The relative prevalence of the Omicron variant within SARS-CoV-2 infected cohorts in different countries: A systematic review.

The Omicron variant of SARS-CoV-2 was detected in October 2021 and exhibited high transmissibility, immune evasion, and reduced severity when compared to the earlier variants. The lesser vaccine effectiveness against Omicron and its reduced severity created vaccination hesitancy among the public. This review compiled data reporting the relative prevalence of Omicron as compared to the early variants to give an insight into the existing variants, which may shape the decisions regarding the targets of the newly developed vaccines. Complied data revealed more than 90% prevalence within the infected cohorts in some countries. The BA.1 subvariant predominated over the BA.2 during the early stages of the Omicron wave. Moreover, BA.4/BA.5 subvariants were detected in South Africa, USA and Italy between October 2021 and April 2022. It is therefore important to develop vaccines that protect against Omicron as well as the early variants, which are known to cause more severe complications.

The effect of microbiome-modulating probiotics, prebiotics and synbiotics on glucose homeostasis in type 2 diabetes: A systematic review, meta-analysis, and meta-regression of clinical trials.

AIM/HYPOTHESIS: The globally escalating diabetes epidemic is responsible for significant morbidity and mortality. Microbiome-modulating nutraceuticals have been investigated for their potential to restore metabolic and floral homeostasis in type 2 diabetic patients METHODS: A systematic review, meta-analyses and meta-regressions were conducted to investigate the effect of probiotics, prebiotics, and synbiotics on various biomarkers of glucose homeostasis based on a multi-database search of clinical trials published through April 10, 2022. Data was pooled using random effects meta-analyses and reported as mean differences with 95% confidence intervals (CIs), followed by univariate linear model meta-regression. RESULTS: Data from 68 trial comparisons across 58 studies (n = 3835) revealed that, compared to placebo/control group, administration of pro/pre/synbiotics was associated with statistically significant changes in fasting plasma glucose (-12.41 mg/dl [95% CI: -15.94; -8.88], p 0.0001), glycated hemoglobin (-0.38% [95% CI: -0.47; -0.30], p 0.0001), fasting insulin (-1.49 µU/mL [95% CI: -2.12; -0.86], p 0.0001), HOMA-IR (-0.69 [95% CI: -1.16; -0.23], p = 0.0031) and QUICKI (0.0148 [95% CI: 0.0052; 0.0244], p = 0.0025), but not C-peptide (-0.0144 ng/mL [95% CI: -0.2564; -0.2275], p = 0.9069). Age, baseline BMI, baseline biomarker value, pro/prebiotic dosage, trial duration, nutraceutical type, and recruitment region significantly affected the potential of pro/pre/synbiotics use as personalized diabetes adjunct therapy. Lastly, we discuss unexplained observations and directives for future trials, with the aim of maximizing our understanding of how microbiome-modulating nutraceuticals can treat various metabolic diseases CONCLUSIONS: Pro/pre/synbiotic supplementation improved glucose homeostasis in diabetic patients. Our results support their potential use as adjunct therapy for improving glycemia and insulinemia alongside pharmacological therapeutics.

Combination of stromal cell-derived factor-1 and collagen-glycosaminoglycan scaffold delays contraction and accelerates reepithelialization of dermal wounds in wild-type mice.

While dermal substitutes can mitigate scarring and wound contraction, a significant drawback of current dermal replacement technologies is the apparent delay in vascular ingrowth compared with conventional skin grafts. Herein, we examined the effect of the chemokine stromal cell-derived factor-1 (SDF-1) on the performance of a porous collagen-glycosaminoglycan dermal analog in excisional wounds in mice. C57BL/6 mice with 1 cm × 1 cm dorsal full-thickness wounds were covered with a collagen-glycosaminoglycan scaffold, followed by four daily topical applications of 1 µg SDF-1 or phosphate-buffered saline vehicle. Some animals were also pretreated with five daily doses of 300 mg/kg granulocyte colony-stimulating factor. Animals treated with SDF-1 and no granulocyte colony-stimulating factor reepithelialized 36% faster than vehicle controls (16 vs. 25 days), and exhibited less wound contraction on postwounding day 18 (∼ 35% greater wound area) plus three-fold longer neoepidermis formed than controls. Conversely, granulocyte colony-stimulating factor promoted contraction and no epidermal regeneration. Early (postwounding Day 3) inflammatory cell infiltration in the SDF-1-treated group was 86% less, while the fraction of proliferating cells (positive Ki67 staining) was 32% more, when compared with controls. These results suggest that SDF-1 simultaneously delays contraction and promotes reepithelialization and may improve the wound-healing performance of skin substitutes.

Cerebral PET imaging and histological evidence of transglutaminase inhibitor cystamine induced neuroprotection in transgenic R6/2 mouse model of Huntington's disease.

To investigate efficacy of cystamine induced neuroprotection, we conducted PET imaging studies of cerebral glucose metabolism with [(18)F]FDG (2-deoxy-2-[(18)F]fluoro-d-glucose) and striatal dopamine D2 receptor function with [(11)C]raclopride in R6/2 transgenic Huntington mice. In the control mice, exponentially decreasing glucose utilization was observed in the striatum N(str) [SUV]=(41.75+/-11.80)(58,str)*exp(-(0.041+/-0.007)*t [days]); cortex N(cort) [SUV]=24.14+/-3.66)(58,cort)*exp(-(0.043+/-0.007)*t [days]); and cerebellum N(cer) [SUV]=(34.97+/-10.58)(58,cer)*exp(-(0.037+/-0.008)*t [days]) as a function of age starting at 58 days. Given that the underlying degeneration rate in the cystamine treated mice is similar to that observed in control animals, the protection coefficient (beta) calculated from the equation N(t)=N(58)*exp(-(1-beta)*k*t) was 0.133+/-0.035 for the striatum; 0.122+/-0.028 for the cortex and 0.224+/-00.042 for the cerebellum with a dose of 100 mg/kg. The 50 mg/kg cystamine dose provided significant protection only for the striatum and only minor protection was obtained using lower doses. Striatal binding potential of [(11)C]raclopride was 1.059+/-0.030 in the control mice, and enhanced in the cystamine treated animals in a dose dependent manner up to 1.245+/-0.063 using the 100 mg/kg dose. Histological analysis confirmed cystamine induced neuroprotection of striatal and cortical neurons and Nissl staining revealed that formation of cellular inclusions was reversed in a dose dependent manner. Cerebral imaging and histological evidence support the use of cystamine as a neuroprotective agent for Huntington's disease (HD) pathology.

Macrocyclic polyamines deplete cellular ATP levels and inhibit cell growth in human prostate cancer cells.

In solid tumors, when O(2) partial pressure drops below 10 mmHg, ATP levels rapidly decrease due to the Warburg effect. It is known that certain macrocyclic polyamines catalyze the chemical hydrolysis of ATP with release of inorganic phosphate. Since tumor cells have diminished ATP levels as compared to normal cells, we attempted to deplete cellular ATP with macrocyclic polyamines in an effort to inhibit tumor cell proliferation. Five macrocyclic polyamines, related to the budmunchamine family of alkaloids, were prepared by total synthesis. They were the [17]-N(4) macrocycle 1, the [16]-N(4) macrocycle 20, the [18]-N(4) macrocycle 13, the [20]-N(5) macrocycle 8, and the [13]-N(3) macrocycle 17. Each one of them hydrolyzed ATP in vitro with release of P(i); the largest ring macrocycle 8 was the most efficient catalyst, while the smallest ring macrocycle 17 was the least efficient (P(i) released in these runs was on the order of 40-100 microM). The linear polyamine spermine had no hydrolytic effect on ATP. The macrocycles were found to be cytotoxic when assessed by means of a MTT assay against two human prostate cell lines, DuPro and PC-3, with resultant ID(50) values ranging between 0.5 and 1.8 microM. Colony forming efficiency (CFE) assays performed on DuPro cells, where the macrocycles were used in a concentration range of 1-8 microM, confirmed the cytotoxic effect of each macrocycle. Each killed 3-4 log of DuPro cells. The smallest ring 17 was the least cytotoxic after 24 h of incubation, although after 144 h of incubation it showed significant cytotoxicity at 8 microM. The macrocycles were equally efficient in depleting the intracellular ATP pools; after a 24 h incubation with each macrocycle other than 17 at 1-8 microM concentrations, cellular ATP concentrations were decreased by 3 orders of magnitude. The decrease in ATP levels was more pronounced after a 72 h incubation, when even 17 reduced ATP by 2 orders of magnitude. A linear pentamine of established cytotoxicity was without effect on the ATP pools. The macrocycles depleted almost entirely the intracellular pools of polyamines and were efficiently taken up by cells. A rough correlation could be established between the cytotoxic effect of the macrocyclic polyamines and their ATP-ase like activity in the DuPro cell line. As ATP is a scarce metabolite in cancer cells, where it can only be replenished through the very ATP-inefficient glycolytic pathway; macrocyclic polyamines appear to be promising new anticancer agents.

Cyclopropane-containing polyamine analogues are efficient growth inhibitors of a human prostate tumor xenograft in nude mice.

Polyamine analogues 7, 10, 18, 27, and 32 containing cyclopropane rings were obtained by chemical synthesis. Their antineoplastic activities were assessed against the cultured human prostate tumor cell lines DU-145, DuPro, and PC-3. Decamines 32 and 27 exhibited variable levels of cytotoxicity against all three cell lines, while 7, 10, and 18 were efficacious against DU-145 and DuPro. Maximum tolerated doses (MTD) for all five compounds in a NCr-nu mouse model were determined at dosing schedules of q1d x 5 (ip) in two cycles with a break of 10 days between cycles. Their antitumor efficacies were then tested against DU-145 tumor xenografts in mice treated with all five agents at their respective MTDs. In addition, the efficacies of 7 and 10 against the same tumor xenograft were assessed at doses below their respective MTDs. In all experiments, administration began two weeks after tumor implantation. All compounds efficiently inhibited tumor growth for up to 50 days postimplantation, with negligible animal body weight loss. Tetramine 10 and hexamine 18 were the most efficient among the five analogues in arresting tumor growth. Tetramine 10 containing two cyclopropane rings had the lowest systemic toxicity as reflected in animal body weight loss. It was further assessed at a weekly administration regimen of (q1w x 4) in two cycles with a four-week break between the cycles. At this dosing schedule, 10 again efficiently arrested tumor growth with negligible effect on animal body weight. Tetramine 10 also arrested the growth of large tumors (ca. 2000 mm(3)) treated 66 days postimplantation. Studies on the metabolism of 10 showed that it accumulates in tumor within 6 h after the end of administration and reached a maximum level 72 h after cessation of dosing. Intracellular concentrations of 10 in liver and kidney were much smaller when compared to those in the tumor when measured 72 h after cessation of dosing. In liver and kidney, the deethyl metabolites of 10 accumulated over a 96 h period after cessation of dosing.

Long-chain polyamines (oligoamines) exhibit strong cytotoxicities against human prostate cancer cells.

alpha N,(omega)N-bis(ethyl) octamine SL-11160, decamine SL-11159, dodecamine SL-11226, and tetradecamine SL-11175 were chemically synthesized. We called this class of compounds 'oligoamines'. In these compounds, each -NH(2)(+) residue is separated by four CH(2) residues. trans-Unsaturation was also introduced into the center of the oligoamine chain resulting in the trans-octamine SL-11158, trans-decamine SL-11144, trans-dodecamine SL-11172 and trans-tetradecamine SL-11227. cis-Unsaturation gave the cis-octamine SL-11157 and cis-decamine SL-11150. When assayed for their growth inhibitory effect against four human prostate cancer cell lines LnCap, DU-145, DuPro, and PC-3 by a MTT assay, the ID(50) values were less than 1 microM in all four cell lines. On day 6 of treatment, 2 microM SL-11159, SL-11144 and SL-11175 killed over five logs of DuPro cells while SL-11172 killed over four logs as determined by a colony forming efficiency (CFE) assay. In addition, SL-11159, SL-11226 and SL-11227 killed four logs of PC-3 cells. PC-3 cells are generally resistant to shorter chain polyamine analogues. Such a level of cytotoxicity in any of the prostate tumor cell lines has not been observed for any other polyamine analogues tested thus far. The DU-145 cell line was too sensitive to oligoamines to perform a CFE analysis and the DuPro cell line was too sensitive to SL-11227 treatment to obtain reproducible CFE data. Interestingly, all 10 oligoamines were efficient DNA aggregators in a cell-free system and their cytotoxicities generally parallel their capacities to aggregate DNA.

A novel polyamine analog (SL-11093) inhibits growth of human prostate tumor xenografts in nude mice.

PURPOSE: We tested the polyamine analog SL-11093 (3,8,13,18-tetraaza-10,11-[(E)-1,2-cyclopropyl]eicosane tetrahydrochloride) as an effective chemotherapeutic agent against human prostate cancer grown in nude mice. METHODS: NCr-nu mice grafted with DU-145 human prostate tumor cells were treated i.p. with SL-11093 at 50 mg/kg q1dx5 for either three or five cycles separated by intervals of about 10-15 days. RESULTS: In treated animals, tumor growth remained arrested for up to 100 days with minimal animal weight loss. None of the animals died during the treatment and in one experiment two out of six animals showed no palpable tumor. SL-11093 was readily taken up by the tumors, where its levels remained elevated for about 48 h after the end of drug administration. In liver and in kidney, SL-11093 (a (alpha)N,(omega)N-bisethyl derivative) was oxidatively N-deethylated predominantly to its monoethyl and di-deethyl derivatives. In time, the monoethyl derivative was further dealkylated, with a loss of an aminobutyl chain to form an aminomethyl cyclopropyl derivative. In tumor (and in lung), N-dealkylation reactions were less evident. CONCLUSION: SL-11093 is an effective chemotherapeutic agent against a human prostate tumor xenograft grown in nude mice. The drug accumulation and slow metabolism in tumor compared to other tissues would most likely reduce systemic toxicity of the drug and contribute to a larger therapeutic window for SL-11093 as compared to other cytotoxic polyamine analogs.