by MVC concentrations capable of inducing HIV transcription have not been explored in depth. We cultured isolated CD4 T cells in the absence or presence of MVC, and evaluated the frequency of CD4 T cell subpopulations and activation markers levels by flow cytometry, and the oxidative and glycolytic metabolic rates of CD4 T cells using a Seahorse Analyzer. Our results indicate that a high concentration of MVC did not increase the levels of activation markers, as well as glycolytic or oxidative metabolic rates in CD4 T cells. Furthermore, MVC did not induce significant changes in the frequency and activation levels of memory cell subpopulations. Our data support a safety profile of MVC as a promising LRA candidate since it does not induce alterations of the immunological and metabolic parameters that could affect the functionality of these immune cells.
Topics: Maraviroc; CD4-Positive T-Lymphocytes; Humans; Glycolysis; HIV Infections; Cells, Cultured; Triazoles; HIV-1; Lymphocyte Activation; Male; CCR5 Receptor Antagonists; Cyclohexanes; Adult
PubMed: 38886484
DOI: 10.1038/s41598-024-64902-y -
Oncogene May 2024Approximately 40% of patients with lung adenocarcinoma (LUAD) often develop bone metastases during the course of their disease. However, scarcely any in vivo model of...
Approximately 40% of patients with lung adenocarcinoma (LUAD) often develop bone metastases during the course of their disease. However, scarcely any in vivo model of LUAD bone metastasis has been established, leading to a poor understanding of the mechanisms underlying LUAD bone metastasis. Here, we established a multiorgan metastasis model via the left ventricular injection of luciferase-labeled LUAD cells into nude mice and then screened out lung metastasis (LuM) and bone metastasis (BoM) cell subpopulations. BoM cells exhibited greater stemness and epithelial-mesenchymal transition (EMT) plasticity than LuM cells and initially colonized the bone and subsequently disseminated to distant organs after being reinjected into mice. Moreover, a CD74-ROS1 fusion mutation (C6; R34) was detected in BoM cells but not in LuM cells. Mechanistically, BoM cells bearing the CD74-ROS1 fusion highly secrete the C-C motif chemokine ligand 5 (CCL5) protein by activating STAT3 signaling, recruiting macrophages in tumor microenvironment and strongly inducing M2 polarization of macrophages. BoM cell-activated macrophages produce a high level of TGF-β1, thereby facilitating EMT and invasion of LUAD cells via TGF-β/SMAD2/3 signaling. Targeting the CD74-ROS1/CCL5 axis with Crizotinib (a ROS1 inhibitor) and Maraviroc (a CCL5 receptor inhibitor) in vivo strongly impeded bone metastasis and secondary metastasis of BoM cells. Our findings reveal the critical role of the CD74-ROS1/STAT3/CCL5 axis in the interaction between LUAD bone metastasis cells and macrophages for controlling LUAD cell dissemination, highlighting the significance of the bone microenvironment in LUAD bone metastasis and multiorgan secondary metastasis, and suggesting that targeting CD74-ROS1 and CCL5 is a promising therapeutic strategy for LUAD bone metastasis.
PubMed: 38802647
DOI: 10.1038/s41388-024-03072-7 -
International Immunopharmacology Jun 2024CCR5 may be involved in the pathogenesis of asthma; however, the underlying mechanisms remain unclear. In comparison with a mild asthma model, subepithelial fibrosis was...
CCR5 may be involved in the pathogenesis of asthma; however, the underlying mechanisms remain unclear. In comparison with a mild asthma model, subepithelial fibrosis was more severe and CCR5 gene expression in the lungs was significantly higher in our recently developed murine model of steroid-resistant severe asthma. Treatment with the CCR5 antagonist, maraviroc, significantly suppressed the development of subepithelial fibrosis in bronchi, whereas dexamethasone did not. On the other hand, increases in leukocytes related to type 2 inflammation, eosinophils, Th2 cells, and group 2 innate lymphoid cells in the lungs were not affected by the treatment with maraviroc. Increases in neutrophils and total macrophages were also not affected by the CCR5 antagonist. However, increases in transforming growth factor (TGF)-β-producing interstitial macrophages (IMs) were significantly reduced by maraviroc. The present results confirmed increases in CCR5-expressing IMs in the lungs of the severe asthma model. In conclusion, CCR5 on IMs plays significant roles in the development of subepithelial fibrosis in severe asthma through TGF-β production in the lungs.
Topics: Animals; Asthma; Receptors, CCR5; Maraviroc; CCR5 Receptor Antagonists; Macrophages; Transforming Growth Factor beta; Pulmonary Fibrosis; Mice; Lung; Mice, Inbred BALB C; Disease Models, Animal; Humans; Female
PubMed: 38795597
DOI: 10.1016/j.intimp.2024.112331 -
BMC Neurology Jun 2024Post-stroke depression (PSD) is a significant impediment to successful rehabilitation and recovery after a stroke. Current therapeutic options are limited, leaving an... (Clinical Trial)
Clinical Trial
BACKGROUND
Post-stroke depression (PSD) is a significant impediment to successful rehabilitation and recovery after a stroke. Current therapeutic options are limited, leaving an unmet demand for specific and effective therapeutic options. Our objective was to investigate the safety of Maraviroc, a CCR5 antagonist, as a possible mechanism-based add-on therapeutic option for PSD in an open-label proof-of-concept clinical trial.
METHODS
We conducted a 10-week clinical trial in which ten patients with subcortical and cortical stroke, suffering from PSD. were administered a daily oral dose of 300 mg Maraviroc. Participants were then monitored for an additional eight weeks. The primary outcome measure was serious treatment-emergent adverse events (TEAEs) and TEAEs leading to discontinuation. The secondary outcome measure was a change in the Montgomery-Asberg Depression Rating Scale (MADRS).
RESULTS
Maraviroc was well tolerated, with no reports of serious adverse events or discontinuations due to intolerance. The MADRS scores substantially reduced from baseline to week 10 (mean change: -16.4 ± 9.3; p < 0.001). By the conclusion of the treatment phase, a favorable response was observed in five patients, with four achieving remission. The time to response was relatively short, approximately three weeks. After the cessation of treatment, MADRS scores increased at week 18 by 6.1 ± 9.6 points (p = 0.014).
CONCLUSIONS
Our proof-of-concept study suggests that a daily dosage of 300 mg of Maraviroc may represent a well-tolerated and potentially effective pharmacological approach to treating PSD. Further comprehensive placebo-controlled studies are needed to assess the impact of Maraviroc augmentation on PSD.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT05932550, Retrospectively registered: 28/06/2023.
Topics: Humans; Maraviroc; Male; Female; Middle Aged; CCR5 Receptor Antagonists; Proof of Concept Study; Stroke; Aged; Depression; Treatment Outcome; Triazoles; Adult; Receptors, CCR5
PubMed: 38844862
DOI: 10.1186/s12883-024-03683-3 -
AIDS (London, England) Nov 2023Chemokine receptor CCR5 is the principal co-receptor for entry of M-tropic HIV virus into immune cells. It is expressed in the central nervous system and may contribute... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
Chemokine receptor CCR5 is the principal co-receptor for entry of M-tropic HIV virus into immune cells. It is expressed in the central nervous system and may contribute to neuro-inflammation. The CCR5 antagonist maraviroc (MVC) has been suggested to improve HIV-associated neurocognitive impairment (NCI).
DESIGN
A double-blind, placebo-controlled, 48-week, randomized study of MVC vs. placebo in people with HIV (PWH) on stable antiretroviral therapy (ART) for more than one year in Hawaii and Puerto Rico with plasma HIV RNA less than 50 copies/ml and at least mild NCI defined as an overall or domain-specific neuropsychological z (NPZ) score less than -0.5.
METHODS
Study participants were randomized 2 : 1 to intensification of ART with MVC vs. placebo. The primary endpoint was change in global and domain-specific NPZ modeled from study entry to week 48. Covariate adjusted treatment comparisons of average changes in cognitive outcome were performed using winsorized NPZ data. Monocyte subset frequencies and chemokine expression as well as plasma biomarker levels were assessed.
RESULTS
Forty-nine participants were enrolled with 32 individuals randomized to MVC intensification and 17 to placebo. At baseline, worse NPZ scores were seen in the MVC arm. Comparison of 48-week NPZ change by arm revealed no differences except for a modest improvement in the Learning and Memory domain in the MVC arm, which did not survive multiplicity correction. No significant changes between arms were seen in immunologic parameters.
CONCLUSION
This randomized controlled study found no definitive evidence in favor of MVC intensification among PWH with mild cognitive difficulties.
Topics: Humans; Maraviroc; HIV Infections; Cyclohexanes; Triazoles; Antiretroviral Therapy, Highly Active
PubMed: 37418541
DOI: 10.1097/QAD.0000000000003650 -
Frontiers in Medicine 2024[This corrects the article DOI: 10.3389/fmed.2023.1122529.].
[This corrects the article DOI: 10.3389/fmed.2023.1122529.].
PubMed: 38813382
DOI: 10.3389/fmed.2024.1375607 -
Self-start HIV postexposure prophylaxis (PEPSE), to reduce time to first dose and increase efficacy.Sexually Transmitted Infections Aug 2023Effectiveness of HIV postexposure prophylaxis (PEPSE) correlates with speed of uptake following HIV exposure. Time to first dose has not improved in the UK for over 10... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Effectiveness of HIV postexposure prophylaxis (PEPSE) correlates with speed of uptake following HIV exposure. Time to first dose has not improved in the UK for over 10 years. On-demand pre-exposure prophylaxis (PrEP) has shown that people can self-start medication for HIV prevention.We hypothesised that advanced provision of PEPSE (HOME PEPSE) for men who have sex with men (MSM) to self- initiate would reduce time to first dose following HIV exposure.
METHODS
Phase IV, randomised, prospective, 48-week, open-label study was carried out. MSM at medium risk of acquiring HIV were randomised (1:1) to immediate or deferred standard of care (SOC) HOME PEPSE. Every 12 weeks, participants self-completed mental health/risk behaviour surveys and had HIV/sexually transmitted infection (STI) testing.HOME PEPSE comprised a 5-day pack of emtricitabine/tenofovir disoproxil fumarate/maraviroc 600 mg once daily initiated following potential exposure to HIV. If taken, participants completed a risk survey; PEPSE continuation was physician directed. Primary outcome was time from potential exposure to HIV to first PEPSE dose.
FINDINGS
139 participants randomised 1:1; 69 to immediate HOME PEPSE and 70 to deferred HOME PEPSE. Median age 30 years (IQR 26-39), 75% white, 55% UK born and 72% university educated. 31 in HOME PEPSE and 15 in SOC arm initiated PEPSE. Uptake of HOME PEPSE was appropriate in 27/31 cases (87%, 95% CI: 71% to 95%). Median time from exposure to first dose was 7.3 hours (3.0, 20.9) for HOME PEPSE and 28.5 hours (17.3, 34.0) for SOC (p<0.01). HOME PEPSE was well tolerated with no discontinuations.No significant differences in missed opportunities for PEPSE uptake, sexual behaviour or bacterial STI infections between treatment arms.
INTERPRETATION
HOME PEPSE reduced the time from exposure to first-dose PEPSE by 21+ hours, with no impact on safety. This significantly improves the efficacy of PEPSE and provides an option for people declining PrEP.
Topics: Male; Humans; Adult; Homosexuality, Male; HIV Infections; Prospective Studies; Sexual and Gender Minorities; Sexually Transmitted Diseases; Pre-Exposure Prophylaxis; Anti-HIV Agents; Emtricitabine; Post-Exposure Prophylaxis
PubMed: 36564186
DOI: 10.1136/sextrans-2022-055622 -
Journal of Biomolecular Structure &... Jan 2024The aldehyde dehydrogenase 1A1 (ALDH1A1) also known as retinal dehydrogenase, is an enzyme normally involved in the cellular metabolism, development and detoxification...
The aldehyde dehydrogenase 1A1 (ALDH1A1) also known as retinal dehydrogenase, is an enzyme normally involved in the cellular metabolism, development and detoxification processes in healthy cells. However, it's also considered a cancer stem cell marker and its high levels of expression in several cancers, including breast, lung, ovarian, and colon cancer have been associated with poor prognosis and resistance to chemotherapy. Given its crucial role in chemotherapy resistance by detoxification of chemotherapeutic drugs, ALDH1A1 has attracted significant research interest as a potential therapeutic target for cancer. Though a few synthetic inhibitors of ALDH1A1 have been synthesized and their efficacy has been proved in-vitro and in-vivo studies, none of them have passed clinical trials so far. In this scenario, we have performed an in-silico study to verify whether any of the already approved drugs used for various purposes has the ability to inhibit catalytic activity of ALDH1A1, so that they can be repurposed for cancer therapy. Keeping in mind the feasibility of repurposing in a larger population we have selected the approved drugs from five widely used drug categories such as antibiotic, antiviral, antifungal, anti diabetic and antihypertensive for screening. Computational techniques like molecular docking, molecular dynamics simulations and MM-PBSA binding energy calculation have been used in this study to screen the approved drugs. Based on the logical analysis of results, we propose that three drugs - telmisartan, irbesartan and maraviroc can inhibit the catalytic activity of ALDH1A1 and thus can be repurposed to increase chemotherapy sensitivity in cancer cells.Communicated by Ramaswamy H. Sarma.
PubMed: 38189344
DOI: 10.1080/07391102.2023.2300127 -
Organic Process Research & Development May 2024A simple and benign continuous flow oxidation protocol for the selective conversion of primary and secondary alcohols into their respective aldehyde and ketone products...
A simple and benign continuous flow oxidation protocol for the selective conversion of primary and secondary alcohols into their respective aldehyde and ketone products is reported. This approach makes use of catalytic amounts of TEMPO in combination with sodium bromide and sodium hypochlorite in a biphasic solvent system. A variety of substrates are tolerated including those containing heterocycles based on potentially sensitive nitrogen and sulfur moieties. The flow approach can be coupled with inline reactive extraction by formation of the carbonyl-bisulfite adduct which aids in separation of remaining substrate or other impurities. Process robustness is evaluated for the preparation of phenylpropanal at decagram scale, a trifluoromethylated oxazole building block as well as a late-stage intermediate for the anti-HIV drug maraviroc which demonstrates the potential value of this continuous oxidation method.
PubMed: 38783858
DOI: 10.1021/acs.oprd.3c00237 -
Journal of Neurovirology May 2024Progressive multifocal leukoencephalopathy (PML) is an opportunistic infectious demyelinating disease of the central nervous system caused by JC polyomavirus...
Progressive multifocal leukoencephalopathy (PML) is an opportunistic infectious demyelinating disease of the central nervous system caused by JC polyomavirus predominantly affecting immunocompromised individuals. Nowadays, HIV, hematological malignancies and iatrogenic immune suppression account for most PML cases. For unknown reasons, spinal cord is classically protected from PML lesions. Here, we report the course of a patient harboring spinal cord lesions in the context of PML with immune reconstitution inflammatory syndrome and review the eight other cases reported in the literature so far. Then, we discuss the evolving spectrum of PML over recent years, potentially making its diagnosis more challenging.
PubMed: 38778006
DOI: 10.1007/s13365-024-01213-y