Efficacy of daprodustat for patients on dialysis with anemia: systematic review and network meta-analysis.

Chronic kidney disease (CKD) is commonly complicated by anemia. Treating dialysis-dependent patients with anemia, including daprodustat and other inhibitors of prolyl hydroxylase of hypoxia-inducible factor, recombinant human erythropoietin (rhEPO), and iron supplements. We conducted this study to test our postulation; daprodustat is superior to rhEPO and other conventional treatments respecting efficacy and safety parameters. We made systematic search through PubMed, Web of Science, Scopus, and Cochrane. Seven unique trials were eventually included for systematic review; six of them with a sample size of 759 patients entered our network meta-analysis (NMA). Daprodustat 25-30 mg was associated with the greatest change in serum hemoglobin (MD=1.86, 95%CI= [1.20; 2.52]), ferritin (MD= -180.84, 95%CI= [-264.47; -97.20]), and total iron binding capacity (TIBC) (MD=11.03, 95%CI= [3.15; 18.92]) from baseline values. Dialysis-dependent patients with anemia had a significant increment in serum Hemoglobin and TIBC and a reduction in serum ferritin, in a dose-dependent manner, when administered daprodustat.

Glyoxalase System in Breast and Ovarian Cancers: Role of MEK/ERK/SMAD1 Pathway.

The glyoxalase system, comprising GLO1 and GLO2 enzymes, is integral in detoxifying methylglyoxal (MGO) generated during glycolysis, with dysregulation implicated in various cancer types. The MEK/ERK/SMAD1 signaling pathway, crucial in cellular processes, influences tumorigenesis, metastasis, and angiogenesis. Altered GLO1 expression in cancer showcases its complex role in cellular adaptation and cancer aggressiveness. GLO2 exhibits context-dependent functions, contributing to both proapoptotic and antiapoptotic effects in different cancer scenarios. Research highlights the interconnected nature of these systems, particularly in ovarian cancer and breast cancer. The glyoxalase system's involvement in drug resistance and its impact on the MEK/ERK/SMAD1 signaling cascade underscore their clinical significance. Furthermore, this review delves into the urgent need for effective biomarkers, exemplified in ovarian cancer, where the RAGE-ligand pathway emerges as a potential diagnostic tool. While therapeutic strategies targeting these pathways hold promise, this review emphasizes the challenges posed by context-dependent effects and intricate crosstalk within the cellular milieu. Insights into the molecular intricacies of these pathways offer a foundation for developing innovative therapeutic approaches, providing hope for enhanced cancer diagnostics and tailored treatment strategies.

Correction: Exploring the potential impact of applying web-based training program on nurses' knowledge, skills, and attitudes regarding evidence-based practice: A quasi-experimental study.

[This corrects the article DOI: 10.1371/journal.pone.0297071.].

Molecular Assessment of Methylglyoxal-Induced Toxicity and Therapeutic Approaches in Various Diseases: Exploring the Interplay with the Glyoxalase System.

This comprehensive exploration delves into the intricate interplay of methylglyoxal (MG) and glyoxalase 1 (GLO I) in various physiological and pathological contexts. The linchpin of the narrative revolves around the role of these small molecules in age-related issues, diabetes, obesity, cardiovascular diseases, and neurodegenerative disorders. Methylglyoxal, a reactive dicarbonyl metabolite, takes center stage, becoming a principal player in the development of AGEs and contributing to cell and tissue dysfunction. The dual facets of GLO I-activation and inhibition-unfold as potential therapeutic avenues. Activators, spanning synthetic drugs like candesartan to natural compounds like polyphenols and isothiocyanates, aim to restore GLO I function. These molecular enhancers showcase promising outcomes in conditions such as diabetic retinopathy, kidney disease, and beyond. On the contrary, GLO I inhibitors emerge as crucial players in cancer treatment, offering new possibilities in diseases associated with inflammation and multidrug resistance. The symphony of small molecules, from GLO I activators to inhibitors, presents a nuanced understanding of MG regulation. From natural compounds to synthetic drugs, each element contributes to a molecular orchestra, promising novel interventions and personalized approaches in the pursuit of health and wellbeing. The abstract concludes with an emphasis on the necessity of rigorous clinical trials to validate these findings and acknowledges the importance of individual variability in the complex landscape of health.

Exploring the potential impact of applying web-based training program on nurses' knowledge, skills, and attitudes regarding evidence-based practice: A quasi-experimental study.

Evidence-based practice (EBP) has gained significant importance in clinical practice worldwide, including in nursing. This study aimed to explore the potential impact of applying a web-based training program on nurses' knowledge, skills, and attitudes regarding EBP. A quasi-experimental pretest-posttest research design was utilized with a purposive sample of 64 professional nurses who agreed to participate. The study took place in different hospitals and primary healthcare centers in the Bisha Governorate, Aseer region, Saudi Arabia. A four-week standardized web-based training program was implemented using an online learning approach. Nurses were provided with an online self-rated data collection tool through the Google Forms platform. The findings indicated a highly significant difference in the total knowledge and EBP skills mean scores of the post-intervention (53.08±15.9) and (66.03±8.95), respectively compared to pre-intervention (P<0.05). Additionally, there was marked improvement in the mean scores of the positive attitude of the training sessions post-intervention compared to pre-intervention. The program was also well-received by the nurses in terms of quality and usability. The program has the potential to enhance nurses' knowledge, skills, and attitudes toward EBP. Therefore, healthcare organizations may consider adopting web-based training as a means of continuing professional education to promote EBP competencies among nurses.

Nurses' experiences and perspectives regarding evidence-based practice implementation in healthcare context: A qualitative study.

AIM: To explore nurses' experiences and perspectives about evidence-based practice (EBP) implementation in the healthcare context. DESIGN: A qualitative descriptive study design using focus group discussions (FGDs). METHOD: Sixty-four nurses who purposefully selected and worked at various healthcare organizations in Bisha Governorate, Saudi Arabia, were included. Eight FGDs were used to obtain data using open-ended questions. The collected data underwent inductive qualitative content analysis. RESULTS: Two main categories were extracted: experiences and perspectives towards EBP. The experiences category emerged into four sub-categories: familiarity with concepts and benefits, steps, dissemination sources of EBP and sources of EBP knowledge, while perspectives towards the EBP category included four sub-categories: application of EBP in clinical practice, barriers, facilitators and EBP application methods. The participants experienced being in a non-supportive and non-encouraging atmosphere which results from a lack of organizational commitment to EBP implementation and illuminates the complexities involved in the integration process. CONCLUSION: The nurses' experience with EBP indicated that there was limited support for the implementation of this approach. Furthermore, they experienced varying barriers to EBP implementation. They viewed EBP as a complex technique as they lacked knowledge and skills related to the formulation of research questions, and retrieving, applying and disseminating of EBP in clinical practice decision-making. That is due to barriers pertinent to the individual, organizational and patient factors. The key to successfully implementing an EBP in nursing practice is to promote professional development, comprehensive and continuous training, a culture of change, organizational support and motivation. CLINICAL RELEVANCE: Through the construction and provision of ongoing educational interventions and mentoring programmes about EBP, healthcare organizations and nursing leadership may develop a comprehensive strategy to encourage staff nurses' participation in the EBP process. This is to enhance nurses' experiences and perspectives towards the EBP approach and overcome the barriers to effective implementation. NO PATIENT OR PUBLIC CONTRIBUTION TO THIS STUDY: Patients or the general public were not involved in the design, analysis or interpretation of the data in this study.

The transcription factor HNF-4α: a key player in haematological disorders.

HNF-4α is a member of the steroid hormone receptor family of transcription factors with roles in the development of the liver and the regulation of several critical metabolic pathways, such as glycolysis, drug metabolism, apolipoproteins and blood coagulation. The transcriptional potency of HNF-4α is well known due to its involvement in diabetes and other metabolic diseases. However, recently HNF-4α has been discovered to be closely associated with several haematological disorders, mainly because of genetic mutations, drugs, and hepatic disorders. We review HNF-4α structure and function, and its role in haematological disorders. We discuss possible novel therapies that are based on targeting HNF-4α.

Safety and efficacy of daridorexant in the treatment of insomnia: a systematic review and meta-analysis of randomized controlled trials.

Daridorexant is a novel dual orexin receptor antagonist used in treating insomnia disorder. Daridorexant improves sleep quality without impairing daytime functioning. We assess the safety and efficacy of this novel drug in the treatment of insomnia. We performed a systematic search for electronic databases in SCOPUS, PubMed, Web of Science and the Cochrane library. Seven randomized controlled trials were included in this review, with 2425 participants enrolled. Daridorexant was superior to placebo in reducing wake time after sleep onset (MD = -13.26; 95% CI, -15.48 to -11.03; P < 0.00001), latency to persistent sleep (MD = -7.23; 95% CI, -9.60 to -4.85; P < 0.00001), with increasing the total sleep time (MD = 14.80; 95% CI, 11.18-18.42; P < 0.00001) and subjective total sleep time (MD = 14.80; 95% CI, 11.18-18.42], P < 0.00001). The 25 mg and 50 mg were the most officious doses. Treatment with daridorexant has resulted in a slightly higher incidence of adverse events [risk ratio (RR) = 1.19; 95% CI, 1.05-1.35;, P = 0.005], specifically somnolence (RR = 1.19; 95% CI, 1.13-3.23; P = 0.005) and fatigue (RR = 2.01; 95% CI, 1.21-3.36; P = 0.007). Daridorexant is superior to placebo in improving sleep quality. However, the drug resulted in a slightly higher incidence of adverse events, including somnolence and fatigue.

Association between inflammatory cytokines/chemokines, clinical laboratory parameters, disease severity and in-hospital mortality in critical and mild COVID-19 patients without comorbidities or immune-mediated diseases.

There are limited data on inflammatory cytokines and chemokines; the humoral immune response; and main clinical laboratory parameters as indicators for disease severity and mortality in patients with critical and mild COVID-19 without comorbidities or immune-mediated diseases in Saudi Arabia. We determined the expression levels of major proinflammatory cytokines and chemokines; C-reactive protein (CRP); procalcitonin; SARS-CoV-2 IgM antibody and twenty-two clinical laboratory parameters and assessed their usefulness as indicators of disease severity and in-hospital death. Our results showed a significant increase in the expression levels of SARS-CoV-2 IgM antibody; IL1-ß; IL-6; IL-8; TNF-α and CRP in critical COVID-19 patients; neutrophil count; urea; creatinine and troponin were also increased. The elevation of these biomarkers was significantly associated and positively correlated with in-hospital death in critical COVID-19 patients. Our results suggest that the levels of IL1-ß; IL-6; IL-8; TNF-α; and CRP; neutrophil count; urea; creatinine; and troponin could be used to predict disease severity in COVID-19 patients without comorbidities or immune-mediated diseases. These inflammatory mediators could be used as predictive early biomarkers of COVID-19 disease deterioration; shock and death among COVID-19 patients without comorbidities or immune-mediated diseases.

Percutaneous needle aspiration versus catheter drainage in the management of liver abscess: an updated systematic review and meta-analysis.

BACKGROUND: Liver abscesses differ in their aetiology, location, and number. Image-guided percutaneous drainage techniques are the currently used management for liver abscesses. We conducted our study to compare the clinical safety and efficacy of percutaneous needle aspiration (PNA) to percutaneous catheter drainage (PCD). METHODS: A systematic review of major reference databases was undertaken in February 2022 for randomized controlled trials (RCTs) that compare PNA to PCD in treating liver abscess patients. The quality of the included trials was assessed using the Cochrane tool. Statistical meta-analysis was conducted using RevMan and open meta-analyst software. RESULTS: Fifteen RCTs were included in this review, with 1676 patients enrolled. The overall quality of the included trials was moderate, with most domains of unclear risk. PCD was superior to PNA in the success rate (RR = 1.23; 95% CI [1.12, 1.36], P < 0.00001), time for achieving 50% reduction of cavity size (MD = -2.32; 95% CI [-3.07, -1.57], P < 0.00001), and time for clinical improvement (MD = -1.92; 95% CI [-2.55, -1.28], P < 0.00001). The two modalities did not differ in the days of hospital stay, duration of IV antibiotics, and time needed for total or subtotal reduction of cavity size (P = 0.36, P = 0.06 and P = 0.40, respectively). High heterogeneity levels were detected. Regarding major complications, the two modalities were equally safe (P = 0.39). CONCLUSION: PCD has a higher success rate and results in a faster 50% reduction in the abscess cavity size and clinical improvement. The two modalities are equally safe.

Recent Advances in Plant-Mediated Zinc Oxide Nanoparticles with Their Significant Biomedical Properties.

Compared to traditional physical and chemical approaches, nanobiotechnology and plant-based green synthesis procedures offer significant advantages, as well as having a greater range of medical and biotechnological applications. Nanoparticles of zinc oxide (ZnO NPs) have recently been recognized as a promising option for many industries, including optics, electrics, packaged foods, and medicine, due to their biocompatibility, low cytotoxicity, and cost-effectiveness. Several studies have shown that zinc ions are important in triggering cell apoptosis by promoting the generation of reactive oxygen species (ROSs) and releasing zinc ions (Zn2+), which are toxic to cells. The toxic nature of the chemicals used in the synthesis of ZnO nanoparticles limits their clinical utility. An overview of recent developments in green ZnO NP synthesis is presented in this review, emphasizing plant parts as reducing agents and their medical applications, including their antimicrobial, anticancer, antioxidant, and anti-inflammatory properties, as well as key mechanisms of action for these applications to facilitate further research on the biomedical fields in the future.

Evaluation of the Antibacterial Properties of Iron Oxide, Polyethylene Glycol, and Gentamicin Conjugated Nanoparticles against Some Multidrug-Resistant Bacteria.

Antibacterial resistance is observed as a public health issue around the world. Every day, new resistance mechanisms appear and spread over the world. For that reason, it is imperative to improve the treatment schemes that have been developed to treat infections caused by wound infections, for instance, Staphylococcus epidermidis (S. epidermidis), Proteus mirabilis (P. mirabilis), and Acinetobacter baumannii (A. baumannii). In this case, we proposed a method that involves mixing the Gentamicin (Gen) with iron oxide nanoparticles (Fe3O4 NPs) and a polymer (polyethylene glycol (PEG)) with Fe3O4 NPs. X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR), energy dispersive X-ray (EDX), scanning electron microscope (SEM), and transmission electron microscope (TEM) were used to characterize Fe3O4 NPs. Zeta potential and dynamic light scattering (DLS) were also assessed. The antibacterial activity of Fe3O4 NPs, Fe3O4 NPs+PEG, Fe3O4 NPs+Gen, and Fe3O4 NPs+PEG+Gen composites was investigated. The results showed a significant improvement in the antibacterial activity of nanoparticles against bacterial isolates, especially for the Fe3O4 NPs+PEG+Gen as the diameter of the inhibition zone reached 26.33 ± 0.57 mm for A. baumannii, 25.66 ± 0.57 mm for P. mirabilis, and 23.66 ± 0.57 mm for S. epidermidis. The Fe3O4 NPs, Fe3O4 NPs+PEG, Fe3O4+Gen, and Fe3O4+PEG+Gen also showed effectiveness against the biofilm produced by these isolated bacteria. The minimum inhibitory concentration (MIC) of Fe3O4 NPs for S. epidermidis was 25 µg mL-1 and for P. mirabilis and A. baumannii was 50 µg mL-1. The findings suggest that the prepared nanoparticles could be potential therapeutic options for treating wound infections caused by S. epidermidis, P. mirabilis, and A. baumannii.

Selenium and/or vitamin E upregulate the antioxidant gene expression and parameters in broilers.

BACKGROUND: In contrast to free radicals, the first line of protection is assumed to be vitamin E and selenium. The present protocol was designed to assess the roles of vitamin E and/or a selenium-rich diet that affected the blood iron and copper concentrations, liver tissue antioxidant and lipid peroxidation, and gene expression linked to antioxidants in the liver tissue of broilers. The young birds were classified according to the dietary supplement into four groups; control, vitamin E (100 mg Vitamin/kg diet), selenium (0.3 mg sodium selenite/kg diet), and vitamin E pulse selenium (100 mg vitamin/kg diet with 0.3 mg sodium selenite/kg diet) group. RESULTS: The results of this experiment suggested that the addition of vitamin E with selenium in the broiler diet significantly increased (P ≤ 0.05) serum iron when compared with the other groups and serum copper when compared with the vitamin E group. Moreover, the supplements (vitamin E or vitamin E with selenium) positively affected the enzymatic activity of the antioxidant-related enzymes with decreased malondialdehyde (MDA),which represents lipid peroxidation in broiler liver tissue. Moreover, the two supplements significantly upregulated genes expression related to antioxidants. CONCLUSION: Therefore, vitamin E and/or selenium can not only act as exogenous antioxidants to prevent oxidative damage by scavenging free radicals and superoxide, but also act as gene regulators, regulating the expression of endogenous antioxidant enzymes.

Differential impact of the angiotensin-converting enzyme-2 (ACE2 rs4343 G>A) and miR-196a2 rs11614913 C>T gene alterations in COVID-19 disease severity and mortality.

The recent coronavirus outbreak from Wuhan China in late 2019 caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) resulted in a global pandemic of coronavirus-19 disease (COVID-19). Understating the underlying mechanism of the pathogenesis of coronavirus infection is important not only because it will help in accurate diagnosis and treatment of the infection but also in the production of effective vaccines. The infection begins when SARS-CoV-2 enters the cells through binding of its envelope glycoprotein to angiotensin-converting enzyme2 (ACE2). Gene variations of ACE2 and microRNA (miR)-196 are associated with viral infection and other diseases. The present study investigated the association of the ACE2 rs4343 G>A and miR-196a2 rs11614913 C>T gene polymorphisms with severity and mortality of COVID-19 using amplification refractory mutation system PCR in 117 COVID-19 patients and 103 healthy controls from three regions of Saudi Arabia. The results showed that ACE2 rs4343 GA genotype was associated with severity of COVID-19 (OR=2.10, P-value 0.0028) and ACE2 rs4343 GA was associated with increased mortality with OR=3.44, P-value 0.0028. A strong correlation between the ACE2 rs4343 G>A genotype distribution among COVID-19 patients was reported with respect to their comorbid conditions including sex (P<0.023), coronary artery disease (P<0.0001), oxygen saturation <60 mm Hg (P<0.0009) and antiviral therapy (0.003). The results also showed that the CT genotype and T allele of the miR-196a2 rs11614913 C>T were associated with decreased risk to COVID-19 with OR=0.76, P=0.006 and OR=0.54, P=0.005, respectively. These results need to be validated with future molecular genetic studies in a larger sample size and different populations.

Shuttle Transfer of mRNA Transcripts via Extracellular Vesicles From Male Reproductive Tract Cells to the Cumulus-Oocyte Complex in Rabbits (Oryctolagus cuniculus).

Semen is known to contain an ovulation-inducing factor (identified as a nerve growth factor, NGF) that shows a significant increase in ovulation after semen deposition in induced ovulatory species. However, the interplay between the male reproductive tract cells and oocyte maturation through messenger RNA (mRNA) cargo is yet to be investigated. Extracellular vesicles (EVs) from the primary culture of rabbit prostate (pEVs), epididymis (eEVs), and testis (tEVs) were isolated to examine their contents for several mRNA transcripts through relative quantitative PCR (RT-qPCR). The expressions of NGF, neurotrophin (NTF3), vascular endothelial growth factor A (VEGFA), A disintegrin and metalloprotease 17 (ADAM17), midkine (MDK), kisspeptin (KISS1), and gonadotrophin-releasing hormone (GNRH1) were examined in isolated EVs. EVs were characterized through transmission electron microscopy. EV uptake by cumulus cell culture was confirmed through microscopic detection of PKH26-stained EVs. Furthermore, the effects of pEVs, eEVs, and tEVs were compared with NGF (10, 20, and 30 ng/ml) supplementation on oocyte in vitro maturation (IVM) and transcript expression. KISS1, NTF3, MDK, ADAM17, GAPDH, and ACTB were detected in all EV types. GNRH1 was detected in tEVs. NGF was detected in pEVs, whereas VEGFA was detected in eEVs. pEVs, eEVs, and 20 ng/ml NGF showed the highest grade of cumulus expansion, followed by tEVs and 10 ng/ml NGF. Control groups and 30 ng/ml NGF showed the least grade of cumulus expansion. Similarly, first polar body (PB) extrusion was significantly increased in oocytes matured with eEVs, pEVs, tEVs, NGF20 (20 ng/ml NGF), NGF10 (10 ng/ml NGF), control, and NGF30 (30 ng/ml NGF). Additionally, the expression of NGFR showed a 1.5-fold increase in cumulus cells supplemented with eEVs compared with the control group, while the expression of PTGS2 (COX2) and NTRK showed 3-fold and 5-fold increase in NGF20-supplemented cumulus-oocyte complexes (COCs), respectively. Oocyte PMP15 expression showed a 1.8-fold increase in IVM medium supplemented with eEVs. Additionally, oocyte NGFR and NTRK expressions were drastically increased in IVM medium supplemented with pEVS (3.2- and 1.6-fold, respectively) and tEVs (4- and 1.7-fold, respectively). This is the first report to examine the presence of mRNA cargo in the EVs of male rabbit reproductive tract cells that provides a model for the stimulation of female rabbits after semen deposition.

Clinical Implications of Glyoxalase1 Gene Polymorphism and Elevated Levels of the Reactive Metabolite Methylglyoxal in the Susceptibility of Type 2 Diabetes Mellitus in the Patients from Asir and Tabuk Regions of Saudi Arabia.

Diabetes mellitus constitutes a big challenge to the global health care system due to its socioeconomic impacts and very serious complications. The incidence and the prevalence rate are increased in the Gulf region including the KSA. Type 2 diabetes mellitus (T2DM) is caused by diverse risk factors including obesity, unhealthy dietary habits, physical inactivity, smoking and genetic factors. The molecular genetic studies have helped in the detection of many single nucleotide polymorphisms (SNP) with different diseases including cancers, cardiovascular diseases and T2DM. The glyoxalase 1 (GLO1) is a detoxifying enzyme and catalyzes the elimination of the cytotoxic product methylglyoxal (MG) by converting it to D-lactate, which is not toxic to tissues. MG accumulation is associated with the pathogenesis of different diseases including T2DM. In this study, we have investigated the association of the glyoxalase 1 SNPs (rs2736654) rs4746 C>A and rs1130534 T>A with T2DM using the amplification refractory mutation system PCR. We also measured the concentration of MG by ELISA in T2DM patients and matched heathy controls. Results show that the CA genotype of the GLO rs4647 A>C was associated with T2DM with OR = 2.57, p-value 0.0008 and the C allele was also associated with increased risk to T2DM with OR = 2.24, p-value = 0.0001. It was also observed that AT genotype of the rs1130534 was associated with decreased susceptibility to T2DM with OR = 0.3, p-value = 0.02. The A allele of rs1130534 was also associated with reduced risk to T2DM with PR = 0.27 = 0.006. In addition, our ELISA results demonstrate significantly increased MG concentrations in serum of the T2DM patients. We conclude that the GLO1 SNP may be associated with decreased enzyme activity and a resultant susceptibility to T2DM. Further well-designed studies in different and large patient populations are recommended to verify these findings.

Insighting the optoelectronic, charge transfer and biological potential of benzo-thiadiazole and its derivatives.

The current investigation applies the dual approach containing quantum chemical and molecular docking techniques to explore the potential of benzothiadiazole (BTz) and its derivatives as efficient electronic and bioactive materials. The charge transport, electronic and optical properties of BTz derivatives are explored by quantum chemical techniques. The density functional theory (DFT) and time dependent DFT (TD-DFT) at B3LYP/6-31G** level of theory utilized to optimize BTz and newly designed ligands at the ground and first excited states, respectively. The heteroatoms substitution effects on different properties of 4,7-bis(4-methylthiophene-2yl) benzo[c] [1,2,5]thiadiazole (BTz2T) as initial compound are studied at molecular level. Additionally, we also study the possible inhibition potential of COVID-19 from benzothiadiazole (BTz) containing derivatives by implementing the grid based molecular docking methods. All the newly designed ligands docked with the main protease (MPRO:PDB ID 6LU7) protein of COVID-19 through molecular docking methods. The studied compounds showed strong binding affinities with the binding site of MPRO ranging from -6.9 to -7.4 kcal/mol. Furthermore, the pharmacokinetic properties of the ligands are also studied. The analysis of these results indicates that the studied ligands might be promising drug candidates as well as suitable for photovoltaic applications.

Silica Nanoparticle Acute Toxicity on Male Rattus norvegicus Domestica: Ethological Behavior, Hematological Disorders, Biochemical Analyses, Hepato-Renal Function, and Antioxidant-Immune Response.

With extensive production and various applications of silica nanoparticles (SiNPs), there is a controversy regarding the ecotoxicological impacts of SiNPs. Therefore, the current study was aimed to assess the acute toxicity of silica nanoparticles in male Rattus norvegicus domestica after 24 and 96 h. Hematological, serum biochemical, stress biomarker, and immune-antioxidant parameters were addressed. Chemical composition, crystal structure, and the particle shape and morphology of SiNPs were investigated using XRD, FTIR, BET, UV-Vis, and SEM, while TEM was used to estimate the average size distribution of particles. For the exposure experiment, 48 male rats were divided into four groups (12 rat/group) and gavaged daily with different levels of zero (control), 5, 10, and 20 mg of SiNPs corresponding to zero, 31.25, 62.5, and 125 mg per kg of body weight. Sampling was carried out after 24 and 96 h. Relative to the control group, the exposure to SiNPs induced clear behavioral changes such as inactivity, lethargy, aggressiveness, and screaming. In a dose-dependent manner, the behavior scores recorded the highest values. Pairwise comparisons with the control demonstrated a significant (p < 0.05) decrease in hematological and immunological biomarkers [lysozymes and alternative complement activity (ACH50)] with a concomitant reduction in the antioxidant enzymes [catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD)] in all exposed groups to SiNPs. On the contrary, there was a noticeable increase in biochemical parameters (glucose, cortisol, creatinine, urea, low-density lipoproteins (LDL), high-density lipoproteins (HDL), total protein, and albumin) and hepato-renal indicators, including alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST), of all SiNP-exposed groups. It was observed that SiNPs induced acute toxicity, either after 24 h or 96 h, post-exposure of rats to SiNPs evidenced by ethological changes, hepato-renal dysfunction, hyperlipemia, and severe suppression in hematological, protein, stress, and immune-antioxidant biomarkers reflecting an impaired physiological status. The obtained outcomes create a foundation for future research to consider the acute toxicity of nanoparticles to preserve human health and sustain the environment.

Potential impact of GCK, MIR-196A-2 and MIR-423 gene abnormalities on the development and progression of type 2 diabetes mellitus in Asir and Tabuk regions of Saudi Arabia.

Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by persistent hyperglycemia and is associated with serious complications. The risk factors for T2DM include both genetic and lifestyle factors. Genome­wide association studies have indicated the association of genetic variations with many diseases, including T2DM. Glucokinase (GCK) plays a key role in the regulation of insulin release in the pancreas and catalyzes the first step in glycolysis in the liver. Genetic alterations in the GCK gene have been implicated in both hyperglycemia and hypoglycemia. MicroRNAs (miRNAs/miRs) are small non­coding RNA molecules that are involved in the important physiological processes including glucose metabolism. In the present study, the association of the single nucleotide polymorphisms (SNPs) in the GCK, MIR­196A­2 and MIR­423 genes with susceptibility to T2DM in patients from two regions of Saudi Arabia were examined, using the tetra­primer amplification refractory mutation system. The results showed that the AA genotype and the A allele of GCK rs1799884 were associated with T2DM [odds ratio (OR)=2.25, P=0.032 and OR=1.55, P=0.021, respectively]. Likewise, the CT genotype and T allele of MIR­196A­2 rs11614913 were associated with an increased risk of T2DM (OR=2.36, P=0.0059 and OR=1.74, P=0.023, respectively). In addition, the CA genotype of MIR­423 rs6505162 C>A was found to be linked with T2DM (OR=2.12 and P=0.021). It was concluded in the present research study that gene variations in GCK, MIR­196A­2 and MIR­423 are potentially associated with an increased risk of T2DM. These results, in the future, may help in the identification and stratification of individuals susceptible to T2DM. Future longitudinal studies with larger sample sizes and in different ethnic populations are recommended to validate these findings.

Studies of Glyoxalase 1-Linked Multidrug Resistance Reveal Glycolysis-Derived Reactive Metabolite, Methylglyoxal, Is a Common Contributor in Cancer Chemotherapy Targeting the Spliceosome.

BACKGROUND: Tumor glycolysis is a target for cancer chemotherapy. Methylglyoxal (MG) is a reactive metabolite formed mainly as a by-product in anaerobic glycolysis, metabolized by glyoxalase 1 (Glo1) of the glyoxalase system. We investigated the role of MG and Glo1 in cancer chemotherapy related in multidrug resistance (MDR). METHODS: Human Glo1 was overexpressed in HEK293 cells and the effect on anticancer drug potency, drug-induced increase in MG and mechanism of cytotoxicity characterized. Drug-induced increased MG and the mechanisms driving it were investigated and the proteomic response to MG-induced cytotoxicity explored by high mass resolution proteomics of cytoplasmic and other subcellular protein extracts. Glo1 expression data of 1,040 human tumor cell lines and 7,489 tumors were examined for functional correlates and impact of cancer patient survival. RESULTS: Overexpression of Glo1 decreased cytotoxicity of antitumor drugs, impairing antiproliferative activity of alkylating agents, topoisomerase inhibitors, antitubulins, and antimetabolites. Antitumor drugs increased MG to cytotoxic levels which contributed to the cytotoxic, antiproliferative mechanism of action, consistent with Glo1-mediated MDR. This was linked to off-target effects of drugs on glycolysis and was potentiated in hypoxia. MG activated the intrinsic pathway of apoptosis, with decrease of mitochondrial and spliceosomal proteins. Spliceosomal proteins were targets of MG modification. Spliceosomal gene expression correlated positively with Glo1 in human tumor cell lines and tumors. In clinical chemotherapy of breast cancer, increased expression of Glo1 was associated with decreased patient survival, with hazard ratio (HR) = 1.82 (logrank p < 0.001, n = 683) where upper quartile survival of patients was decreased by 64% with high Glo1 expression. CONCLUSIONS: We conclude that MG-mediated cytotoxicity contributes to the cancer chemotherapeutic response and targets the spliceosome. High expression of Glo1 contributes to multidrug resistance by shielding the spliceosome from MG modification and decreasing survival in the chemotherapy of breast cancer. Adjunct chemotherapy with Glo1 inhibitor may improve treatment outcomes.