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1.
Single-Molecule Imaging of Membrane Proteins on Vascular Endothelial Cells.
Park, J, Jin, S, Jang, J, Seo, D
Journal of lipid and atherosclerosis. 2023;(1):58-72
Abstract
Transporting substances such as gases, nutrients, waste, and cells is the primary function of blood vessels. Vascular cells use membrane proteins to perform crucial endothelial functions, including molecular transport, immune cell infiltration, and angiogenesis. A thorough understanding of these membrane receptors from a clinical perspective is warranted to gain insights into the pathogenesis of vascular diseases and to develop effective methods for drug delivery through the vascular endothelium. This review summarizes state-of-the-art single-molecule imaging techniques, such as super-resolution microscopy, single-molecule tracking, and protein-protein interaction analysis, for observing and studying membrane proteins. Furthermore, recent single-molecule studies of membrane proteins such as cadherins, integrins, caveolins, transferrin receptors, vesicle-associated protein-1, and vascular endothelial growth factor receptor are discussed.
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A Systematic Review of the Benefit of B-Vitamins as a Complementary Treatment in Cancer Patients.
Heilfort, L, Kutschan, S, Dörfler, J, Freuding, M, Büntzel, J, Münstedt, K, Hübner, J
Nutrition and cancer. 2023;(1):33-47
Abstract
B-vitamins act as enzymatic co-factors in immune functions, therefore they are considered to reduce chemotherapy-induced side effects in cancer patients. We conducted a systematic search, screening five electronic databases (Embase, Cochrane, PsychInfo, CINAHL and Medline) to find studies on the effectiveness and potential harm of B-vitamin therapy on cancer patients. Out of the 7465 search results, 11 RCTs about vitamin B6, B12 and B-vitamins in combination were included in this systematic review. A total of 1546 patients with diverse types of cancer were evaluated. Overall, most studies were of acceptable quality and reported consistent results. Studies examining the effectiveness of vitamin B6 reported that there is no significant impact on decreasing the incidence and severity of chemotherapy-induced side effects (e.g., hand-foot syndrome), the necessity of chemotherapy dose-modifications or improving patients' quality of life, tumor response/progression, and overall survival. Two studies reported that vitamin B12 could be effective in the alleviation of symptoms resulting from chemotherapy; it might decrease motor, sensory and pain symptoms of peripheral neuropathy. However, a combination of B vitamins may not reduce the incidence of chemotherapy-induced peripheral neuropathy. All in all, the evidence on B-vitamins in cancer patients is low and supplementation cannot be recommended.
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De novo design and Rosetta-based assessment of high-affinity antibody variable regions (Fv) against the SARS-CoV-2 spike receptor binding domain (RBD).
Boorla, VS, Chowdhury, R, Ramasubramanian, R, Ameglio, B, Frick, R, Gray, JJ, Maranas, CD
Proteins. 2023;(2):196-208
Abstract
The continued emergence of new SARS-CoV-2 variants has accentuated the growing need for fast and reliable methods for the design of potentially neutralizing antibodies (Abs) to counter immune evasion by the virus. Here, we report on the de novo computational design of high-affinity Ab variable regions (Fv) through the recombination of VDJ genes targeting the most solvent-exposed hACE2-binding residues of the SARS-CoV-2 spike receptor binding domain (RBD) protein using the software tool OptMAVEn-2.0. Subsequently, we carried out computational affinity maturation of the designed variable regions through amino acid substitutions for improved binding with the target epitope. Immunogenicity of designs was restricted by preferring designs that match sequences from a 9-mer library of "human Abs" based on a human string content score. We generated 106 different antibody designs and reported in detail on the top five that trade-off the greatest computational binding affinity for the RBD with human string content scores. We further describe computational evaluation of the top five designs produced by OptMAVEn-2.0 using a Rosetta-based approach. We used Rosetta SnugDock for local docking of the designs to evaluate their potential to bind the spike RBD and performed "forward folding" with DeepAb to assess their potential to fold into the designed structures. Ultimately, our results identified one designed Ab variable region, P1.D1, as a particularly promising candidate for experimental testing. This effort puts forth a computational workflow for the de novo design and evaluation of Abs that can quickly be adapted to target spike epitopes of emerging SARS-CoV-2 variants or other antigenic targets.
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4.
Optimizing targeted drug selection in combination therapy for patients with advanced or metastatic renal cell carcinoma: A systematic review and network meta-analysis of safety.
Xie, R, Wu, J, Shang, B, Bi, X, Jiang, W, Cao, C, Zhou, A, Shi, H, Shou, J
Cancer medicine. 2023;(6):7051-7064
Abstract
OBJECTIVE For patients with advanced or metastatic renal cell carcinoma (RCC), the dose of targeted agents was recommended in combination with immune checkpoint inhibitors. We performed a network meta-analysis to describe a categorized safety ranking profile and assess the adaptability of the combination options of targeted agents. METHODS The targeted agents refer to vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs) and mammalian target of rapamycin (mTOR) inhibitors. Randomized controlled trials comparing these drugs were enrolled in a Bayesian model network meta-analysis. RESULTS Nineteen clinical trials with 11 treatments and 10,615 patients were included. For grade ≥ 3 adverse events (AEs), compared with placebo, lenvatinib plus everolimus showed worse safety than all other treatments except for lenvatinib (placebo vs. OR 0.23, 95% CI 0.07-0.78). Everolimus was generally the safest agent (OR 1.23, 95% CI 0.50-3.14). Sorafenib arose the least renal AEs (placebo vs. OR 0.85, 95% CI 0.06-11.64), whereas lenvatinib plus everolimus had the highest risk of renal toxicity (placebo vs. 0.17 95% CI 0.01-1.02). For gastrointestinal symptoms, everolimus was related to much lower toxicity than other agents. In the respiratory safety analysis, tivozanib (placebo vs. OR 0.15, 95% CI 0.07-0.31) and axitinib (OR 5.43, 95% CI 3.26-9.22) were the riskiest agents. In terms of hepatobiliary (placebo vs. OR 0.44, 95% CI 0.09-2.10) and hemotoxicity (placebo vs. OR 1.03, 95% CI 0.14-7.68) related AEs, lenvatinib was found to be the safest treatment compared to placebo. CONCLUSIONS Everolimus, with the best safety of grade ≥ 3, gastrointestinal, and respiratory AEs, was more likely to be considered for combination therapies. Lenvatinib appears to be the safest for blood/lymphatic and hepatobiliary AEs. For patients with renal disorders, sorafenib arises the least renal toxicity AEs. This study will guide treatment options and optimize the trial design for advanced or metastatic RCC.
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5.
A cytotoxic effect of human lactoferrin fusion with Fc domain of IgG.
Zaczyńska, E, Kocięba, M, Artym, J, Kochanowska, I, Kruzel, ML, Zimecki, M
Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine. 2023;(3):617-627
Abstract
Lactoferrin (LTF) is a natural iron-binding protein with a potential for clinical utility in many human immune disorders, including cancer. A fusion of LTF with the Fc domain of IgG2 (FcLTF) was designed with inherent properties of an extended the half-life in circulation. Furthermore, the effects of LTF and FcLTF were assessed for influence on the activity of natural killer (NK) cells isolated from human peripheral blood, on the NK-92 cell line, and on human monocytes. The NK cytotoxic activity induced by LTF and FcLTF was determined against the human leukemia K562 cell line, and also for monocytes, by measuring TNFα and granzyme B production, and in an assay for Jurkat cell viability. Selected gene expression in NK-92 cells and monocytes, induced by LTF and FcLTF, was performed by Real Time PCR. No significant difference was observed in NK-92 cytotoxicity stimulated by LTF and FcLTF. The effects on NK cells isolated from the human peripheral blood were varied, possibly due to the immunoregulatory nature of LTF sensing the immune status of donors. Furthermore, only the FcLTF group strongly stimulated production of TNFα and granzyme B in isolated monocytes. In addition, only supernatants from the monocyte cultures treated with FcLTF decreased the viability of Jurkat cells. The ability of FcLTF to induce TNFα in monocytes was strongly inhibited by anti-CD32 and moderately inhibited by anti-CD14 antibody. Lastly, it was demonstrated that FcLTF, strongly induced expression of PI3K, with subsequent activation of AKT/mTOR signaling pathway. Overall, it was demonstrated that this novel fusion molecule may be a perferred choice for clinical utility than the wild type LTF.
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6.
Selenium and immune function: a systematic review and meta-analysis of experimental human studies.
Filippini, T, Fairweather-Tait, S, Vinceti, M
The American journal of clinical nutrition. 2023;(1):93-110
Abstract
BACKGROUND Selenium is an essential trace element with both beneficial and detrimental effects on health depending on dose and chemical form. Currently, there is debate on recommendations for selenium supplementation as a public health measure to improve immune function and reduce infectious disease susceptibility. OBJECTIVES We performed a systematic review and meta-analysis of experimental studies assessing the effect of selenium supplementation on immunity-related outcomes in healthy people. METHODS We undertook a search of published and unpublished studies in literature databases such as PubMed/MEDLINE, Embase, and clinicaltrials.gov up to 17 October, 2022, and performed a meta-analysis comparing the effects on immunity-related outcomes between Se-supplemented versus control arms. Whenever possible we assessed the nonlinear relation using a dose-response approach. RESULTS 9 trials were included, 5 in North America, and 4 in Europe, with a duration between 8 and 48 weeks and supplementation of both inorganic and organic selenium forms. Selenium supplementation did not substantially affect immunoglobulin or white blood cell concentrations, and the dose-response meta-analysis indicated that an increase in plasma selenium concentrations above 100 μg/L did not further increase IgA levels nor T cells. An inverted U-shaped relation emerged for NK cell count, with a lower number of these cells both below and above 120 μg/L. The only beneficial effect of selenium supplementation was the increased activity for NK lysis, but the available data did not permit dose-response analysis. Cytokine levels were substantially unaffected by selenium supplementation. CONCLUSIONS Although some of the data suggested beneficial effects of selenium supplementation on immune function, the overall picture appears to be inconsistent and heterogeneous due to differences in trial duration and interventions, plus evidence of null and even detrimental effects. Overall, the evidence that we extracted from the literature in this systematic review does not support the need to supplement selenium beyond the recommended dietary intake to obtain beneficial effects on immune function. This trial was registered at PROSPERO (CRD42022312280).
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7.
Potential Benefit of Vitamin D Supplementation in COVID-19.
Stafford, A, White, ND
American journal of lifestyle medicine. 2023;(2):202-205
Abstract
Vitamin D is an important nutrient in the body that plays a vital role in immune system function. Several epidemiologic studies have shown that low vitamin D levels are found in a large percentage of COVID-19 patients with acute respiratory failure and that vitamin D levels may predict mortality in COVID-19 infection. Based on these findings, vitamin D supplementation may be an effective approach to preventing and/or treating COVID-19. Potential underlying mechanisms and clinical trial data evaluating the impact of supplementation in humans are described below.
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8.
The role of the gut microbiome in eye diseases.
Zysset-Burri, DC, Morandi, S, Herzog, EL, Berger, LE, Zinkernagel, MS
Progress in retinal and eye research. 2023;:101117
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Abstract
The gut microbiome is a complex ecosystem of microorganisms and their genetic entities colonizing the gastrointestinal tract. When in balanced composition, the gut microbiome is in symbiotic interaction with its host and maintains intestinal homeostasis. It is involved in essential functions such as nutrient metabolism, inhibition of pathogens and regulation of immune function. Through translocation of microbes and their metabolites along the epithelial barrier, microbial dysbiosis induces systemic inflammation that may lead to tissue destruction and promote the onset of various diseases. Using whole-metagenome shotgun sequencing, several studies have shown that the composition and associated functional capacities of the gut microbiome are associated with age-related macular degeneration, retinal artery occlusion, central serous chorioretinopathy and uveitis. In this review, we provide an overview of the current knowledge about the gut microbiome in eye diseases, with a focus on interactions between the microbiome, specific microbial-derived metabolites and the immune system. We explain how these interactions may be involved in the pathogenesis of age-related macular degeneration, retinal artery occlusion, central serous chorioretinopathy and uveitis and guide the development of new therapeutic approaches by microbiome-altering interventions for these diseases.
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9.
Protective role of vitamin D status against COVID-19: a mini-review.
Vasheghani, M, Rekabi, M, Sadr, M
Endocrine. 2023;(2):235-242
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Abstract
An outbreak of pneumonia caused by a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is called COVID-19 and has led to a pandemic worldwide. It is reasonable to investigate and control factors affecting disease severity and mortality. The relation between vitamin D and viral pneumonia has been previously reported. Vitamin D deficiency is common and may increase hospital admission and mortality rate in patients with COVID-19. This mini-review examines the pathways that show the association between vitamin D and COVID-19. On the other hand, it deals with the available evidence related to the relationship between vitamin D deficiency and the effect of vitamin D supplementation on the prevalence, severity, and mortality of COVID-19. Also, we described the pathophysiology of the organs' involvement in COVID-19 and the effect of vitamin D on these outcomes. Vitamin D strengthens the innate and adaptive immune system, modulates immune responses, prevents lung and cardiovascular system damage, and reduces thrombotic events. Vitamin D exerts these effects in several pathways. Vitamin D prevents virus entry and replication by maintaining the integrity of the body's physical barrier. Vitamin D reduces the damage to vital organs and thrombotic events by increasing the level of Angiotensin-converting enzyme 2 (ACE2), nitric oxide, and antioxidants or by reducing inflammatory cytokines and free radicals. Sufficient vitamin D may be reduced morbidity and mortality due to COVID-19. However, this issue should be investigated and confirmed by further research in the future.
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10.
Immunomodulatory action of Lactococcuslactis.
Saleena, LAK, Teo, MYM, How, YH, In, LLA, Pui, LP
Journal of bioscience and bioengineering. 2023;(1):1-9
Abstract
Fermented foods are gaining popularity due to health-promoting properties with high levels of nutrients, phytochemicals, bioactive compounds, and probiotic microorganisms. Due to its unique fermentation process, Lactococcus lactis plays a key role in the food business, notably in the manufacturing of dairy products. The superior biological activities of L. lactis in these functional foods include anti-inflammatory and immunomodulatory capabilities. L. lactis boosted growth performance, controlled amino acid profiles, intestinal immunology, and microbiota. Besides that, the administration of L. lactis increased the rate of infection clearance. Innate and acquired immune responses would be upregulated in both local and systemic compartments, resulting in these consequences. L. lactis is often employed in the food sector and is currently being exploited as a delivery vehicle for biological research. These bacteria are being eyed as potential candidates for biotechnological applications. With this in mind, we reviewed the immunomodulatory effects of different L. lactis strains.
