BMC Complement Med Ther. 2021 Jan 13;21(1):31
Authors: Krepkova LV, Bortnikova VV, Babenko AN, Mizina PG, Mkhitarov VA, Job KM, Sherwin CM, Enioutina EY
Abstract
BACKGROUND: The dysfunction of the thyroid gland is a common medical condition. Nowadays, patients frequently use medicinal herbs as complementary or alternative options to conventional drug treatments. These patients may benefit from treatment of thyroid dysfunctions with Potentilla alba L. preparations. While it has been reported that Potentilla alba preparations have low toxicity, nothing is known about their ability to affect reproductive functions in patients of childbearing age.
METHODS: Male Wistar rats were orally treated with a thyrotrophic botanical drug, standardized Potentilla alba Dry Extract (PADE), at doses 8 and 40 times higher than the median therapeutic dose recommended for the clinical trials, for 60 consecutive days. Male Wistar rats receiving water (H2O) were used as controls. After completing treatment, half of the PADE-treated and control males were used to determine PADE gonadotoxicity, and the remaining half of PADE-treated and control males were mated with intact females. Two female rats were housed with one male for two estrus cycles. PADE effects on fertility and fetal/offspring development were evaluated.
RESULTS: Herein, we report that oral treatment of male Wistar rats with PADE before mating with intact females instigated marked effects on male reproductive organs. Treatment significantly decreased the motility of the sperm and increased the number of pathological forms of spermatozoa. Additionally, a dose-dependent effect on Leydig cells was observed. However, these PADE effects did not significantly affect male fertility nor fetal and offspring development when PADE-treated males were mated with intact females.
CONCLUSIONS: PADE treatment of male rates negatively affected sperm and testicular Leydig cell morphology. However, these changes did not affect male fertility and offspring development. It is currently not known whether PADE treatment may affect human male fertility and offspring development. Therefore, these results from an animal study need to be confirmed in humans. Results from this animal study can be used to model the exposure-response relationship and adverse outcomes in humans.
PMID: 33441114 [PubMed - in process]
Virol J. 2021 01 04;18(1):1
Authors: Zheng Y, Larragoite ET, Williams ESCP, Lama J, Cisneros I, Delgado JC, Slev P, Rychert J, Innis EA, Coiras M, Rondina MT, Spivak AM, Planelles V
Abstract
BACKGROUND: Virus neutralization by antibodies is an important prognostic factor in many viral diseases. To easily and rapidly measure titers of neutralizing antibodies in serum or plasma, we developed pseudovirion particles composed of the spike glycoprotein of SARS-CoV-2 incorporated onto murine leukemia virus capsids and a modified minimal murine leukemia virus genome encoding firefly luciferase. This assay design is intended for use in laboratories with biocontainment level 2 and therefore circumvents the need for the biocontainment level 3 that would be required for replication-competent SARS-CoV-2 virus. To validate the pseudovirion assay, we set up comparisons with other available antibody tests including those from Abbott, Euroimmun and Siemens, using archived, known samples.
RESULTS: 11 out of 12 SARS-CoV-2-infected patient serum samples showed neutralizing activity against SARS-CoV-2-spike pseudotyped MLV viruses, with neutralizing titers-50 (NT50) that ranged from 1:25 to 1:1,417. Five historical samples from patients hospitalized for severe influenza infection in 2016 tested negative in the neutralization assay (NT50 < 25). Three serum samples with high neutralizing activity against SARS-CoV-2/MLV pseudoviruses showed no detectable neutralizing activity (NT50 < 25) against SARS-CoV-1/MLV pseudovirions. We also compared the semiquantitative Siemens SARS-CoV-2 IgG test, which measures binding of IgG to recombinantly expressed receptor binding domain of SARS-CoV-2 spike glycoprotein with the neutralization titers obtained in the pseudovirion assay and the results show high concordance between the two tests (R2 = 0.9344).
CONCLUSIONS: SARS-CoV-2 spike/MLV pseudovirions provide a practical means of assessing neutralizing activity of antibodies in serum or plasma from infected patients under laboratory conditions consistent with biocontainment level 2. This assay offers promise also in evaluating immunogenicity of spike glycoprotein-based candidate vaccines in the near future.
PMID: 33397387 [PubMed - indexed for MEDLINE]
Br J Nutr. 2020 05 28;123(10):1187-1200
Authors: Kiblawi R, Holowatyj AN, Gigic B, Brezina S, Geijsen AJMR, Ose J, Lin T, Hardikar S, Himbert C, Warby CA, Böhm J, Bours MJL, van Duijnhoven FJB, Gumpenberger T, Kok DE, Koole JL, van Roekel EH, Schrotz-King P, Ulvik A, Gsur A, Habermann N, Weijenberg MP, Ueland PM, Schneider M, Ulrich A, Ulrich CM, Playdon M
Abstract
B vitamins involved in one-carbon metabolism have been implicated in the development of inflammation- and angiogenesis-related chronic diseases, such as colorectal cancer (CRC). Yet, the role of one-carbon metabolism in inflammation and angiogenesis among CRC patients remains unclear. The objective of this study was to investigate associations of components of one-carbon metabolism with inflammation and angiogenesis biomarkers among newly diagnosed CRC patients (n 238) in the prospective ColoCare Study, Heidelberg. We cross-sectionally analysed associations between twelve B vitamins and one-carbon metabolites and ten inflammation and angiogenesis biomarkers from pre-surgery serum samples using multivariable linear regression models. We further explored associations among novel biomarkers in these pathways with Spearman partial correlation analyses. We hypothesised that pyridoxal-5'-phosphate (PLP) is inversely associated with inflammatory biomarkers. We observed that PLP was inversely associated with C-reactive protein (CRP) (r -0·33, Plinear < 0·0001), serum amyloid A (SAA) (r -0·23, Plinear = 0·003), IL-6 (r -0·39, Plinear < 0·0001), IL-8 (r -0·20, Plinear = 0·02) and TNFα (r -0·12, Plinear = 0·045). Similar findings were observed for 5-methyl-tetrahydrofolate and CRP (r -0·14), SAA (r -0·14) and TNFα (r -0·15) among CRC patients. Folate catabolite acetyl-para-aminobenzoylglutamic acid (pABG) was positively correlated with IL-6 (r 0·27, Plinear < 0·0001), and pABG was positively correlated with IL-8 (r 0·21, Plinear < 0·0001), indicating higher folate utilisation during inflammation. Our data support the hypothesis of inverse associations between PLP and inflammatory biomarkers among CRC patients. A better understanding of the role and inter-relation of PLP and other one-carbon metabolites with inflammatory processes among colorectal carcinogenesis and prognosis could identify targets for future dietary guidance for CRC patients.
PMID: 32019627 [PubMed - indexed for MEDLINE]
J Natl Cancer Inst. 2020 06 01;112(6):617-627
Authors: Andreou T, Rippaus N, Wronski K, Williams J, Taggart D, Cherqui S, Sunderland A, Kartika YD, Egnuni T, Brownlie RJ, Mathew RK, Holmen SL, Fife C, Droop A, Lorger M
Abstract
BACKGROUND: Brain metastases (BrM) develop in 20-40% of cancer patients and represent an unmet clinical need. Limited access of drugs into the brain because of the blood-brain barrier is at least partially responsible for therapeutic failure, necessitating improved drug delivery systems.
METHODS: Green fluorescent protein (GFP)-transduced murine and nontransduced human hematopoietic stem cells (HSCs) were administered into mice (n = 10 and 3). The HSC progeny in mouse BrM and in patient-derived BrM tissue (n = 6) was characterized by flow cytometry and immunofluorescence. Promoters driving gene expression, specifically within the BrM-infiltrating HSC progeny, were identified through differential gene-expression analysis and subsequent validation of a series of promoter-green fluorescent protein-reporter constructs in mice (n = 5). One of the promoters was used to deliver tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to BrM in mice (n = 17/21 for TRAIL vs control group).
RESULTS: HSC progeny (consisting mostly of macrophages) efficiently homed to macrometastases (mean [SD] = 37.6% [7.2%] of all infiltrating cells for murine HSC progeny; 27.9% mean [SD] = 27.9% [4.9%] of infiltrating CD45+ hematopoietic cells for human HSC progeny) and micrometastases in mice (19.3-53.3% of all macrophages for murine HSCs). Macrophages were also abundant in patient-derived BrM tissue (mean [SD] = 8.8% [7.8%]). Collectively, this provided a rationale to optimize the delivery of gene therapy to BrM within myeloid cells. MMP14 promoter emerged as the strongest promoter construct capable of limiting gene expression to BrM-infiltrating myeloid cells in mice. TRAIL delivered under MMP14 promoter statistically significantly prolonged survival in mice (mean [SD] = 19.0 [3.4] vs mean [SD] = 15.0 [2.0] days for TRAIL vs control group; two-sided P = .006), demonstrating therapeutic and translational potential of our approach.
CONCLUSIONS: Our study establishes HSC gene therapy using a myeloid cell-specific promoter as a new strategy to target BrM. This approach, with strong translational value, has potential to overcome the blood-brain barrier, target micrometastases, and control multifocal lesions.
PMID: 31501884 [PubMed - indexed for MEDLINE]
AIDS Behav. 2020 Nov 12.
Authors: Watt MH, Minja L, Knettel BA, Mwamba RN, Osaki H, Ngocho JS, Kisigo GA, Renju J, Vissoci JRN, Sao SS, Mmbaga BT
Abstract
HIV stigma is a persistent barrier to curbing the spread of HIV and improving quality of life for people living with HIV. We developed and pilot tested Maisha, an HIV stigma reduction intervention in antenatal care (ANC) with two objectives: 1) among individuals living with HIV, reduce internalized and anticipated HIV stigma, with subsequent improvements in HIV care engagement, and 2) among individuals who are HIV-seronegative, reduce HIV stigmatizing attitudes. We enrolled and baselined 1039 women and 492 male partners presenting to a first ANC appointment and randomized them to standard of care or the Maisha intervention. All women living with HIV (WLHIV) and a subset of HIV-negative participants completed a 3-month follow-up assessment. Participation in the three Maisha sessions was high (99.6%, 92.8%, 89.3%), and nearly all participants noted satisfaction with the intervention content (99.8%) and counselor (99.8%). Among 55 WLHIV, care engagement outcomes did not differ by condition. Among 293 HIV-negative participants, Maisha participants had significantly greater reductions in the moral judgment sub-scale of the stigma attitudes measure (p < .001), but not the social distancing subscale. The ANC setting, where women and their partners are routinely tested for HIV, is an ideal venue for addressing HIV stigma. The Maisha intervention was feasible and acceptable, and had an impact on HIV stigma attitudes. A full trial is needed to examine impacts on HIV outcomes; modifications to the intervention should be considered to reduce social alienation of PLWH.
PMID: 33180253 [PubMed - indexed for MEDLINE]
J Allergy Clin Immunol. 2020 Oct 16:S0091-6749(20)31412-3.
Authors: Joshi HR, Hill HR, Asch J, Margraf RL, Coonrod E, Durtschi J, Zhou Q, He X, Voelkerding KV, Kumánovics A.
Abstract
Primary immunodeficiency disorders (PIDs) are a group of heterogenous genetic defects that affect the development and/or function of the immune cells. An increasing number of novel gene mutations have been identified in patients with PIDs thanks to the advent and improvement of next-generation sequencing technologies. In the present study, we performed whole exome sequencing on a patient to identify the cause for progressive decline in antibody and blood cell production. The patient had an immunodeficiency starting in early childhood and suffered recurrent otitis media, sinusitis, and an occasional pneumonia starting at approximately 4 years of age. His IgG level was 150 mg/dL (reference range for age 444-1187 mg/dL), and his IgA and IgM levels were also reported to be low. He was diagnosed with hypogammaglobulinemia and began receiving immunoglobulin replacement therapy, but he continued to have recurrent severe sinopulmonary and gastrointestinal infections. At around 13 years of age, when he was first seen by 1 of the authors of this letter (H.R.H.). He had a normal number of B cells, but in the next 20 years, he experienced a progressive loss of all major types of blood cells (Fig 1, A). The loss was most severe in the lymphoid compartment. In particular, in the B-cell compartment he had hardly any detectable B cells in the peripheral blood by his early 30s.
