Attenuation of hyperglycemia-associated dyslipidemic, oxidative, cognitive, and inflammatory crises via modulation of neuronal ChEs/NF-κB/COX-2/NOx, and hepatorenal functional deficits by the Tridax procumbens extract.

Tridax procumbens (cotton buttons) is a flowering plant with a medicinal reputation for treating infections, wounds, diabetes, and liver and kidney diseases. The present research was conducted to evaluate the possible protective effects of the T. procumbens methanolic extract (TPME) on an experimentally induced type 2 diabetes rat model. Wistar rats with streptozotocin (STZ)-induced diabetes were randomly allocated into five groups of five animals each, viz., a normal glycemic group (I), diabetic rats receiving distilled water group (II), diabetic rats with 150 (III) and 300 mg/kg of TPME (IV) groups, and diabetic rats with 100 mg/kg metformin group (V). All treatments were administered for 21 consecutive days through oral gavage. Results: Administration of the T. procumbens extract to diabetic rats significantly restored alterations in levels of fasting blood glucose (FBG), body weight loss, serum and pancreatic insulin levels, and pancreatic histology. Furthermore, T. procumbens significantly attenuated the dyslipidemia (increased cholesterol, low-density lipoprotein-cholesterol (LDL-C), triglycerides, and high-density lipoprotein (HDL) in diabetic rats), serum biochemical alterations (alanine transaminase (ALT), aspartate transaminase (AST), alanine phosphatase (ALP), blood urea nitrogen (BUN), creatinine, uric acid, and urea) and full blood count distortion in rats with STZ-induced diabetes. The TPME also improved the antioxidant status as evidenced by increased superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), and decreased malondialdehyde (MDA); and decreased levels of cholinesterases (acetylcholinesterase (AChE) and butyrylcholinesterase (BChE)), and proinflammatory mediators including nuclear factor (NF)-κB, cyclooxygenase (COX)- 2, and nitrogen oxide (NOx) in the brain of rats with STZ-induced diabetes compared to rats with STZ-induced diabetes that received distilled water. However, TPME treatment failed to attenuate the elevated monoamine oxidases and decreased dopamine levels in the brain of rats with STZ-induced diabetes. Extract characterization by liquid chromatography mass spectrometry (LC-MS) identified isorhamnetin (retention time (RT)= 3.69 min, 8.8%), bixin (RT: 25.06 min, 4.72%), and lupeol (RT: 25.25 min, 2.88%) as the three most abundant bioactive compounds that could be responsible for the bioactivity of the plant. In conclusion, the TPME can be considered a promising alternative therapeutic option for managing diabetic complications owing to its antidiabetic, antihyperlipidemic, antioxidant, and anti-inflammatory effects in rats with STZ-prompted diabetes.

Targeting of neuroinflammation by glibenclamide in Covid-19: old weapon from arsenal.

In coronavirus disease 2019 (Covid-19) era, neuroinflammation may develop due to neuronal tropism of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) and/or associated immune activation, cytokine storm, and psychological stress. SARS-CoV-2 infection and linked cytokine storm may cause blood-brain barrier (BBB) injury through which activated immune cells and SARS-CoV-2 can pass into the brain causing activation of glial cells with subsequent neuroinflammation. Different therapeutic regimens were suggested to alleviate Covid-19-induced neuroinflammation. Since glibenclamide has anti-inflammatory and neuroprotective effects, it could be effective in mitigation of SARS-CoV-2 infection-induced neuroinflammation. Glibenclamide is a second-generation drug from the sulfonylurea family, which acts by inhibiting the adenosine triphosphate (ATP)-sensitive K channel in the regulatory subunit of type 1 sulfonylurea receptor (SUR-1) in pancreatic ß cells. Glibenclamide reduces neuroinflammation and associated BBB injury by inhibiting the nod-like receptor pyrin 3 (NLRP3) inflammasome, oxidative stress, and microglial activation. Therefore, glibenclamide through inhibition of NLRP3 inflammasome, microglial activation, and oxidative stress may attenuate SARS-CoV-2-mediated neuroinflammation.

Barhi date (Phoenix dactylifera) extract ameliorates hepatocellular carcinoma in male rats.

Hepatocellular carcinoma (HCC) is a malignant tumor with limited treatment options. Given this fact, it may be important to develop new molecular targeted therapies from natural products, especially those which are primary sources of effective anticancer drugs with distinct mechanisms. Moreover, the complementary use of traditional herbs or fruit may increase the possibility of finding curative options for cancer. Here we explore the anticancer effects and possible molecular mechanism of Barhi date extract using an HCC rat model. Thirty two male albino rats were arbitrarily allocated into four groups: a negative control group (NCG); a positive control group (PCG), which received CCl4 (1 ml/kg b.wt./ i.p.) twice a week for three months; a Barhi date extract (400 mg/kg b.wt./day/orally) treatment group (DTG) during the third month of CCl4 administration; and a cisplatin (1.5 mg/kg b.wt./ i.p.) treatment group ( CTG) during the third month of CCl4 administration. After treatment we performed biochemical analyses of all groups to assess relative eukaryotic initiation factor 2 alpha (eIF2α), extracellular signal-regulated kinases (ERKs), protein kinase RNA-like endoplasmic reticulum kinase (PERK), poly (ADP-ribose) polymerase (PARP), and CASPASE 3 protein content, and examined expression of the genes phosphatase and tensin homolog (PTEN) and protein kinase B (AKT). We also performed an immunohistochemistry assay for alpha-fetoprotein (AFP). Our data showed higher PARP and CASPASE3 levels and liver enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST], and alkaline phosphatase [ALP]) in the PCG compared to the DTG and the cisplatin treatment group CTG. However, we also found a significant decrease in PTEN in the PCG relative to both the DTG and the CTG. We conclude that the anti-tumor activity of Barhi date extract may be mediated by the inhibition of cell proliferation and apoptosis via the ERK /PARP/caspase3 pathway and the AKT/ PTEN signaling pathways.

Phytochemical Analysis and Understanding the Antioxidant and Anticancer Properties of Methanol Extract from Litsea glutinosa: In Vitro and In Vivo Studies.

Litsea glutinosa (L. glutinosa) is considered an evidence-based medicinal plant for the treatment of cancer, the leading cause of death worldwide. In our study, the in vitro antioxidant and in vivo anticancer properties of an essential ethno-medicinal plant, L. glutinosa, were examined using non-toxic doses and a phytochemical analysis was executed using gas-chromatography-mass-spectrometry. The in vitro antioxidant study of the L. glutinosa methanolic extract (LGBME) revealed a concentration-dependent antioxidant property. The bark extract showed promising antioxidant effects in the 2,2-diphenyl-1-picryl-hydrazyl (DPPH) assay. The strongest antioxidant activity was demonstrated at the maximum concentration (50 µg/mL). The IC50 values of the LGBME and BHT were 5.51 and 5.01 µg/mL, respectively. At the same concentration, the total antioxidant capacity of the LGBME was 0.161 µg/mL and the ferric reducing antioxidant power assay result of the LGBME was 1.783 µg/mL. In the cytotoxicity study, the LD50 of the LGBME and gallic acid were 24.93 µg/mL and 7.23 µg/mL, respectively. In the in vivo anticancer-activity studies, the LGBME, particularly at a dose of 150 mg/kg/bw, showed significant cell-growth inhibition, decreased tumor weight, increased mean survival rate, and upregulated the reduced hematological parameters in EAC (Ehrlich's ascites carcinoma)-induced Swiss albino mice. The highest cell-growth inhibition, 85.76%, was observed with the dose of 150 mg/kg/bw. Furthermore, the upregulation of pro-apoptotic genes (p53, Bax) and the downregulation of anti-apoptotic Bcl-2 were observed. In conclusion, LGBME extract has several bioactive phytoconstituents, which confirms the antioxidant and anticancer properties of L. glutinosa.

Pentoxifylline and berberine mitigate diclofenac-induced acute nephrotoxicity in male rats via modulation of inflammation and oxidative stress.

Nephrotoxicity (NT) is a renal-specific situation caused by different toxins and drugs like non-steroidal anti-inflammatory drugs (NSAIDs). NSAIDs like diclofenac (DCF) lead to glomerular dysfunction. Pentoxifylline (PTX) and berberine (BER) have antioxidant and anti-inflammatory properties. Thus, the objective of the present study was to investigate the ameliorative effect of PTX, BER and their combination against DCF-mediated acute NT. Induction of acute NT was done via DCF injection (150 mg/kg I.P, for 6 days) in rats. PTX 200 mg/kg, BER 200 mg/kg and their combination were administrated for 6 days prior to DCF injection and concurrently with DCF for additional 6 days. Acute NT was evaluated biochemically and histopathologically by measuring blood urea (BU), serum creatinine (SCr), kidney injury molecule-1(KIM-1), integrin (ITG), and vitronectin (VTN), interleukin (IL)-18, Neutrophil gelatinase-associated lipocalin (NGAL), glomerular filtration rate (GFR), superoxide dismutase (SOD) and glutathione (GSH) and malondialdehyde (MDA) with the scoring of histopathological alterations. PTX, BER and their combination significantly (P < 0.05) attenuated biochemical and histopathological changes in DCF-mediated acute NT by amelioration of BU, SCr, KIM-1, ITG, VTN, IL-18, NGAL, GFR, SOD, GSH, MDA and scoring of histopathological alterations. The combined effects of PTX and BER produced more significant effects (P < 0.05) than either PTX or BER when used alone against DCF-induced acute NT. In conclusion, BER and BTX were found to have potential renoprotective effects against DCF-induced NT in rats by inhibiting inflammatory reactions and oxidative stress.

Combination Treatment of Omega-3 Fatty Acids and Vitamin C Exhibited Promising Therapeutic Effect against Oxidative Impairment of the Liver in Methotrexate-Intoxicated Mice.

Drug-induced liver injury (DILI) is the main cause of liver damage mediated by the excretion of toxic active drug metabolites. Omega-3 fatty acids and vitamin C have potent antioxidant, anti-inflammatory, and antiapoptotic effects that could offer protection against oxidative stress and liver damage. This study evaluated the hepatoprotective effect of omega-3 and vitamin C alone as well as in a combined form in methotrexate- (MTX-) induced acute liver injury in mice. Male ICR mice of seven groups (7 mice per group) were used. Groups 1 (control group) and 2 (MTX) received 0.9% saline/day (po) for 9 days. Groups 3 and 4 received 100 and 200 mg/kg bw/day omega-3 (po), respectively, for 9 days. Groups 5 and 6 received 100 and 200 mg/kg bw/day vitamin C (po), respectively, for 9 days, while group 7 received omega-3 (100 mg/kg bw/day) and vitamin C (100 mg/kg bw/day) (po) for 9 days. All animals in groups 2 to 7 received 20 mg/kg/day MTX (I.P.) once on the 10th day. Our results revealed that MTX significantly induced the elevation of transaminases, alkaline phosphates (ALP), lactate dehydrogenase (LDH), and malonaldehyde (MDA) while depleting the levels of superoxide dismutase (SOD) and glutathione (GSH) when compared to the control group. Treatment with omega-3 fatty acids or vitamin C significantly attenuated the antioxidants and biochemical alterations in a dose-independent manner. Our molecular docking study of ligand-receptor interaction revealed that both ascorbic acid and omega-3 docked well to the binding cavity of LDH with high binding affinities of -5.20 and -4.50 kcal/mol, respectively. The histopathological features were also improved by treatment with omega-3 and vitamin C. The combined form of omega-3 and vitamin C showed a remarkable improvement in the liver enzymes, oxidative stress biomarkers, and the histopathological architecture of the mice. Conclusively, the combination of omega-3 and vitamin C demonstrated a synergistic therapeutic effect against MTX-intoxicated mice, hence representing a potential novel strategy for the management of drug-induced liver disorders.

Efficacy of Bacillus subtilis, Moringa oleifera seeds extract and potassium bicarbonate on Cercospora leaf spot on sugar beet.

Cercospora leaf spot caused by Cercospora beticola are among the most dangerous plant diseases on sugar beet plants. It causes heavy economic losses, whether on the yield of roots, the percentage of sugar in them, or the quality of sugar produced. In addition to the economic cost caused by chemical control, these chemical pesticides cause an imbalance in the ecosystem and harm the health of humans and animals. In an attempt to search for a safer method than pesticides and environmentally friendly, an evaluation of using biocontrol agents, Bacillus subtilis as cell suspension (108 cell/ml), was conducted in this study. Seeds extract of Moringa oleifera with two concentrations (25 and 50 g/L) and potassium bicarbonate at (5 and10 g/L (compared to fungicide Montoro 30% EC (Propiconazole 15% + Difenoconazole 15%). The evaluation results for twenty-five sugar beet varieties showed a significant discrepancy between these varieties in the extent of their susceptibility to infection with the disease under investigation. In-Vitro, B. subtilis induced an antagonist to C. beticola, and both M. oleifera seeds extract and potassium bicarbonate significantly reduced the linear growth of this pathogen. Under field conditions, the treatments used have given positive results in controlling Cercospora leaf spots. They significantly decreased the severity of disease and prevented C. beticola from creating conidiophores and conidiospores, along with examining their cell walls with the formation of plasmolysis of the fungus cells and reducing both the number and diameter of the spots on the surface leaves; this was demonstrated using a scanning electron microscope (SEM). It is worth noting that the best results obtained were most often when treated with M. oleifera seeds extract, followed by potassium bicarbonate, then cell suspension of B. subtilis. In addition, the percentage of the content of beet roots from total soluble solids and sucrose has improved significantly due to spraying sugar beet plants with the substances mentioned earlier. These treatments also contributed to a significant improvement in the enzymes polyphenol oxidase, peroxidase, and phenylalanine ammonia-lyase.

Diacerein ameliorates letrozole-induced polycystic ovarian syndrome in rats.

Polycystic ovary syndrome (PCOS) is the most common gynaecological endocrine disease that causes anovulatory infertility. The current study aimed to explore the possible role of diacerein (DIA), an IL-1ß inhibitor, in treating letrozole-induced PCOS in rats that exhibit the metabolic and endocrinal criteria of PCOS patients. PCOS was induced in female Wistar rats by the oral administration of letrozole (1 mg/kg, per orally, p.o.) for 21 days. Rats were then treated with DIA (25 mg/kg/day, p.o.), DIA (50 mg/kg/day, p.o.), or metformin (2 mg/100 g/day, p.o.) for 14 days after the PCOS induction. PCOS resulted in a significantly higher body weight, ovarian weight, ovarian size, and cysts, as well as an elevation in serum testosterone, LH, insulin, glycemia, and lipid profile levels. All of these effects were significantly reduced by the DIA administration. Additionally, DIA remarkably inhibited the letrozole-induced oxidative stress in the ovaries, muscles, and liver by reducing the upraised levels of malondialdehyde and total nitrite and increasing the suppressed levels of superoxide dismutase and catalase. DIA enhanced the protective proteins Keap-1, Nrf2, and OH-1 levels. Finally, DIA inhibited the elevated mRNA levels of NLRP3 and caspase-1, the up-regulated inflammatory cytokines IL-6, TNF-α, and the IL-1ß/NFκB signaling pathway. Our results proved that DIA ameliorates letrozole-induced PCOS through its antioxidant and anti-inflammatory properties.

Therapeutic efficacy of Clompanus pubescens leaves fractions via downregulation of neuronal cholinesterases/Na+-K+ATPase/IL-1 ß, and improving the neurocognitive and antioxidants status of streptozotocin-induced diabetic rats.

The increasing global burden of diabetes mellitus has called for the search for a therapeutic alternative that offers better activities and safety than conventional chemotherapy. Herein, we evaluated the neuroprotective and antioxidant properties of different fractions (ethyl acetate, N-butanol and residual aqueous) of Clompanus pubescens leaves in streptozotocin (STZ)-induced diabetic rats. Our results revealed a significant elevation in the levels of blood glucose, pro-inflammatory cytokines, lipid peroxidation, neuronal activities of acetylcholinesterase, butyrylcholinesterase, nitric oxide, epinephrine, norepinephrine, and Na+/K+-ATPase in diabetic non treated rats. In addition, decreased levels of enzymatic and non-enzymatic antioxidants were observed. Treatment with different fractions of C. pubescens leaves resulted in significant reversal of the biochemical alteration and improved the neurocognitive deficit in STZ induced diabetic rats. However, the ethyl-acetate fraction demonstrated higher activities than the other fractions and was characterized for its phytoconstituents, revealing the presence of Gallic acid (713.00 ppm), catechin (0.91 ppm), ferulic acid (0.98 ppm), rutin (59.82 ppm), quercetin (3.22 ppm) and kaempferol (4.07 ppm). Our molecular docking analysis revealed that these compounds exhibited different binding affinities and potentials for targeting BChE/AChE/ IL-1 ß/Na+ -K+ -ATPase. However, only Kampferol and ferulic exhibited good drug-like, ADMET, and permeability properties suitable for use as a neuronal drug target agent. Hence, the ethyl-acetate fraction of C. pubescens leaves could be considered as a source of promising bioactive metabolite for the treatment and management of cognitive impairments related to type II diabetes mellitus.

Identification of DPP4/CTNNB1/MET as a Theranostic Signature of Thyroid Cancer and Evaluation of the Therapeutic Potential of Sitagliptin.

In recent years, the incidence of thyroid cancer has been increasing globally, with papillary thyroid cancer (PTCa) being the most prevalent pathological type, accounting for approximately 80% of all cases. Although PTCa has been regarded to be slow growing and has a good prognosis, in some cases, PTCa can be aggressive and progress despite surgery and radioactive iodine treatment. In addition, most cancer treatment drugs have been shown to be cytotoxic and nonspecific to cancer cells, as they also affect normal cells and consequently cause harm to the body. Therefore, searching for new targets and therapies is required. Herein, we explored a bioinformatics analysis to identify important theranostic markers for THCA. Interestingly, we identified that the DPP4/CTNNB1/MET gene signature was overexpressed in PTCa, which, according to our analysis, is associated with immuno-invasive phenotypes, cancer progression, metastasis, resistance, and unfavorable clinical outcomes of thyroid cancer cohorts. Since most cancer drugs were shown to exhibit cytotoxicity and to be nonspecific, herein, we evaluated the anticancer effects of the antidiabetic drug sitagliptin, which was recently shown to possess anticancer activities, and is well tolerated and effective. Interestingly, our in silico molecular docking results exhibited putative binding affinities of sitagliptin with DPP4/CTNNB1/MET signatures, even higher than standard inhibitors of these genes. This suggests that sitagliptin is a potential THCA therapeutic, worthy of further investigation both in vitro and in vivo and in clinical settings.