scholarly journals Azvudine is a thymus-homing anti-SARS-CoV-2 drug effective in treating COVID-19 patients

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Jin-Lan Zhang ◽  
Yu-Huan Li ◽  
Lu-Lu Wang ◽  
Hong-Qi Liu ◽  
Shuai-Yao Lu ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Rhesus Macaques ◽  
Discharge Rate ◽  
Active Form ◽  
Organ Damage ◽  
Phase Iii ◽  
Peripheral Blood Mononuclear ◽  
Phase Iii Trial ◽  
Chest X Ray ◽  
Negative Conversion

AbstractAzvudine (FNC) is a nucleoside analog that inhibits HIV-1 RNA-dependent RNA polymerase (RdRp). Recently, we discovered FNC an agent against SARS-CoV-2, and have taken it into Phase III trial for COVID-19 patients. FNC monophosphate analog inhibited SARS-CoV-2 and HCoV-OC43 coronavirus with an EC50 between 1.2 and 4.3 μM, depending on viruses or cells, and selective index (SI) in 15–83 range. Oral administration of FNC in rats revealed a substantial thymus-homing feature, with FNC triphosphate (the active form) concentrated in the thymus and peripheral blood mononuclear cells (PBMC). Treating SARS-CoV-2 infected rhesus macaques with FNC (0.07 mg/kg, qd, orally) reduced viral load, recuperated the thymus, improved lymphocyte profiles, alleviated inflammation and organ damage, and lessened ground-glass opacities in chest X-ray. Single-cell sequencing suggested the promotion of thymus function by FNC. A randomized, single-arm clinical trial of FNC on compassionate use (n = 31) showed that oral FNC (5 mg, qd) cured all COVID-19 patients, with 100% viral ribonucleic acid negative conversion in 3.29 ± 2.22 days (range: 1–9 days) and 100% hospital discharge rate in 9.00 ± 4.93 days (range: 2–25 days). The side-effect of FNC is minor and transient dizziness and nausea in 16.12% (5/31) patients. Thus, FNC might cure COVID-19 through its anti-SARS-CoV-2 activity concentrated in the thymus, followed by promoted immunity.

Capecitabine + epirubicin + cyclophosphamide (CEX) has comparable safety to 5-FU + epirubicin + cyclophosphamide (FEC) as neoadjuvant therapy in patients (pts) with operable breast cancer (BC): Early safety findings from a randomized phase III trial

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10655-10655
Author(s):  
H. Roché ◽  
R. Deporte ◽  
D. Berton-Rigaud ◽  
B. Coudert ◽  
N. Tubiana-Mathieu ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Early Stage ◽  
Operable Breast Cancer ◽  
Phase Iii ◽  
Peripheral Blood Mononuclear ◽  
Phase Iii Trial ◽  
Hand Foot Syndrome ◽  
Baseline Characteristics ◽  
Grade 3 ◽  
To Receive

10655 Background: FEC100 is an established regimen in early-stage BC. Substituting capecitabine (X) for 5-FU in the neoadjuvant setting is logical. Here we present interim safety findings from a phase III trial of CEX vs. FEC as neoadjuvant chemotherapy in operable BC. Methods: Between Mar 04 and Jan 05, 60/182 planned pts were randomized to receive CEX (X 900mg/m2 bid d1–14, epirubicin 100mg/m2 and cyclophosphamide 500mg/m2 d1) or FEC (short i.v. infusions of 5-FU 500mg/m2, epirubicin 100mg/m2 and cyclophosphamide 500mg/m2 d1), q3w x4. Surgery with lymph node dissection was performed <5 wks (±1 wk) after last course of treatment. The primary endpoint was pCR. All patients received 4 courses of docetaxel 100 mg/m2 d1 after surgery. All adverse events (AEs) were graded according to the NCI-CTC (v3.0) and the Hand-Foot Syndrome (HFS) classification. Peripheral blood mononuclear cells (PBMC) were evaluated for dihydropyrimidine deshydrogenase (DPD) deficiency. Results: Baseline characteristics in the CEX (n = 30) vs. FEC (n = 30) groups: median age (49.1 vs. 50.8 years); ER+/PR+ (60%/53% vs. 73%/37%). The median no. of cycles received was 4 in each group. The overall rate of AEs was very similar in the two groups, with no difference in grade 3/4 neutropenia. FEC was associated with more grade 3/4 nausea/vomiting (see table) . No evidence of PBMC DPD deficiency was observed. Conclusions: CEX and FEC are well tolerated in neoadjuvant BC. CEX offers the potential benefit of greater tumor exposure to 5-FU. Our findings also indicate that toxicity is not related to DPD activity. Recruitment is ongoing. [Table: see text] [Table: see text]

scholarly journals Integrated cytokine and metabolite analysis reveals immunometabolic reprogramming in COVID-19 patients with therapeutic implications

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Nan Xiao ◽  
Meng Nie ◽  
Huanhuan Pang ◽  
Bohong Wang ◽  
Jieli Hu ◽  
...  
Keyword(s):  
Proinflammatory Cytokines ◽  
Mononuclear Cells ◽  
Inflammatory Responses ◽  
Ex Vivo ◽  
Rhesus Macaques ◽  
Fatal Outcome ◽  
Organ Injury ◽  
Cytokine Release ◽  
Serum Samples ◽  
Peripheral Blood Mononuclear

AbstractCytokine release syndrome (CRS) is a major cause of the multi-organ injury and fatal outcome induced by SARS-CoV-2 infection in severe COVID-19 patients. Metabolism can modulate the immune responses against infectious diseases, yet our understanding remains limited on how host metabolism correlates with inflammatory responses and affects cytokine release in COVID-19 patients. Here we perform both metabolomics and cytokine/chemokine profiling on serum samples from healthy controls, mild and severe COVID-19 patients, and delineate their global metabolic and immune response landscape. Correlation analyses show tight associations between metabolites and proinflammatory cytokines/chemokines, such as IL-6, M-CSF, IL-1α, IL-1β, and imply a potential regulatory crosstalk between arginine, tryptophan, purine metabolism and hyperinflammation. Importantly, we also demonstrate that targeting metabolism markedly modulates the proinflammatory cytokines release by peripheral blood mononuclear cells isolated from SARS-CoV-2-infected rhesus macaques ex vivo, hinting that exploiting metabolic alterations may be a potential strategy for treating fatal CRS in COVID-19.

scholarly journals A sand fly salivary protein vaccine shows efficacy against vector-transmitted cutaneous leishmaniasis in nonhuman primates

2015 ◽  
Vol 7 (290) ◽  
pp. 290ra90-290ra90 ◽  
Author(s):  
Fabiano Oliveira ◽  
Edgar Rowton ◽  
Hamide Aslan ◽  
Regis Gomes ◽  
Philip A. Castrovinci ◽  
...  
Keyword(s):  
Cutaneous Leishmaniasis ◽  
Nonhuman Primates ◽  
Mononuclear Cells ◽  
Rhesus Macaques ◽  
Parasite Burden ◽  
Salivary Protein ◽  
Sand Fly ◽  
Protein Vaccine ◽  
Peripheral Blood Mononuclear ◽  
Phlebotomus Duboscqi

Currently, there are no commercially available human vaccines against leishmaniasis. In rodents, cellular immunity to salivary proteins of sand fly vectors is associated to protection against leishmaniasis, making them worthy targets for further exploration as vaccines. We demonstrate that nonhuman primates (NHP) exposed to Phlebotomus duboscqi uninfected sand fly bites or immunized with salivary protein PdSP15 are protected against cutaneous leishmaniasis initiated by infected bites. Uninfected sand fly–exposed and 7 of 10 PdSP15-immunized rhesus macaques displayed a significant reduction in disease and parasite burden compared to controls. Protection correlated to the early appearance of Leishmania-specific CD4+IFN-γ+ lymphocytes, suggesting that immunity to saliva or PdSP15 augments the host immune response to the parasites while maintaining minimal pathology. Notably, the 30% unprotected PdSP15-immunized NHP developed neither immunity to PdSP15 nor an accelerated Leishmania-specific immunity. Sera and peripheral blood mononuclear cells from individuals naturally exposed to P. duboscqi bites recognized PdSP15, demonstrating its immunogenicity in humans. PdSP15 sequence and structure show no homology to mammalian proteins, further demonstrating its potential as a component of a vaccine for human leishmaniasis.

Abstract MP44: A Novel And 2 Known Differentially Expressed MicroRNAs Were Identified In Peripheral Blood Mononuclear Cells Of Patients With Hypertension Associated With Metabolic Syndrome

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Olga Berillo ◽  
Kugeng Huo ◽  
Julio C Fraulob-Aquino ◽  
Chantal Richer ◽  
Na Li ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Peripheral Blood Mononuclear Cells ◽  
Immune Cells ◽  
Mononuclear Cells ◽  
Target Organ Damage ◽  
Organ Damage ◽  
Target Organ ◽  
Rna Seq ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells

Background: Hypertension (HTN) is associated with subclinical target organ damage including cardiac, vascular and kidney injury. The immune system plays a role in hypertension and target organ damage. Activation of T cells has been reported among peripheral blood mononuclear cells (PBMCs) of patients with HTN. MicroRNAs (miRNAs) are crucial post-transcriptional regulators of immune cells. Whether miRNAs play a role in the activation of immune cells in hypertension complicated by target organ damage in humans remains unknown. We aimed to address this question by identifying differentially expressed (DE) miRNAs and their mRNA targets in PBMCs of patients with hypertension complicated or not with metabolic syndrome (MetS) or chronic kidney disease (CKD). Methods: Normotensive subjects and patients with hypertension (HTN) associated or not with at least 2 other features of MetS or CKD were studied (n=15-16). PBMCs were isolated from blood, RNA extracted for small and total RNA sequencing (RNA-seq) using Illumina HiSeq-2500 and data were analyzed using a systems biology approach. MiRDeep2 was used for novel miRNAs prediction, miRNA annotation and counting. TargetScan 7.07 was used to predict DE miRNA targets with weighted context score percentile >50%. DE genes miRNAs and mRNAs were identified with fold change (FC) >1.5 and P <0.005. DE miRNAs with FC>2 and mean read count number (MRCM) >500, and with predicted targets with MRCM>300 were validated by reverse transcription-quantitative PCR (RT-qPCR). Results: DE miRNAs, mRNAs and non-coding RNAs were identified in HTN (22, 19 and 0), MetS (57, 401 and 11) and CKD (6, 26 and 2) compared to NTN. TargetScan predicted that 7 miRNAs target 3 mRNAs in NTN, 57 miRNAs target 55 mRNAs in MetS and 3 miRNAs target 2 mRNAs in CKD. DE miR-409-5p (FC: 0.54±0.10 vs 1.00±0.09, P <0.05), miR-411-5p (FC: 0.40±0.06, vs 1.00±0.11, P <0.001) and the novel miR-pl-86 (FC: 1.96±0.17 vs 1.00±0.15, P <0.05) in MetS vs NTN were validated by RT-qPCR. RNA-seq data were correlated with RT-qPCR for miR-409-5p (R 2 =0.40, P <2.4E-07, n=55), miR-411-5p (R 2 =0.55, P <1.1E-10, n=55), miR-pl-86 (R 2 =0.37, P <5.5E-07, n=56). Conclusion: This study showed that DE miR-409-5p, miR-411-5p and miR-pl-86 may play a role in HTN associated with MetS.

scholarly journals Simian Immunodeficiency Virus SIVagm Efficiently Utilizes Non-CCR5 Entry Pathways in African Green Monkey Lymphocytes: Potential Role for GPR15 and CXCR6 as Viral Coreceptors

2015 ◽  
Vol 90 (5) ◽  
pp. 2316-2331 ◽  
Author(s):  
Nadeene E. Riddick ◽  
Fan Wu ◽  
Kenta Matsuda ◽  
Sonya Whitted ◽  
Ilnour Ourmanov ◽  
...  
Keyword(s):  
T Cells ◽  
Mononuclear Cells ◽  
Rhesus Macaques ◽  
Target Cells ◽  
Peripheral Blood Mononuclear ◽  
Immunodeficiency Virus ◽  
Sooty Mangabeys ◽  
Natural Hosts

ABSTRACTAfrican green monkeys (AGM) are natural hosts of simian immunodeficiency virus (SIV), and infection in these animals is generally nonpathogenic, whereas infection of nonnatural hosts, such as rhesus macaques (RM), is commonly pathogenic. CCR5 has been described as the primary entry coreceptor for SIVin vivo, while human-derived CXCR6 and GPR15 also appear to be usedin vitro. However, sooty mangabeys that are genetically deficient in CCR5 due to an out-of-frame deletion are infectible with SIVsmm, indicating that SIVsmm can use alternative coreceptorsin vivo. In this study, we examined the CCR5 dependence of SIV strains derived from vervet AGM (SIVagmVer) and the ability of AGM-derived GPR15 and CXCR6 to serve as potential entry coreceptors. We found that SIVagmVer replicated efficiently in AGM and RM peripheral blood mononuclear cells (PBMC) in the presence of the CCR5 antagonist maraviroc, despite the fact that maraviroc was capable of blocking the CCR5-tropic strains SIVmac239, SIVsmE543-3, and simian-human immunodeficiency virus SHIV-AD8 in RM PBMC. We also found that AGM CXCR6 and AGM GPR15, to a lesser extent, supported entry of pseudotype viruses bearing SIVagm envelopes, including SIVagm transmitted/founder envelopes. Lastly, we found that CCR5, GPR15, and CXCR6 mRNAs were detected in AGM and RM memory CD4+T cells. These results suggest that GPR15 and CXCR6 are expressed on AGM CD4+T cells and are potential alternative coreceptors for SIVagm usein vivo. These data suggest that the use of non-CCR5 entry pathways may be a common feature of SIV replication in natural host species, with the potential to contribute to nonpathogenicity in these animals.IMPORTANCEAfrican green monkeys (AGM) are natural hosts of SIV, and infection in these animals generally does not cause AIDS, whereas SIV-infected rhesus macaques (RM) typically develop AIDS. Although it has been reported that SIV generally uses CD4 and CCR5 to enter target cellsin vivo, other molecules, such as GPR15 and CXCR6, also function as SIV coreceptorsin vitro. In this study, we investigated whether SIV from vervet AGM can use non-CCR5 entry pathways, as has been observed in sooty mangabeys. We found that SIVagmVer efficiently replicated in AGM and RM peripheral blood mononuclear cells in the presence of the CCR5 antagonist maraviroc, suggesting that non-CCR5 entry pathways can support SIVagm entry. We found that AGM-derived GPR15 and CXCR6 support SIVagmVer entryin vitroand may serve as entry coreceptors for SIVagmin vivo, since their mRNAs were detected in AGM memory CD4+T cells, the preferred target cells of SIV.

scholarly journals Infection of cynomolgus macaques (Macaca fascicularis) and rhesus macaques (Macaca mulatta) with different wild-type measles viruses

2007 ◽  
Vol 88 (7) ◽  
pp. 2028-2034 ◽  
Author(s):  
H. Sittana El Mubarak ◽  
Selma Yüksel ◽  
Geert van Amerongen ◽  
Paul G. H. Mulder ◽  
Maowia M. Mukhtar ◽  
...  
Keyword(s):  
Measles Virus ◽  
Mononuclear Cells ◽  
Rhesus Macaques ◽  
Wild Type ◽  
Immunological Parameters ◽  
Peripheral Blood Mononuclear ◽  
Cynomolgus Monkeys ◽  
Cynomolgus Macaques ◽  
Measles Vaccination ◽  
Kinetics Of

Both rhesus and cynomolgus macaques have been used as animal models for measles vaccination and immunopathogenesis studies. A number of studies have suggested that experimental measles virus (MV) infection induces more-characteristic clinical features in rhesus than in cynomolgus monkeys. In the present study, both macaque species were infected with two different wild-type MV strains and clinical, virological and immunological parameters were compared. The viruses used were a genotype C2 virus isolated in The Netherlands in 1991 (MV-Bil) and a genotype B3 virus isolated from a severe measles case in Sudan in 1997 (MV-Sudan). Following infection, all rhesus monkeys developed a skin rash and conjunctivitis, which were less obvious in cynomolgus monkeys. Fever was either mild or absent in both species. Virus reisolation profiles from peripheral blood mononuclear cells and broncho-alveolar lavage cells and the kinetics of MV-specific IgM and IgG responses were largely identical in the two animal species. However, in animals infected with MV-Sudan, viraemia appeared earlier and lasted longer than in animals infected with MV-Bil. This was also reflected by the earlier appearance of MV-specific serum IgM antibodies after infection with MV-Sudan. Collectively, these data show that cynomolgus and rhesus macaques are equally susceptible to wild-type MV infection, although infection in the skin seems to follow a different course in rhesus macaques. MV-Sudan proved more pathogenic for non-human primates than MV-Bil, which may render it more suitable for use in future pathogenesis studies.

scholarly journals Changes in Human Immunodeficiency Virus Type 1 Envelope Glycoproteins Responsible for the Pathogenicity of a Multiply Passaged Simian-Human Immunodeficiency Virus (SHIV-HXBc2)

1999 ◽  
Vol 73 (2) ◽  
pp. 976-984 ◽  
Author(s):  
Mark Cayabyab ◽  
Gunilla B. Karlsson ◽  
Bijan A. Etemad-Moghadam ◽  
Wolfgang Hofmann ◽  
Tavis Steenbeke ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Lymphocyte ◽  
Mononuclear Cells ◽  
Rhesus Macaques ◽  
Envelope Glycoproteins ◽  
Peripheral Blood Mononuclear ◽  
Lymphocyte Depletion ◽  
Immunodeficiency Virus

ABSTRACT In vivo passage of a poorly replicating, nonpathogenic simian-human immunodeficiency virus (SHIV-HXBc2) generated an efficiently replicating virus, KU-1, that caused rapid CD4+T-lymphocyte depletion and AIDS-like illness in monkeys (S. V. Joag, Z. Li, L. Foresman, E. B. Stephens, L.-J. Zhao, I. Adany, D. M. Pinson, H. M. McClure, and O. Narayan, J. Virol. 70:3189–3197, 1996). The env gene of the KU-1 virus was used to create a molecularly cloned virus, SHIV-HXBc2P 3.2, that differed from a nonpathogenic SHIV-HXBc2 virus in only 12 envelope glycoprotein residues. SHIV-HXBc2P 3.2 replicated efficiently and caused rapid and persistent CD4+ T-lymphocyte depletion in inoculated rhesus macaques. Compared with the envelope glycoproteins of the parental SHIV-HXBc2, the SHIV-HXBc2P 3.2 envelope glycoproteins supported more efficient infection of rhesus monkey peripheral blood mononuclear cells. Both the parental SHIV-HXBc2 and the pathogenic SHIV-HXBc2P 3.2 used CXCR4 but none of the other seven transmembrane segment receptors tested as a second receptor. Compared with the parental virus, viruses with the SHIV-HXBc2P 3.2 envelope glycoproteins were more resistant to neutralization by soluble CD4 and antibodies. Thus, changes in the envelope glycoproteins account for the ability of the passaged virus to deplete CD4+ T lymphocytes rapidly and specify increased replicative capacity and resistance to neutralization.

scholarly journals Vitamin D Treatment Sequence Is Critical for Transcriptome Modulation of Immune Challenged Primary Human Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Henna-Riikka Malmberg ◽  
Andrea Hanel ◽  
Mari Taipale ◽  
Sami Heikkinen ◽  
Carsten Carlberg
Keyword(s):  
Vitamin D ◽  
Mononuclear Cells ◽  
Fungal Infections ◽  
Human Peripheral Blood ◽  
Active Form ◽  
Biologically Active ◽  
Treatment Sequence ◽  
Peripheral Blood Mononuclear ◽  
Lps Challenge ◽  
Immune Challenges

Microbe-associated molecular patterns, such as lipopolysaccharide (LPS) and β-glucan (BG), are surrogates of immune challenges like bacterial and fungal infections, respectively. The biologically active form of vitamin D, 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3), supports the immune system in its fight against infections. This study investigated significant and prominent changes of the transcriptome of human peripheral blood mononuclear cells that immediately after isolation are exposed to 1,25(OH)2D3-modulated immune challenges over a time frame of 24-48 h. In this in vitro study design, most LPS and BG responsive genes are downregulated and their counts are drastically reduced when cells are treated 24 h after, 24 h before or in parallel with 1,25(OH)2D3. Interestingly, only a 1,25(OH)2D3 pre-treatment of the LPS challenge results in a majority of upregulated genes. Based on transcriptome-wide data both immune challenges display characteristic differences in responsive genes and their associated pathways, to which the actions of 1,25(OH)2D3 often oppose. The joined BG/1,25(OH)2D3 response is less sensitive to treatment sequence than that of LPS/1,25(OH)2D3. In conclusion, the functional consequences of immune challenges are significantly modulated by 1,25(OH)2D3 but largely depend on treatment sequence. This may suggest that a sufficient vitamin D status before an infection is more important than vitamin D supplementation afterwards.

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