RESUMEN

This study investigated the efficacy of existing vaccines against hospitalization and infection due to the Omicron variant of COVID-19, particularly for those who received two doses of Moderna or Pfizer vaccines and one dose of Johnson & Johnson vaccine or who were vaccinated more than five months before. A total of 36 variants in Omicron's spike protein, targeted by all three vaccinations, have made antibodies less effective at neutralizing the virus. The genotyping of the SARS-CoV-2 viral sequence revealed clinically significant variants such as E484K in three genetic mutations (T95I, D614G, and del142-144). A woman showed two of these mutations, indicating a potential risk of infection after successful immunization, as recently reported by Hacisuleyman (2021). We examine the effects of mutations on domains (NID, RBM, and SD2) found at the interfaces of the spike domains Omicron B.1.1529, Delta/B.1.1529, Alpha/B.1.1.7, VUM B.1.526, B.1.575.2, and B.1.1214 (formerly VOI Iota). We tested the affinity of Omicron for ACE2 and found that the wild- and mutant-spike proteins were using atomistic molecular dynamics simulations. According to the binding free energies calculated during mutagenesis, the ACE2 bound Omicron spikes more strongly than the wild strain SARS-CoV-2. T95I, D614G, and E484K are three substitutions that significantly contribute to RBD, corresponding to ACE2 binding energies and a doubling of the electrostatic potential of Omicron spike proteins. The Omicron appears to bind to ACE2 with greater affinity, increasing its infectivity and transmissibility. The spike virus was designed to strengthen antibody immune evasion through binding while boosting receptor binding by enhancing IgG and IgM antibodies that stimulate human ß-cell, as opposed to the wild strain, which has more vital stimulation of both antibodies.

Asunto(s)

RESUMEN

SARS, or severe acute respiratory syndrome, is caused by a novel coronavirus (COVID-19). This situation has compelled many pharmaceutical R&D companies and public health research sectors to focus their efforts on developing effective therapeutics. SARS-nCoV-2 was chosen as a protein spike to targeted monoclonal antibodies and therapeutics for prevention and treatment. Deep mutational scanning created a monoclonal antibody to characterize the effects of mutations in a variable antibody fragment based on its expression levels, specificity, stability, and affinity for specific antigenic conserved epitopes to the Spike-S-Receptor Binding Domain (RBD). Improved contacts between Fv light and heavy chains and the targeted antigens of RBD could result in a highly potent neutralizing antibody (NAbs) response as well as cross-protection against other SARS-nCoV-2 strains. It undergoes multipoint core mutations that combine enhancing mutations, resulting in increased binding affinity and significantly increased stability between RBD and antibody. In addition, we improved. Structures of variable fragment (Fv) complexed with the RBD of Spike protein were subjected to our established in-silico antibody-engineering platform to obtain enhanced binding affinity to SARS-nCoV-2 and develop ability profiling. We found that the size and three-dimensional shape of epitopes significantly impacted the activity of antibodies produced against the RBD of Spike protein. Overall, because of the conformational changes between RBD and hACE2, it prevents viral entry. As a result of this in-silico study, the designed antibody can be used as a promising therapeutic strategy to treat COVID-19.

Asunto(s)

RESUMEN

The World Health Organization has declared the rapidly spreading coronavirus to be a global pandemic. The FDA is yet to approve a vaccine for human novel coronavirus. Here, we developed a peptide-based vaccine and used high-throughput screening by molecular dynamics simulation to identify T-cell- and ß-cell-recognized epitopes for producing specific antibodies against SARS-nCoV-2. We construct ~ 12 P' antigenic epitope peptides to develop a more effective vaccine and identify specific antibodies. These epitope peptides selectively presented the best antigen presentation scores for both human pMHC class I and II alleles to develop a strong binding affinity. All antigens identified of SARS-nCoV-2 different proteins by each attached specific ~ 1-7 L linker adaptor were used to construct a broad single peripheral peptide vaccine. It is expected to be highly antigenic with a minimum allergic effect. As a result of these exciting outcomes, expressing a vaccine using the intimated peptide was highly promising and positive to be highly proposed as epitope-based peptide vaccine of specific antibody against SARS-nCoV-2 by initiating T cells and ß-cells. An in vitro study for the proposed peptide-based vaccine is mostly recommended. Further clinical trials are required to check the efficacy of this vaccine.

RESUMEN

Exposure to the mycotoxin ochratoxin A (OTA) causes nephropathy in domestic animals and rodents and renal tumors in rodents and poultry. Humans are exposed to OTA by consuming foods made with contaminated cereal grains and other commodities. Management of human health risks due to OTA exposure depends, in part, on establishing a mode of action (MOA) for OTA carcinogenesis. To further investigate OTA's MOA, p53 heterozygous (p53+/-) and p53 homozygous (p53+/+) mice were exposed to OTA in diet for 26 weeks. The former are susceptible to tumorigenesis upon chronic exposure to genotoxic carcinogens. OTA-induced renal damage but no tumors were observed in either strain, indicating that p53 heterozygosity conferred little additional sensitivity to OTA. Renal changes included dose-dependent increases in cellular proliferation, apoptosis, karyomegaly, and tubular degeneration in proximal tubules, which were consistent with ochratoxicosis. The lowest observed effect level for renal changes in p53+/- and p53+/+ mice was 200 µg OTA/kg bw/day. Based on the lack of tumors and the severity of renal and body weight changes at a maximum tolerated dose, the results were interpreted as suggestive of a primarily nongenotoxic (epigenetic) MOA for OTA carcinogenesis in this mouse model.

Asunto(s)

RESUMEN

BACKGROUND: The role of fermentation compared with the source or type of the fermentable material in colon tumorigenesis remains an issue in refining the definition of dietary fiber (DF). OBJECTIVE: The aim of this study was to investigate the fermentation and source-specific effects of various carbohydrates in a medium-term colon tumorigenesis model. METHODS: Six-week-old male Fischer 344 rats were randomly allocated into 6 groups (n = 36/group) to receive either AIN-93G (control) or diets containing fructooligosaccharides, wheat bran (WB), oat bran (OB), polydextrose, or high-amylose maize starch (HAMS), each adjusted to contain a total DF concentration of 7% (wt:wt) and have a fermentability of 3% (wt:wt). After 2 wk, 24 rats/group received 2 subcutaneous doses of azoxymethane (at 15 mg/kg body weight) 1 wk apart while 12 rats/group were injected with a saline vehicle; all rats were maintained on the assigned diets for 24 wk postinjection and then killed. Colon tumor outcomes and pathology together with cecal short-chain fatty acid composition were assessed. RESULTS: No tumors were found in saline-injected rats, and all subsequent analyses were restricted to azoxymethane-injected rats. Colon tumor incidence was significantly lower in the polydextrose (21%) and WB (13%) groups than in the control group (63%; P < 0.05) but not different from the fructooligosaccharide (58%), HAMS (46%), and OB (33%) groups. In comparison to the control group (8 proximal/31 total tumors), fermentable materials reduced the number of tumors (P < 0.05) originating in the proximal colon: HAMS (5/15), polydextrose (2/7), OB (2/9), fructooligosaccharides (1/21), and WB (1/3). The mean ± SEM number of tumors/tumor-bearing rats was significantly lower in the WB (1.00 ± 0.00), OB (1.13 ± 0.13), and HAMS (1.36 ± 0.15) groups than in the control group (2.07 ± 0.27; P < 0.02); other groups did not differ. The mean ± SEM tumor burden/diet group was lower in the WB (1.2 ± 0.7 mm2), polydextrose (6.7 ± 3.2 mm2), and OB (7.0 ± 3.0 mm2) groups than in the control (21.4 ± 5.9 mm2) and fructooligosaccharide (22.1 ± 7.1 mm2; P < 0.05) groups but not significantly different from the HAMS group (15.1 ± 6.1 mm2). Total cecal SCFA concentrations did not differ among diet groups (overall mean ± SEM: 81 ± 4 µmol/g wet weight). CONCLUSION: The rate and extent of fermentation of the carbohydrate material as well as the characteristics of the material in the lumen of the lower gastrointestinal tract all appear to have an important role in tumor outcomes in the azoxymethane-induced rat colon tumorigenesis assay.

RESUMEN

Accumulation of hepatic lipid droplet (HLD) is the hallmark pathology of non-alcoholic fatty liver disease (NAFLD). This study examined the effects of soy isoflavones (ISF) and different amounts of soy proteins on the accumulation of HLD, lipid metabolism and related gene expression in rats. Weanling Sprague-Dawley rats were fed diets containing either 20 % casein protein without (D1) or with (D2) supplemental ISF (50 mg/kg diet) or substitution of casein with increasing amounts of alcohol-washed soy protein isolate (SPI, 5, 10, and 20 %; D3, D4, D5) for 90 days. Dietary casein (20 %) induced accumulation of HLD in female, but not in male rats. Both soy proteins and ISF remarkably prevented the formation of HLD. Soy proteins lowered hepatic total cholesterol and triglyceride in a dose-dependent manner. Interestingly, soy proteins but not ISF significantly increased free fatty acids in the liver of the female rats compared to D1. Proteomic analysis showed that at least 3 enzymes involved in lipogenesis were down-regulated and 7 proteins related to fatty acid ß-oxidation or lipolysis were up-regulated by soy protein over D1. Additionally, 9 differentially expressed proteins identified were related to amino acid metabolism, 5 to glycolysis and 2 to cholesterol metabolism. Dietary ISF and SPI markedly reduced hepatic-peroxisome-proliferator-activated receptor γ2 (PPARγ2) and fat-specific protein 27 (FSP27) in female rats. Overall, this study has shown that partial or full replacement of dietary casein by soy protein or supplementation with soy ISF can effectively prevent the accumulation of HLD. The potential molecular mechanism(s) involved might be due to suppression of lipogenesis and stimulation of lipolysis and down-regulation of PPARγ2 and FSP27. This suggests that consumption of soy foods or supplements might be a useful strategy for the prevention or treatment of fatty liver diseases.

RESUMEN

Acrylamide, a possible human carcinogen, is formed in certain carbohydrate-rich foods processed at high temperature. We evaluated if dietary acrylamide, at doses (0.5, 1.0 or 2.0 mg/kg diet) reflecting upper levels found in human foods, modulated colon tumorigenesis in two rodent models. Male F344 rats were randomized to receive diets without (control) or with acrylamide. 2-weeks later, rats in each group received two weekly subcutaneous injections of either azoxymethane (AOM) or saline, and were killed 20 weeks post-injections; colons were assessed for tumors. Male athymic nude (nu/nu) mice bearing HT-29 human colon adenocarcinoma cells-derived tumor xenografts received diets without (control) or with acrylamide; tumor growth was monitored and mice were killed 4 weeks later. In the F344 rat study, no tumors were found in the colons of the saline-injected rats. However, the colon tumor incidence was 54.2% and 66.7% in the control and the 2 mg/kg acrylamide-treated AOM-injected groups, respectively. While tumor multiplicity was similar across all diet groups, tumor size and burden were higher in the 2 mg/kg acrylamide group compared to the AOM control. These results suggest that acrylamide by itself is not a "complete carcinogen", but acts as a "co-carcinogen" by exacerbating the effects of AOM. The nude mouse study indicated no differences in the growth of human colon tumor xenografts between acrylamide-treated and control mice, suggesting that acrylamide does not aid in the progression of established tumors. Hence, food-borne acrylamide at levels comparable to those found in human foods is neither an independent carcinogen nor a tumor promoter in the colon. However, our results characterize a potential hazard of acrylamide as a colon co-carcinogen in association with known and possibly other environmental tumor initiators/promoters.

Asunto(s)

RESUMEN

Acrylamide, a known rodent and a probable human carcinogen, is spontaneously formed in foods cooked at high temperature. We studied the role of dietary acrylamide in modulating the early stages of colon carcinogenesis and assessed if dietary fat level was critical in altering the effects of acrylamide. Male F344 rats were subcutaneously injected with azoxymethane and were simultaneously randomized into 8 dietary groups (n=8 rats/group). Diets were based on AIN-93G semi-synthetic formula modified to contain either low fat (7% corn oil) or high fat (23.9% corn oil) and acrylamide at 0, 5, 10 or 50 mg/kg diet (wt/wt). All rats received the experimental diets ad libitum for 8 weeks, after which they were killed and their colons assessed for aberrant crypt foci (ACF), putative precancerous lesions. Irrespective of dietary fat level, rats with the highest tested dose of acrylamide (50 mg/kg diet) had significantly lower total ACF (p<0.05) and lower large ACF (those with 4 or more crypts/focus; p<0.001) compared with their respective controls (0 mg/kg diet). A significantly lower number of large ACF (p=0.046) was noted in rats treated with 10 mg/kg diet acrylamide exclusively in the high fat group, compared to the high fat control. This short-term bio-assay to test carcinogenicity of dietary acrylamide in the colon demonstrates that acrylamide, when administered through the diet at doses known to cause rat tumors, does not increase the risk of developing azoxymethane-induced precancerous lesions of the colon in rats. On the contrary, a high dose of dietary acrylamide decreased the growth of precancerous lesions in both low and high fat diet regimens in this model.

Asunto(s)