Epigenetic alterations of miR-155 and global DNA methylation as potential mediators of ochratoxin A cytotoxicity and carcinogenicity in human lung fibroblasts.

Ochratoxin A (OTA) is a well-known mycotoxin that adversely affects different human cells. Inhalational exposure to OTA and subsequent pulmonary diseases have been previously reported, yet its potential carcinogenicity and underlying molecular mechanisms have not been fully elucidated. This study aimed to evaluate the OTA-induced cytotoxicity and the epigenetic changes underlying its potential carcinogenicity in fetal lung fibroblast (WI-38) cells. OTA cytotoxicity was assessed by MTT assay; RT-qPCR was used to determine the expression of BAX, BCL-2, TP53, and miR-155, while ELISA was used for measuring 5-methyl cytosine percentage to assess global DNA methylation in OTA-treated versus control cells. WI-38 cells demonstrated sensitivity to OTA with IC50 at 22.38 µM. Though BAX and Bcl-2 were downregulated, with low BAX/BCL-2 ratio, and TP53 was upregulated, their fold changes showed decline trend with increasing OTA concentration. A significant dose-dependent miR-155 upregulation was observed, with dynamic time-related decline. Using subtoxic OTA concentrations, a significant global DNA hypermethylation with significant dose-dependent and dynamic alterations was identified. Global DNA hypermethylation and miR-155 upregulation are epigenetic mechanisms that mediate OTA toxicity on WI-38 cells. BAX downregulation, reduced BAX/BCL-2 ratio together with miR-155 upregulation indicated either the inhibition of TP53-dependent apoptosis or a tissue specific response to OTA exposure. The aforementioned OTA-induced variations present a new molecular evidence of OTA cytotoxicity and possible carcinogenicity in lung fibroblast cells.

Exploiting Signal Joint T Cell Receptor Excision Circle to Investigate the Impact of COVID-19 and Autoimmune Diseases on Age Prediction and Immunosenescence.

Signal joint T cell receptor excision circles (sjTRECs) are a promising marker for age estimation and immunosenescence in different ethnic groups. Several limitations are expected to overshadow their use as accurate markers for age prediction. The current study was conducted to determine the influence of immunologic disorders, such as autoimmune diseases and COVID-19, on the accuracy of sjTRECs as molecular markers for age estimation and immunosenescence among living Egyptians. Peripheral blood sjTRECs level was measured by qPCR in 90 autoimmune patients, 58 COVID-19 patients, and 85 healthy controls. The mean dCt values were significantly (p = 0.0002) different between the three groups, with the highest values in healthy subjects, followed by autoimmune and COVID-19 patients. A significant negative correlation was identified between the sjTRECs levels and ages in all studied cases. There were significant positive correlations between chronological age and predicted age for healthy individuals, autoimmune, and COVID-19 patients with mean absolute deviations (MAD) of 9.40, 11.04, and 9.71, respectively. The two patients' groups exhibited early immunosenescence, which was more noticeable among the young adults with COVID-19 and autoimmune patients of age range (18-49 years). Autoimmunity may represent a critical factor impacting the accuracy of sjTRECs quantitation for age prediction.

Elevated plasma level of the glycolysis byproduct methylglyoxal on admission is an independent biomarker of mortality in ICU COVID-19 patients.

Biomarkers to identify ICU COVID-19 patients at high risk for mortality are urgently needed for therapeutic care and management. Here we found plasma levels of the glycolysis byproduct methylglyoxal (MG) were 4.4-fold higher in ICU patients upon admission that later died (n = 33), and 1.7-fold higher in ICU patients that survived (n = 32),compared to uninfected controls (n = 30). The increased MG in patients that died correlated inversely with the levels of the MG-degrading enzyme glyoxalase-1 (r2 = - 0.50), and its co-factor glutathione (r2 = - 0.63), and positively with monocytes (r2 = 0.29). The inflammation markers, SSAO (r2 = 0.52), TNF-α (r2 = 0.41), IL-1ß (r2 = 0.25), CRP (r2 = 0.26) also correlated positively with MG. Logistic regression analysis provides evidence of a significant relationship between the elevated MG upon admission into ICU and death (P < 0.0001), with 42% of the death variability explained. From these data we conclude that elevated plasma MG on admission is a novel independent biomarker that predicts mortality in ICU COVID-19 patients.

Obviation of dyslipidemia by garlic oil and its organosulfur compound, diallyl disulphide, in experimental animals.

Background and objectives: Garlic and its number of preparations are known to be effective for treatment of dyslipidemia, but the data about the specific active constituents of the garlic on the possible therapeutic value is scarce. Therefore, the aim of this research was to evaluate the role of garlic oil (GO) and its active element, diallyl disulphide (DADS) for obviating dyslipidemia in animal model. Methods: High fat diet (HFD) was given to animals to induce dyslipidemia. Animals of HFD groups were fed with atherogenic diet for 15 days prior to treatment. Animals in their respective groups received vehicle, GO (50 and 100 mg/kg), and DADS (4.47 and 8.94 mg/kg) for five consecutive days. Lipid profiles were estimated in serum, oxidant/antioxidant and liver profile were measured in liver tissue homogenate (LTH). Results: Animals fed on HFD developed significant increase in the serum levels of triglycerides (TG), total cholesterol (TC), lactate dehydrogenase (LDL), malondialdehyde (MDA), glutathione peroxidase (GSHPx), glutathione (GSH), and glutathione disulfide (GSSG) that reduced significantly in groups that received GO and DADS treatments. Additionally, significant elevation in serum high density lipoprotein (HDL) level was observed in animals that received GO and DADS. Moreover, hepatic markers such as alkaline phosphatase (ALP), aspartate aminotransferase (AST), and alanine transferase (ALT), that were abnormally altered by high fat diet, were significantly restored to almost normal values with GO and DADS treatments. Also, antioxidants such as superoxide dismutase (SOD), catalase (CAT), ferric reducing antioxidant power (FRAP), and total thiol (SH) levels in LTH were increased significantly in GO and DADS treated groups. When compared to DADS, GO showed better therapeutic effectiveness in terms of antihyperlipidemic and antioxidant properties. Conclusion: In hyperlipidemic rats, garlic and its principal active component, diallyl disulphide, were effective in avoiding dyslipidemia and neutralizing reactive free radicals induced by a high fat diet. It's an intriguing observation that GO has a larger therapeutic influence than its active constituent, DADS. These findings suggest that other constituents, in addition to GO's DADS, are involved in the compound's synergistic antihyperlipidemic and antioxidant activities.

In Silico Analysis of the L-2-Hydroxyglutarate Dehydrogenase Gene Mutations and Their Biological Impact on Disease Etiology.

The L-2-hydroxyglutarate dehydrogenase (L2HGDH) gene encodes an important mitochondrial enzyme. However, its altered activity results in excessive levels of L-2-hydroxyglutarate, which results in diverse psychiatric features of intellectual disability. In the current study, we executed an in-silico analysis of all reported L2HGDH missense and nonsense variants in order to investigate their biological significance. Among the superimposed 3D models, the highest similarity index for a wild-type structure was shown by the mutant Glu336Lys (87.26%), while the lowest similarity index value was shown by Arg70* (10.00%). Three large active site pockets were determined using protein active site prediction, in which the 2nd largest pocket was shown to encompass the substrate L-2-hydroxyglutarate (L2HG) binding residues, i.e., 89Gln, 195Tyr, 402Ala, 403Gly and 404Val. Moreover, interactions of wild-type and mutant L2HGDH variants with the close functional interactor D2HGDH protein resulted in alterations in the position, number and nature of networking residues. We observed that the binding of L2HG with the L2HGDH enzyme is affected by the nature of the amino acid substitution, as well as the number and nature of bonds between the substrate and protein molecule, which are able to affect its biological activity.

Preparation of Losartan Potassium Controlled Release Matrices and In-Vitro Investigation Using Rate Controlling Agents.

Controlled release matrices have predictable drug release kinetics, provide drugs for an extended period of time, and reduce dosing frequency with improved patient compliance as compared with conventional tablet dosage forms. In the current research work, losartan potassium controlled release matrix tablets were fabricated and prepared with rate altering agents; that is, Ethocel grade 100 combined with Carbopol 934PNF. Various drug to polymer ratios were used. HPMC, CMC, and starch were incorporated in some of the matrices by replacing some amount of filler (5%). The direct compression method was adopted for the preparation of matrices. In phosphate buffer (pH 6.8), the dissolution study was conducted by adopting the USP method-I as the specified method. Drug release kinetics was determined and dissolution profiles were also compared with the reference standard. Prolonged release was observed for all matrices, but those with Ethocel 100FP Premium showed more extended release. The co-excipient (HPMC, CMC, and starch) exhibited enhancement in the drug release rates, while all controlled release matrices released the drug by anamolous non-Fickian diffusion mechanism. This combination of polymers (Ethocel grade 100 with Carbopol 934PNF) efficiently extended the drug release rates up to 24 h. It is suggested that these matrix tablets can be given in once a day dosage, which might improve patient compliance, and the polymeric blend of Ethocel grade 100 with Carbopol 934PNF might be used in the development of prolonged release matrices of other water-soluble drugs.

The role of serotonergic and catecholaminergic systems for possible antidepressant activity of apigenin.

BACKGROUND AND OBJECTIVE: Although, the anti-depressant like effects of apigenin (APG) are documented in the literature, the underlying mechanism for exerting such an effect is still not clear. In this research, an attempt was made to determine the possible role of APG for antidepressant activity through serotonergic and catecholaminergic systems using standardized animal models. MATERIALS AND METHODS: The antidepressant property of APG was determine by involving tail suspension (TST) and modified forced swimming tests (MFST). The effect of APG was evaluated at 25 and 50 mg/kg. In mechanistic models, animals were pretreated with catecholaminergic and serotonergic antagonists prior to administration of APG. The results obtained were statistically analyzed to determine the level of significance. RESULTS: The period of immobility in both models (TST and MFST) was significantly reduced by APG (25 and 50 mg/kg). The best therapetuic dose of APG (50 mg/kg) was selected for the mechanistic study. The anti-immobility effect of APG declined to a significant extent upon pretreatment with catecholaminergic antagonists (α-methyl-para-tyrosine methyl ester; SCH 23390; sulpiride; phentolamine) and serotonergic inhibitors (p-clorophenylalanine-methyl-ester; ondansetron) in both TST and MFST models. The antidepressant benefits of apigenin were only modestly reversed when rats were given propranolol. CONCLUSIONS: The findings suggest that APG's antidepressant effect is mediated by the α-adrenergic, dopaminergic and 5-HT3 serotonergic receptors.

Nanotechnology Integration for SARS-CoV-2 Diagnosis and Treatment: An Approach to Preventing Pandemic.

The SARS-CoV-2 outbreak is the COVID-19 disease, which has caused massive health devastation, prompting the World Health Organization to declare a worldwide health emergency. The corona virus infected millions of people worldwide, and many died as a result of a lack of particular medications. The current emergency necessitates extensive therapy in order to stop the spread of the coronavirus. There are various vaccinations available, but no validated COVID-19 treatments. Since its outbreak, many therapeutics have been tested, including the use of repurposed medications, nucleoside inhibitors, protease inhibitors, broad spectrum antivirals, convalescence plasma therapies, immune-modulators, and monoclonal antibodies. However, these approaches have not yielded any outcomes and are mostly used to alleviate symptoms associated with potentially fatal adverse drug reactions. Nanoparticles, on the other hand, may prove to be an effective treatment for COVID-19. They can be designed to boost the efficacy of currently available antiviral medications or to trigger a rapid immune response against COVID-19. In the last decade, there has been significant progress in nanotechnology. This review focuses on the virus's basic structure, pathogenesis, and current treatment options for COVID-19. This study addresses nanotechnology and its applications in diagnosis, prevention, treatment, and targeted vaccine delivery, laying the groundwork for a successful pandemic fight.

Wireless Networking-Driven Healthcare Approaches in Combating COVID-19.

Since its outbreak, the coronavirus (COVID-19) pandemic has caused havoc on people's lives. All activities were paused due to the virus's spread across the continents. Researchers have been working hard to find new medication treatments for the COVID-19 pandemic. The World Health Organization (WHO) recommends that safety and self-measures play a major role in preventing the virus from spreading from one person to another. Wireless technology is playing a critical role in avoiding viral propagation. This technology mainly comprises of portable devices that assist self-isolated patients in adhering to safe precautionary measures. Government officials are currently using wireless technologies to identify infected people at large gatherings. In this research, we gave an overview of wireless technologies that assisted the general public and healthcare professionals in maintaining effective healthcare services during COVID-19. We also discussed the possible challenges faced by them for effective implementation in day-to-day life. In conclusion, wireless technologies are one of the best techniques in today's age to effectively combat the pandemic.

Psychometric testing of the mental health inventory in an Arabian context: Cross-cultural validation study.

AIM: The aim of this study is to establish a valid and reliable culturally adapted instrument which can be used in the Arabian context to measure emotional well-being. DESIGN: The Mental Health Inventory tool was used to investigate the emotional well-being of Saudi nursing students. The instrument was originally developed in English and in a western cultural setting. As such, there was a need to translate and validate the instrument in Arabic for use in the Arabian setting. METHODS: The Arabic version MHI 38 (AV-MHI-38) was translated, reviewed and revised, then evaluated with a sample of Arabic-speaking nursing students from Saudi Arabia using cross-sectional multicentre survey approach. An iterative forward-backward-forward sequence of item translation and review by a bilingual and bicultural expert panel was then completed. The psychometric properties of the AV-MHI-38 were examined through an exploratory factor analysis, confirmatory factor analysis, correlation among factors and reliability assessment. RESULTS: The sample consisted of 252 nursing students from two different universities located in different geographic regions in Saudi Arabia. The mean age was 20.93 years, made up of 230 female and 22 male participants. An a priori two-factor model showed satisfactory fit with modifications. Results indicated two component AV-MHI-38 with 46.09% of the total variance and excellent internal consistency. The AV-MHI-38 had good psychometric properties and the two subscales had good internal consistency with Cronbach's and acceptable reliability measures. The AV-MHI can be used to assess emotional well-being among Arabic-speaking populations of nursing students, nurses and other healthcare providers. The instrument can be used to identify the emotional well-being of students and initiating strategies to support them to decrease their study and work-related stress, anxiety and depression.