Search

Background: The entry of the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) into the host cell is carried out by specific receptors and enzymes, including human angiotensin‐converting enzyme 2 receptor (ACE2), transmembrane serine protease 2 (TMPRSS2), and cathepsin‐L (CTSL). COVID‐19 patients with comorbidities, such as diabetes mellitus (DM), are more prone to severe symptoms and have a higher risk of mortality. Aims: The present study aimed to investigate the impact of controlled and uncontrolled type 1 DM (T1DM) on the gene expression of mouse Ace2, Tmprss2, and Ctsl and correlate it with the pathological alterations in the lungs and the heart of DM mice. Methods: Balb/c mice were administered a single dose of 240 mg/kg streptozocin to induce T1DM. The blood glucose level was measured to confirm the induction of DM. Normalization of blood glucose levels in T1DM mice was achieved using 0.1 mL/kg Mixtard® insulin therapy. The mice's lungs and hearts were harvested, and the mRNA was extracted and converted to cDNA. The gene expression of Ace2, Tmprss2, Ctsl, Cyp4a11, and Adrb1 genes, which play a role in the homeostasis of lungs and hearts, were measured using quantitative real‐time polymerase chain reaction (RT‐PCR). The pathological alterations in the hearts and lungs induced by T1DM were evaluated using the relative heart and lung weights, in addition to the pathohistological examination. Results: After inducing T1DM for 14 days, we observed a significant reduction in the total weight of uncontrolled DM (UDM) mice (P < 0.05). Pathohistological examination of UDM lung tissues revealed thickening of the alveolar walls with narrowing of the surface of the alveolar sacs. Additionally, we found that UDM mice exhibited downregulation of Ace2 gene expression (P < 0.05) in their lungs, while both UDM and control DM (CDM) mice showed upregulation of Ctsl gene expression in their hearts (P < 0.05). Notably, Cyp4a12 gene expression was significantly downregulated (P < 0.05) in UDM mice but returned to normal levels in CDM mice. Conclusions: We conclude from this study that T1DM downregulates Ace2 receptor and Cyp4a12 gene expression, which is correlated with the thickening of alveolar walls and narrowing of the surface of alveolar sacs in the lungs. Insulin administration for controlling T1DM ameliorated these pathological alterations. These results can help increase our understanding of the impact of controlled and uncontrolled T1DM on the lungs and may explain, at least in part, why DM patients with COVID‐19 experience exacerbation of symptoms. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Aims Methods Results Conclusions The coronavirus disease 2019 (COVID‐19) caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has rapidly become a global health concern. The entry of the virus into host cells is facilitated by the transmembrane protease serine 2 (TMPRSS2) receptor, and genetic variations in the TMPRSS2 gene may influence disease susceptibility. However, there is a lack of knowledge regarding TMPRSS2 genetic variants and haplotypes in the Jordanian population.This study aimed to characterize the genotype and haplotype variations in the TMPRSS2 binding domain with SARS‐CoV‐2 among Jordanian volunteers.The binding domain of TMPRSS2 with SARS‐CoV‐2 (Exons 9 and 10) was amplified using polymerase chain reaction (PCR) for a random sample of 120 healthy unrelated Jordanian volunteers, followed by Sanger DNA sequencing for the PCR products. The effect of the novel genetic variants on the TMPRSS2 protein structure was predicted using in silico methods.The results showed significant (p < 0.05, chi‐square) allele frequencies for known TMPRSS2 variants, with c.888C > T being the most prevalent among Jordanian volunteers. Novel genetic variants, including c.869A > G and c.923T > A, were also identified, with the latter being the most common novel variant. Haplotype analysis showed that the most prevalent TMPRSS2 haplotype is c.911G/1051A/1052T/1010 + 45C/1011 − 38T/1011 − 52C/1011 − 54A. In silico programs predicted that TMPRSS2 c.923T > A and c.1052T > A variants affect transmembrane proteins and catalytic sites.This research provides information about the gene structure of the TMPRSS2 binding domain in Jordanians. Some of the identified variants, especially c.923T > A, may influence protein function, warranting further in vitro and in vivo investigations. In addition, further clinical research studies are needed to link the identified TMPRSS2 variants with COVID‐19 susceptibility and severity among Jordanians. [ABSTRACT FROM AUTHOR]

Male and female rats and rabbits were used in this study to investigate the acute and subchronic toxicity of a new antismoking (A.S.) mouthwash (0.5 silver nitrate as the active ingredient). The LD50 values for ip administration in male and female rats were 35.7 and 37.2 mg kg body weight, respectively. The corresponding values in male and female rabbits were 113 and 128 mg kg body weight, respectively. The oral LD50 values of the mouthwash in male and female rats were 428 and 433 mg kg body weight, respectively. The corresponding values in male and female rabbits were 1261 and 1320 mg kg body weight, respectively. Postmortem and histopathological examination revealed congestion, edema, hemorrhage, and mucosal necrosis with brown pigment deposition in the upper gastrointestinal and respiratory tracts for the orally treated animals and ascitis, peritoneal fat necrosis, and pigment deposition in ip administered animals. Subchronic toxicity involved administration of low (1.5 mg kg), intermediate (15 mg kg) , and high (150 mg kg) doses of A.S. mouthwash by swabbing the oral cavity daily for 30 consecutive days. Body weight, hematologic observations, and histopathological examination showed no significant differences between control and treated animals, except for dark coloration in teeth and increased platelet counts in treated rats. [ABSTRACT FROM AUTHOR]

The erythromycin breath test (EBT), which measures 14CO2 produced from [14C N- methyl] erythromycin, is one of the most frequently employed measures to examine drug interactions involving cytochrome P450 3A4 (CYP3A). However, the reproducibility and reliability of this test, and the effects of drugs that alter CYP3A activity, continue to be defined. In this study, the reproducibility of the EBT was evaluated in eight healthy volunteers before and after oral administration of 600 mg of rifampin daily for 8 days. Two sequential EBT determinations performed 5 days apart before rifampin administration were highly reproducible. Rifampin induced CYP3A, reflected in a mean percent (± standard deviation) increase in EBT values of 86 ± 30%. Recovery of enzyme function after discontinuation of rifampin for 17 days was manifested as a return of EBT values to preinduction levels. These results support the utility of EBT as a valid, reproducible, and reliable measure of CYP3A activity in vivo. [ABSTRACT FROM AUTHOR]

The effect of ethyl acetate extract of pomelo fruit on systemic exposure of verapamil was explored in rabbits. Two groups each of 8 locally-inbred New Zealand male rabbits were used. The first group was used for single-dose treatment (both verapamil and pomelo extract). The second group was used for multiple-dose treatment, pomelo extract (once daily for 14 days) and verapamil single doses (at days 7 and 14). A verapamil dose of 30 mg/kg and a pomelo extract dose of 45 mg/kg were used. Single-dose treatment with pomelo extract resulted in a minor change in mean C(max) of verapamil in plasma, while a decrease of 37.8% in AUC(0-24) and 28.3% in AUC(0-∞) was observed but did not reach statistical significance. After the first period of multiple dose treatment (pomelo extract for 7 days), the combination increased the concentration of verapamil in plasma with a significant increase in mean C(max), AUC(0-24) and AUC(0-∞) by 461.9%, 299.7%, and 261.1%, respectively (p values were 0.005, 0.002, and 0.006, respectively). In contrast, after the second period (day 14 of pomelo extract use), the combination decreased the concentration of verapamil in the plasma with a substantial decrease in mean C(max), AUC(0-24), and AUC(0-∞), by 68.2%, 69.7% and 58.3%, respectively. This decrease did not reach statistical significance (p values were 0.073, 0.081 and 0.083, respectively). The T(max) was not affected significantly in both studies. The study illustrates a complex time-dependent interaction between verapamil and the ethyl acetate extract of pomelo mix. More intensive studies are needed to further understand the nature of the interaction., (©2011 Bentham Science Publishers Ltd.)