High Mobility Group Box 1 Gene Polymorphism and Serum High Mobility Group Box 1, Interleukin 1 Beta, and Alpha-Klotho Crosstalk in Severe COVID-19 Patients.

AIM: To evaluate the serum levels of HMGB1, IL1ß, and α-klotho in COVID-19 patients with different disease severity, investigate their association with clinicopathological parameters, and to assess HMGB1 rs1045411 polymorphism and its relation with clinical severity. METHODS: 120 COVID-19 patients (89 critically ill, 15 severe, and 16 moderately severe) along with 80 healthy control were enrolled.The serum levels of HMGB1,IL1ß, and α-klotho were determined by ELISA. The HMGB1 rs1045411 polymorphism was detected by RT- PCR. RESULTS: The serum levels of HMGB1, IL1ß, and α-klotho were significantly higher in critically ill COVID-19 patients compared to other groups. The HMGB1rs1045411 polymorphism revealed a significant decrease in the percentage of T/T genotypes in COVID-19 patients compared to controls. The (ROC) analysis showed moderate diagnostic potential for serum HMGB1, IL1ß, and α-klotho. CONCLUSION: The serum HMGB1, IL1ß, and α-klotho may be severity markers and promising therapeutic targets for COVID-19 patients.

Antitumor activity and targeting p53-PUMA mRNA expression by 5-flurouracil PLGA-lipid polymeric nanoparticles in mouse mammary carcinomas: comparison to free 5-flurouracil.

Polymeric poly (lactic-co-glycolic acid) (PLGA)-lipid hybrid nanoparticles (PNPs)-based therapy are powerful carriers for various therapeutic agents. This study was conducted to evaluate the chemotherapeutic potential of free 5-flurouracil (5FU) and synthetized 5FU-PNPs and impact on p53-dependent apoptosis in mammary carcinomas (MCs) grown in mice. Breast cancer cells were injected in Swiss albino female mice and 2 bilateral masses of MC were confirmed after one week. Mice were distributed to five experimental groups; Group 1: MC control group. Groups 2 and 3: MC + free 5FU [5 or 10 mg per kg] groups. Groups 4 and 5: synthetized MC+ 5FU-PNPs [5 or 10 mg per kg] groups. Medications were administered orally, twice weekly for 3 weeks. Then, tumors were dissected, and sections were stained with hematoxylin-eosin (HE) while the other MC was used for measuring of cell death and inflammatory markers. Treatment with 5FU-PNPs suppressed the MC masses and pathologic scores based on HE-staining. Similarly, greater proapoptotic activity was recorded in 5FU-PNPs groups compared to free 5FU groups as shown by significant upregulation in tumoral p53 immunostaining. The current results encourage the utility of PNPs for improving the antitumor effect of 5FU. The chemotherapeutic potential was mediated through enhancement of tumoral p53-mediated p53 up-regulated modulator of apoptosis (PUMA) genes. Additional studies are warranted for testing the antitumor activity of this preparation in other mouse models of breast cancer.

Betanin improves motor function and alleviates experimental Parkinsonism via downregulation of TLR4/MyD88/NF-κB pathway: Molecular docking and biological investigations.

Parkinson's disease (PD) is a progressive neuroinflammatory and degenerative disease. In this study, we investigated the neuroprotective action of betanin in the rotenone-induced Parkinson-like mice model. Twenty-eight adult male Swiss albino mice were divided into four groups: Vehicle, Rotenone, Rotenone + Betanin 50 mg/kg, and Rotenone + Betanin 100 mg/kg. Parkinsonism was induced by subcutaneous injection of 9 doses of rotenone (1 mg/kg/48 h) plus betanin at 50 and 100 mg/kg/48 h in rotenone + betanin groups for twenty days. Motor dysfunction was assessed after the end of the therapeutic period using the pole, rotarod, open-field, grid, and cylinder tests. Malondialdehyde, reduced glutathione (GSH), Toll-like receptor 4 (TLR4), myeloid differentiation primary response-88 (MyD88), nuclear factor kappa- B (NF-κB), neuronal degeneration in the striatum were evaluated. In addition, we assessed the immunohistochemical densities of tyrosine hydroxylase (TH) in Str and in substantia nigra compacta (SNpc). Our results showed that rotenone remarkably decreased (results of tests), increased decreased TH density with a significant increase in MDA, TLR4, MyD88, NF-κB, and a decrease in GSH (p < 0.05). Treatment with betanin significantly results of tests), increased TH density. Furthermore, betanin significantly downregulated malondialdehyde and improved GSH. Additionally, the expression of TLR4, MyD88, and NF-κB was significantly alleviated. Betanin's powerful antioxidative and anti-inflammatory properties can be related to its neuroprotective potential as well as its ability to delay or prevent neurodegeneration in PD.

Memantine mitigates ROS/TXNIP/NLRP3 signaling and protects against mouse diabetic retinopathy: Histopathologic, ultrastructural and bioinformatic studies.

Diabetic retinopathy (DRET) triggers vision loss in adults, however, little therapeutic options are existing. Memantine is an anti-Alzheimer drug that antagonizes the activity of glutamate at N-methyl-D-aspartate (NMDA) receptors. Glutamate and thioredoxin-interacting protein (TXNIP) are known to be overexpressed in diabetic retinas and can produce activation of NOD-like receptor protein 3 (NLRP3) with subsequent secretion of interlukin-1ß. This study repurposed memantine for its neuroprotective effect in experimental DRET and tested its impact on ROS/TXNIP/NLRP3. In addition, KEGG pathway database and STRING database identified the protein-protein interaction between glutamate receptors and TXNIP/NLRP3. Male Swiss albino mice received alloxan (180 mg/kg) to induce DRET. After 9 weeks, we divided the mice into groups: (a) saline, (ii) DRET, (iii and iv) DRET + oral memantine (5 or 10 mg per kg) for 28 days. Then, mice were euthanized, and eyeballs were removed. Retinal samples were utilized for biochemical, histopathological, and electron microscopy studies. Retinal levels of glutamate, TXNIP, NLRP3 and interlukin-1ß were estimated using ELISA technique as well as retinal malondialdehyde. Histopathological and ultrastructural examination demonstrated that oral memantine attenuated vacuolization and restored normal retinal cell layers. Moreover, memantine reduced TXNIP, NLRP3, interleukin-1ß and MDA concentrations. These results provide evidence demonstrating memantine' efficacy in alleviating DRET via suppressing reactive oxygen species/TXNIP/NLRP3 signaling cascade. Therefore, memantine might serve as a potential therapy for retinopathy after adequate clinical research.

Association of Interleukin-17F Polymorphism and Mortality Predictors with the Risk of COVID-19.

Background: Th-17 cells, a proinflammatory subset of CD4 T lymphocytes, have been suggested as a possible cause of coronavirus disease-19 (COVID-19)-related immunological injuries. The aim of this study was to investigate the relationship between IL-17F (rs763780) polymorphism and the susceptibility to and outcomes of COVID-19 infection and to determine the clinical and laboratory predictors of COVID-19 death. Methods: This case-control study included 132 COVID-19 patients and 135 healthy age- and sex-matched controls. The participants were tested for IL-17F rs763780 polymorphism via TaqMan-based genotyping and for the expression of IL-17 by enzyme-linked immunosorbent assay. This study also investigated the predictors for COVID-19 mortality. Results: A non-statistically significant association was observed between IL-17F alleles and genotypes with COVID-19 (P=0.309, P=0.138, respectively). Moreover, no significant difference in the IL-17F genotypes was observed between non-survivors and survivors (P=0.482). In the multivariate analysis, the participants with the following characteristics had 17.7-, 11.2-, 8-, and 17.9-fold higher odds of exhibiting in-hospital mortality, respectively: (1) hypertension, (2) age of >57 years, (3) WBC count of >12.6 × 103/mm3, and (4) D-dimer of >0.9 ng/ml. The ROC curve analysis showed that IL-17 at a cutoff point of >46 pg/ml was a perfect discriminator of COVID-19 patients from control subjects (AUC = 1.0). Conclusion: The findings indicate that the IL-17F H161R variant does not influence the risk of COVID-19. However, the IL-17 level is a perfect discriminator of COVID-19 infection. Hypertension, age of >57 years, white blood cell count of >12.6 × 103/mm3, and D-dimer of >0.9 ng/ml are the independent predictors for death among COVID-19 patients.

Formulation and Characterization of O/W Nanoemulsions of Hemp Seed Oil for Protection from Steatohepatitis: Analysis of Hepatic Free Fatty Acids and Oxidation Markers.

Non-alcoholic steatohepatitis (NASH) is a common type of metabolic liver disease which is characterized by fatty changes associated with hepatocyte injury, lobular inflammation, and/or liver fibrosis. Nanoemulsions are kinetically stable colloidal systems characterized by small droplet size. Hemp seed oil is a natural oil derived from Cannabis sativa seeds. The current study was designed to formulate nanoemulsion preparations of hemp seed oil with promising enhanced biological activity against high fat (HF) diet induced NASH in rats. Four nanoemulsion formulas (NEFs) were formulated based on high-pressure homogenization technique and evaluated for droplet size, zeta potential (ZP), polydispersity index (PDI), electrical conductivity, pH, and viscosity, as well as the preparation stability. The best NEF was selected to perform an in vivo rat study; selection was based on the smallest droplet size and highest physical stability. Results showed that NEF#4 showed the best physiochemical characters among the other preparations. Twenty male rats were assigned to four groups as follows: normal, NASH control, NASH + hemp seed oil and NASH + hemp seed oil NEF4. The rats were tested for body weight (BWt) change, insulin resistance (IR) and hepatic pathology. The hemp seed NEF#4 protected against NASH progression in rats and decreased the % of BWt gain compared to the original Hemp seed oil. NEF#4 of Hemp seed oil showed greater protective activity against experimental NASH and IR in rats. Hence, we can consider the nanoemulsion preparations as a useful tool for enhancing the biological action of the hemp seed oil, and further studies are warranted for application of this technique for preparing natural oils aiming at enhancing their activities.