Targeting the PI3K/pAKT/mTOR/NF-κB/FOXO3a signaling pathway for suppressing the development of hepatocellular carcinoma in rats: Role of the natural remedic Suaeda vermiculata forssk.

Liver malignancy is well recognized as a prominent health concern, with numerous treatment options available. Natural products are considered a renewable source, providing inspiring chemical moieties that could be used for cancer treatment. Suaeda vermiculata Forssk has traditionally been employed for management of hepatic conditions, including liver inflammation, and liver cirrhosis, as well as to improve general liver function. The findings of our earlier study demonstrated encouraging in vivo hepatoprotective benefits against liver injury generated by paracetamol and carbon tetrachloride. Additionally, Suaeda vermiculata Forssk exhibited cytotoxic activities in vitro against Hep-G2 cell lines and cell lines resistant to doxorubicin. The present investigation aimed to examine the potential in vivo hepatoprotective efficacy of Suaeda vermiculata Forssk extract (SVE) against hepatocellular carcinoma induced by diethylnitrosamine (DENA) in rats. The potential involvement of the PI3K/AKT/mTOR/NF-κB pathway was addressed. Sixty adult male albino rats were allocated into five groups randomly (n = 10). First group received a buffer, whereas second group received SVE only, third group received DENA only, and fourth and fifth groups received high and low doses of SVE, respectively, in the presence of DENA. Liver toxicity and tumor markers (HGFR, p-AKT, PI3K, mTOR, NF-κB, FOXO3a), apoptosis markers, and histopathological changes were analyzed. The current results demonstrated that SVE inhibited PI3K/AKT/mTOR/NF-κB pathway as well as increased expression of apoptotic parameters and FOXO3a levels, which were deteriorated by DENA treatment. Furthermore, SVE improved liver toxicity markers and histopathological changes induced by DENA administration. This study provided evidence for the conventional hepatoprotective properties attributed to SV and investigated the underlying mechanism by which its extract, SVE, could potentially serve as a novel option for hepatocellular carcinoma (HCC) treatment derived from a natural source.

Phytochemical investigation and anti-inflammatory potential of Atriplex leucoclada Boiss.

BACKGROUND: The plant kingdom has long been considered a valuable source for therapeutic agents, however, some plant species still untapped and need to be phytochemically and biologically explored. Although several Atriplex species have been investigated in depth, A. leucoclada, a halophytic plant native to Saudi Arabian desert, remains to be explored for its phytochemical content and biological potentials. Herein, the current study investigated the metabolic content and the anti-inflammatory potential of A. leucoclada. METHODS: Powdered aerial parts of the plant were defatted with n-hexane then the defatted powder was extracted with 80% methanol. n-Hexane extract (ATH) was analyzed using GC-MS, while the defatted extract (ATD) was subjected to different chromatographic methods to isolate the major phytoconstituents. The structures of the purified compounds were elucidated using different spectroscopic methods including advanced NMR techniques. Anti-inflammatory activity of both extracts against COX-1 and COX-2 enzymes were examined in vitro. Molecular docking of the identified compounds into the active sites of COX-1 and COX-2 enzymes was conducted using pdb entries 6Y3C and 5IKV, respectively. RESULTS: Phytochemical investigation of ATD extract led to purification and identification of nine compounds. Interestingly, all the compounds, except for 20-hydroxy ecdysone (1), are reported for the first time from A. leucoclada, also luteolin (6) and pallidol (8) are isolated for the first time from genus Atriplex. Inhibitory activity of ATD and ATH extracts against COX-1 and COX-2 enzymes revealed concentration dependent activity of both fractions with IC50 41.22, 14.40 µg/ml for ATD and 16.74 and 5.96 µg/ml for ATH against COX-1 and COX-2, respectively. Both extracts displayed selectivity indices of 2.86 and 2.80, respectively as compared to 2.56 for Ibuprofen indicating a promising selectivity towards COX-2. Molecular docking study supported in vitro testing results, where purified metabolites showed binding affinity scores ranged from -9 to -6.4 and -8.5 to -6.6 kcal/mol for COX-1 and 2, respectively, in addition the binding energies of GC-MS detected compounds ranged from -8.9 to -5.5 and -8.3 to -5.1 kcal/mol for COX-1 and 2, respectively as compared to Ibuprofen (-6.9 and -7.5 kcal/mol, respectively), indicating high binding affinities of most of the compounds. Analysis of the binding orientations revealed variable binding patterns depending on the nature of the compounds. Our study suggested A. leucoclada as a generous source for anti-inflammatory agents.

Antioxidant and Anti-Aging Phytoconstituents from Faucaria tuberculosa: In Vitro and In Silico Studies.

Research targeting natural cosmeceuticals is now increasing due to the safety and/or limited side effects of natural products that are highly valued in cosmetology. Within a research program exploring botanical sources for valuable skincare antioxidant components, the current study investigated the phytochemical content and the biological potential of Faucaria tuberculosa. Phytochemical investigation of F. tuberculosa extract resulted in purification and characterization of six phytoconstituents, including a new one. The structure of the new constituent was elucidated as (-) catechin-(2→1',4→2')-phloroglucinol (4). The structural identity of all isolated compounds were confirmed on the basis of extensive physical and spectral (1D, 2D-NMR and HRESIMS) investigations. The ethanolic extract exhibits a rich content of total phenolics (TPC) and total flavonoids (TFC), estimated as 32 ± 0.034 mg GAE/g and 43 ± 0.004 mg RE/g, respectively. In addition, the antioxidant (ABTS and FRAP), antihyaluronidase and antityrosinase activities of all purified phytoconstituents were evaluated. The results noted (-) catechin-(2→1',4→2') phloroglucinol (4) and phloroglucinol (1) for their remarkable antioxidant activity, while isorhamnetin 3-O-rutinoside (3) and 3,5-dihydroxyphenyl ß-D-glucopyranoside (2) achieved the most potent inhibitory activity against tyrosinase (IC50 22.09 ± 0.7 µM and 29.96 ± 0.44 µM, respectively) and hyaluronidase enzymes (IC50 49.30 ± 1.57 µM and 62.58 ± 0.92, respectively) that remarkably exceeds the activity of the standard drugs kojic acid (IC50 = 65.21 ± 0.47 µM) and luteolin, (IC50 = 116.16 ± 1.69 µM), respectively. A molecular docking study of the two active compounds (3 and 2) highlighted their high potential to bind to the active sites of the two enzymes involved in the study.

Involvement of PI3K/HIF-1α/c-MYC/iNOS Pathway in the Anticancer Effect of Suaeda vermiculata in Rats.

Suaeda vermiculata Forssk. ex JF Gmel. (SV), a traditional known plant, has shown in vitro cytotoxic activity against HepG2 and HepG-2/ADR (doxorubicin-resistant cells) liver cell carcinoma cell lines, as well as hepatoprotection against paracetamol and carbon tetrachloride (CCl4)-induced liver injury. The current study evaluated the protective effect of SV, administered against N-diethylnitrosamine (NDEA)-induced HCC in rats. The possible modulatory effect of SV on the PI3K/HIF-1α/c-MYC/iNOS pathway was investigated. Sixty male adult albino rats (200 ± 10 g) were equally classified into five groups. Group I served as a control; Group 2 (SV control group) received SV (p.o., 200 mg/kg body weight); Group 3 (NDEA-administered rats) received freshly prepared NDEA solution (100 mg/L); and Groups 4 and 5 received simultaneously, for 16 weeks, NDEA + SV extract (100 and 200 mg/kg, orally). NDEA-treated rats displayed significant increases in serum levels of AFP, CEA, PI3K, malondialdehyde (MDA), epidermal growth factor receptor (EGFR), and vascular endothelial growth factor (VEGFR), with increased liver tissue protein expression of fibrinogen concomitant and significantly decreased concentrations of antioxidant parameters (catalase (CAT), superoxide dismutase (SOD), and reduced glutathione (GSH)) in comparison to normal rats. On the flip side, AFP, CEA, PI3K, MDA, EGFR, and VEGFR serum levels were significantly reduced in rats that received NDEA with SV, both at low (SV LD) and high (SV HD) doses, accompanied by significant improvements in antioxidant parameters compared to the NDEA-treated group. Conclusions: SV possesses a significant hepatoprotective effect against NDEA-induced HCC via inhibiting the PI3K/HIF-1α/c-MYC/iNOS pathway, suggesting that SV could be a promising hepatocellular carcinoma treatment.

Chemical Profiling and Molecular Docking Study of Agathophora alopecuroides.

Natural products continue to provide inspiring chemical moieties that represent a key stone in the drug discovery process. As per our previous research, the halophyte Agathophora alopecuroides was noted as a potential antidiabetic plant. However, the chemical profiling and highlighting the metabolite(s) responsible for the observed antidiabetic activity still need to be investigated. Accordingly, the present study presents the chemical profiling of this species using the LC-HRMS/MS technique followed by a study of the ligand-protein interaction using the molecular docking method. LC-HRMS/MS results detected twenty-seven compounds in A. alopecuroides extract (AAE) belonging to variable chemical classes. Among the detected compounds, alkaloids, flavonoids, lignans, and iridoids were the most prevailing. In order to highlight the bioactive compounds in AAE, the molecular docking technique was adopted. Results suggested that the two alkaloids (Eburnamonine and Isochondrodendrine) as well as the four flavonoids (Narirutin, Pelargonidin 3-O-rutinoside, Sophora isoflavanone A, and Dracorubin) were responsible for the observed antidiabetic activity. It is worth mentioning that this is the first report for the metabolomic profiling of A. alopecuroides as well as the antidiabetic potential of Isochondrodendrine, Sophora isoflavanone A, and Dracorubin that could be a promising target for an antidiabetic drug.

Characterization of Promising Cytotoxic Metabolites from Tabebuia guayacan Hemsl.: Computational Prediction and In Vitro Testing.

Genus Tabebuia is famous for its traditional uses and valuable phytoconstituents. Our previous investigation of Tabebuia species noted the promising anticancer activity of T. guayacan Hemsl. leaves extract, however, the mechanism underlying the observed anticancer activity is still unexplored. The current research was designed to explore the phytochemical content as well as to address the phytoconstituent(s) responsible for the recorded anticancer activity. Accordingly, sixteen compounds were isolated, and their structures were elucidated using different spectroscopic techniques. The drug-likeness of the isolated compounds, as well as their binding affinity with four anticancer drug target receptors: CDK-2/6, topoisomerase-1, and VEGFR-2, were evaluated. Additionally, the most promising compounds were in vitro evaluated for inhibitory activities against CDK-2/6 and VEGFR-2 enzymes using kinase assays method. Corosolic acid (3) and luteolin-7-O-ß-glucoside (16) were the most active inhibitors against CDK-2 (-13.44 kcal/mol) and topoisomerase 1 (-13.83 kcal/mol), respectively. Meanwhile, quercetin 3-O-ß-xyloside (10) scored the highest binding free energies against both CDK-6 (-16.23 kcal/mol) as well as against VEGFR-2 protein targets (-10.39 kcal/mol). Molecular dynamic simulation indicated that quercetin 3-O-ß-xyloside (10) exhibited the least fluctuations and deviations from the starting binding pose with RMSD (2.6 Å). Interestingly, in vitro testing results confirmed the potent activity of 10 (IC50 = 0.154 µg/mL) compared to IC50 = 0.159 µg/mL of the reference drug ribociclib. These findings suggest the three noted compounds (3, 10, and 16) for further in vivo anticancer studies.

Resveratrol Inhibited ADAM10 Mediated CXCL16-Cleavage and T-Cells Recruitment to Pancreatic ß-Cells in Type 1 Diabetes Mellitus in Mice.

Background: CXCL16 attracts T-cells to the site of inflammation after cleaving by A Disintegrin and Metalloproteinase (ADAM10). Aim: The current study explored the role of ADAM10/CXCL16/T-cell/NF-κB in the initiation of type 1 diabetes (T1D) with special reference to the potential protecting role of resveratrol (RES). Methods: Four sets of Balb/c mice were created: a diabetes mellitus (DM) group (streptozotocin (STZ) 55 mg/kg, i.p.], a control group administered buffer, a RES group [RES, 50 mg/kg, i.p.), and a DM + RES group (RES (50 mg/kg, i.p.) and STZ (55 mg/kg, i.p.) administered daily for 12 days commencing from the fourth day of STZ injection). Histopathological changes, fasting blood insulin (FBI), glucose (FBG), serum and pancreatic ADAM10, CXCL16, NF-κB, T-cells pancreatic expression, inflammatory, and apoptotic markers were analyzed. Results: FBG, inflammatory and apoptotic markers, serum TNF-α, cellular CXCL16 and ADAM10 protein expression, pancreatic T-cell migration and NF-κB were significantly increased in diabetic mice compared to normal mice. RES significantly improved the biochemical and inflammatory parameters distorted in STZ-treated mice. Conclusions: ADAM10 promotes the cleaved form of CXCL16 driving T-cells into the islets of the pancreatic in T1D. RES successfully prevented the deleterious effect caused by STZ. ADAM10 and CXCL16 may serve as novel therapeutic targets for T1D.

Coagulation System Activation for Targeting of COVID-19: Insights into Anticoagulants, Vaccine-Loaded Nanoparticles, and Hypercoagulability in COVID-19 Vaccines.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also known as COVID-19, is currently developing into a rapidly disseminating and an overwhelming worldwide pandemic. In severe COVID-19 cases, hypercoagulability and inflammation are two crucial complications responsible for poor prognosis and mortality. In addition, coagulation system activation and inflammation overlap and produce life-threatening complications, including coagulopathy and cytokine storm, which are associated with overproduction of cytokines and activation of the immune system; they might be a lead cause of organ damage. However, patients with severe COVID-19 who received anticoagulant therapy had lower mortality, especially with elevated D-dimer or fibrin degradation products (FDP). In this regard, the discovery of natural products with anticoagulant potential may help mitigate the numerous side effects of the available synthetic drugs. This review sheds light on blood coagulation and its impact on the complication associated with COVID-19. Furthermore, the sources of natural anticoagulants, the role of nanoparticle formulation in this outbreak, and the prevalence of thrombosis with thrombocytopenia syndrome (TTS) after COVID-19 vaccines are also reviewed. These combined data provide many research ideas related to the possibility of using these anticoagulant agents as a treatment to relieve acute symptoms of COVID-19 infection.

The Glycemic Control Potential of Some Amaranthaceae Plants, with Particular Reference to In Vivo Antidiabetic Potential of Agathophora alopecuroides.

Natural products continue to provide inspiring moieties for the treatment of various diseases. In this regard, investigation of wild plants, which have not been previously explored, is a promising strategy for reaching medicinally useful drugs. The present study aims to investigate the antidiabetic potential of nine Amaranthaceae plants: Agathophora alopecuroides, Anabasis lachnantha, Atriplex leucoclada, Cornulaca aucheri, Halothamnus bottae, Halothamnus iraqensis, Salicornia persia, Salsola arabica, and Salsola villosa, growing in the Qassim area, the Kingdom of Saudi Arabia. The antidiabetic activity of the hydroalcoholic extracts was assessed using in vitro testing of α-glucosidase and α-amylase inhibitory effects. Among the nine tested extracts, A. alopecuroides extract (AAE) displayed potent inhibitory activity against α-glucosidase enzyme with IC50 117.9 µg/mL noting better activity than Acarbose (IC50 191.4 µg/mL). Furthermore, AAE displayed the highest α- amylase inhibitory activity among the nine tested extracts, with IC50 90.9 µg/mL. Based upon in vitro testing results, the antidiabetic activity of the two doses (100 and 200 mg/kg) of AAE was studied in normoglycemic and streptozotocin (STZ)-induced diabetic mice. The effects of the extract on body weight, food and water intakes, random blood glucose level (RBGL), fasting blood glucose level (FBGL), insulin, total cholesterol, and triglycerides levels were investigated. Results indicated that oral administration of the two doses of AAE showed a significant dose-dependent increase (p < 0.05) in the body weight and serum insulin level, as well as a significant decrease in food and water intake, RBGL, FBGL, total cholesterol, and triglyceride levels, in STZ-induced diabetic mice, compared with the diabetic control group. Meanwhile, no significant differences of both extract doses were observed in normoglycemic mice when compared with normal control animals. This study revealed a promising antidiabetic activity of the wild plant A. alopecuroides.

Digalloyl Glycoside: A Potential Inhibitor of Trypanosomal PFK from Euphorbia abyssinica J.F. Gmel.

Human African trypanosomiasis is an endemic infectious disease caused by Trypanosoma brucei via the bite of tsetse-fly. Most of the drugs used for the treatment, e.g., Suramin, have shown several problems, including the high level of toxicity. Accordingly, the discovery of anti-trypanosomal drugs from natural sources has become an urgent requirement. In our previous study on the anti-trypanosomal potential of Euphorbia species, Euphorbia abyssinica displayed significant anti-trypanosomal activity. Therefore, a phytochemical investigation of the methanolic extract of E. abyssinica was carried out. Twelve compounds, including two triterpenes (1, 2); one sterol-glucoside (4); three ellagic acid derivatives (3, 9, 11); three gallic acid derivatives (5, 6, 10); and three flavonoids (7, 8, 12), were isolated. The structures of isolated compounds were determined through different spectroscopic techniques. Compound (10) was obtained for the first time from genus Euphorbia while all other compounds except compound (4), were firstly reported in E. abyssinica. Consequently, an in silico study was used to estimate the anti-trypanosomal activity of the isolated compounds. Several compounds displayed interesting activity where 1,6-di-O-galloyl-d-glucose (10) appeared as the most potent inhibitor of trypanosomal phosphofructokinase (PFK). Moreover, molecular dynamics (MD) simulations and ADMET calculations were performed for 1,6-di-O-galloyl-d-glucose. In conclusion, 1,6-di-O-galloyl-d-glucose revealed high binding free energy as well as desirable molecular dynamics and pharmacokinetic properties; therefore, it could be suggested for further in vitro and in vivo studies for trypanosomiasis.

Characterization of Possible α-Glucosidase Inhibitors from Trigonella stellata Extract Using LC-MS and In Silico Molecular Docking.

The current study accentuates the significance of performing the multiplex approach of LC-HRESIMS, biological activity, and docking studies in drug discovery, taking into consideration a review of the literature. In this regard, the investigation of antioxidant and cytotoxic activities of Trigonella stellata collected from the Egyptian desert revealed a significant antioxidant capacity using DPPH with IC50 = 656.9 µg/mL and a moderate cytotoxicity against HepG2, MCF7, and CACO2, with IC50 values of 53.3, 48.3, and 55.8 µg/mL, respectively. The evaluation of total phenolic and flavonoid contents resulted in 32.8 mg GAE/g calculated as gallic acid equivalent and 5.6 mg RE/g calculated as rutin equivalent, respectively. Chemical profiling of T. stellata extract, using LC-HRESIMS analysis, revealed the presence of 15 metabolites, among which eleven compounds were detected for the first time in this species. Interestingly, in vitro testing of the antidiabetic activity of the alcoholic extract noted an α-glucosidase enzyme inhibitory activity (IC50 = 559.4 µg/mL) better than that of the standard Acarbose (IC50 = 799.9 µg/mL), in addition to a moderate inhibition of the α-amylase enzyme (IC50 = 0.77 µg/mL) compared to Acarbose (IC50 = 0.21 µg/mL). α-Glucosidase inhibition was also virtualized by binding interactions through the molecular docking study, presenting a high binding activity of six flavonoid glycosides, as well as the diterpenoid compound graecumoside A and the alkaloid fenugreekine. Taken together, the conglomeration of LC-HRESIMS, antidiabetic activity, and molecular docking studies shed light on T. stellata as a promising antidiabetic herb.

Simvastatin mitigates streptozotocin-induced type 1 diabetes in mice through downregulation of ADAM10 and ADAM17.

BACKGROUND: T cell mediates immune response in type 1 diabetes mellitus (T1DM) through its trafficking into pancreatic islets. The role of A Disintigrin And Metalloproteinase 10 (ADAM10) and 17 (ADAM17) in pancreatic T-cells recruitment into the pancreatic islets during T1DM is not known. AIM: Explore the role of ADAM10 and ADAM17 in the processing of CXCL16 in T1DM and possible protective effect of simvastatin (SIM) in streptozotocin (STZ)-induced T1DM. MAIN METHODS: Balb/c mice were classified into 4 groups, 10 each. Control group received buffer while SIM group received 50 mg/kg, i.p daily for 12 days starting from day 4 of the experiment. Diabetic group; received STZ (55 mg/kg, i.p.) for 5 consecutive days starting from day 1 of the experiment. SIM + STZ group; received SIM (50 mg/kg, i.p.) daily for 12 days and STZ (55 mg/kg, i.p.) for 5 consecutive days. Biochemical, inflammatory and apoptotic markers as well as expression of CXCL16, ADAM10, NF-κB and pancreatic T-cells expression were analyzed. KEY FINDINGS: Significant increase in biochemical, inflammatory, apoptotic parameters, expression of ADAM10, ADAM17, CXCL16, NF-κB, and infiltrated T-cells to the pancreatic islets were found in STZ group. SIM treatment in the presence of STZ improved biochemical and inflammatory parameters as well as it reduced the expression of CXCL16, ADAM10, ADAM17, NF-κΒ, T-cells migration and apoptosis in the pancreatic islets. SIGNIFICANCE: SIM mitigated pancreatic ß-cell death induced by STZ through down regulation of ADAM10, ADAM17and CXCL16. Therefore, ADAM10/ADAM17 and CXCL16 may serve as novel therapeutic targets for T1DM.

Selected Class of Enamides Bearing Nitro Functionality as Dual-Acting with Highly Selective Monoamine Oxidase-B and BACE1 Inhibitors.

A small series of nitro group-bearing enamides was designed, synthesized (NEA1-NEA5), and evaluated for their inhibitory profiles of monoamine oxidases (MAOs) and ß-site amyloid precursor protein cleaving enzyme 1 (ß-secretase, BACE1). Compounds NEA3 and NEA1 exhibited a more potent MAO-B inhibition (IC50 value = 0.0092 and 0.016 µM, respectively) than the standards (IC50 value = 0.11 and 0.14 µM, respectively, for lazabemide and pargyline). Moreover, NEA3 and NEA1 showed greater selectivity index (SI) values toward MAO-B over MAO-A (SI of >1652.2 and >2500.0, respectively). The inhibition and kinetics studies suggested that NEA3 and NEA1 are reversible and competitive inhibitors with Ki values of 0.013 ± 0.005 and 0.0049 ± 0.0002 µM, respectively, for MAO-B. In addition, both NEA3 and NEA1 showed efficient BACE1 inhibitions with IC50 values of 8.02 ± 0.13 and 8.21 ± 0.03 µM better than the standard quercetin value (13.40 ± 0.04 µM). The parallel artificial membrane permeability assay (PAMPA) method demonstrated that all the synthesized derivatives can cross the blood-brain barrier (BBB) successfully. Docking analyses were performed by employing an induced-fit docking approach in the GLIDE module of Schrodinger, and the results were in agreement with their in vitro inhibitory activities. The present study resulted in the discovery of potent dual inhibitors toward MAO-B and BACE1, and these lead compounds can be fruitfully explored for the generation of newer, clinically active agents for the treatment of neurodegenerative disorders.

Mental depression: Relation to different disease status, newer treatments and its association with COVID-19 pandemic (Review).

The present study aimed to review major depression, including its types, epidemiology, association with different diseases status and treatments, as well as its correlation with the current COVID-19 pandemic. Mental depression is a common disorder that affects most individuals at one time or another. During depression, there are changes in mood and behavior, accompanied by feelings of defeat, hopelessness, or even suicidal thoughts. Depression has a direct or indirect relation with a number of other diseases including Alzheimer's disease, stroke, epilepsy, diabetes, cardiovascular disease and cancer. In addition, antidepressant drugs have several side effects including sedation, increased weight, indigestion, sexual dysfunction, or a decrease in blood pressure. Stopping medication may cause a relapse of the symptoms of depression and pose a risk of attempted suicide. The pandemic of COVID-19 has affected the mental health of individuals, including patients, individuals contacting patients and medical staff with a number of mental disorders that may adversely affect the immune ability of their bodies. Some of the drugs currently included in the protocols for treating COVID-19 may negatively affect the mental health of patients. Evidence accumulated over the years indicates that serotonin (5HT) deficiencies and norepinephrine (NE) in the brain can lead to mental depression. Drugs that increase levels of NE and 5HT are commonly used in the treatment of depression. The common reason for mood disorders, including mania and bipolar disease are not clearly understood. It is assumed that hyperactivity in specific parts of the brain and excessive activity of neurotransmitters may be involved. Early diagnosis and developing new treatment strategies are essential for the prevention of the severe consequences of depression. In addition, extensive research should be directed towards the investigation of the mental health disturbances occurring during and/or after COVID-19 infection. This may lead to the incorporation of a suitable antidepressant into the current treatment protocols.

Pharmacological and pharmacognostical valuation of Canna indica leaves extract by quantifying safety profile and neuroprotective potential.

The current study primarily focused on the pharmacognostical and phytochemical screening of Canna indica and further analyzing the leaves extract for toxicological profile and neuroprotective potential. The microscopic, dry powder properties of the leaf material and phytochemical, physicochemical analysis was evaluated for pharmacognostical assessment. Dry leaves of C. indica were extracted using methanol and then further studied for both in vitro and in vivo toxicological study. The acute toxicity was measured by estimating the antioxidant defense system and anatomical impairment in the rat's organs. Also, the neuroprotective activity of the plant extract was assessed using anticholinesterase enzymatic inhibitory assay. The extract was found to be hemocompatible and showed absences of induction of behavioural changes. Likewise, no changes were seen on the anatomical structure of the rat's organs. The methanolic extract portrayed a significant upsurge in the reduced glutathione level and showed a comparable acetylcholinesterase inhibition in a dosedependent manner with an IC50 value of 14.53 µg/mL compared to the standard Donepezil with an IC50 value of 13.31 µg/mL. C. indica has compelling pharmacognostical characteristics, good safety reports, and significant antioxidant as well as the neuroprotective potential that shows great potential for its further in-depth research for pharmacological use.

Loss of RAR-α and RXR-α and enhanced caspase-3-dependent apoptosis in N-acetyl-p-aminophenol-induced liver injury in mice is tissue factor dependent.

Tissue factor (TF) activates the coagulation system and has an important role in the pathogenesis of various diseases. Our previous study stated that retinoid receptors (RAR-α and RXR-α) are released as a lipid droplet in monocrotaline/ lipopolysaccharide-induced idiosyncratic liver toxicity in mice. Herein, the interdependence between the release of retinoid receptors RAR-α and RXR-α and TF in Nacetyl-p-aminophenol (APAP)-induced mice liver toxicity, is investigated. Serum alanine transaminase (ALT) level, platelet and white blood cells (WBCs) counts, protein expression of fibrin, TF, cyclin D1 and cleaved caspase-3 in liver tissues are analyzed. In addition, histopathological evaluation and survival study are also performed. The results indicate that using of TF-antisense (TF-AS) deoxyoligonucleotide (ODN) injection (6 mg/kg), to block TF protein synthesis, significantly restores the elevated level of ALT and WBCs and corrects thrombocytopenia in mice injected with APAP. TF-AS prevents the peri-central overexpression of liver TF, fibrin, cyclin D1 and cleaved caspase- 3. The release of RXR-α and RAR-α droplets, in APAP treated sections, is inhibited upon treatment with TF-AS. In conclusion, the above findings designate that the released RXR-α and RAR-α in APAP liver toxicity is TF dependent. Additionally, the enhancement of cyclin D1 to caspase-3-dependent apoptosis can be prevented by blocking of TF protein synthesis.

Metabolic profiling of cytotoxic metabolites from five Tabebuia species supported by molecular correlation analysis.

Tabebuia is the largest genus among the family Bignoniaceae. Tabebuia species are known for their high ornamental and curative value. Here, the cytotoxic potential of extracts from the leaves and stems of five Tabebuia species was analyzed. The highest activity was observed for T. rosea (Bertol.) DC. stem extract against HepG2 cell line (IC50 4.7 µg/mL), T. pallida L. stem extract against MCF-7 cell line (IC50 6.3 µg/mL), and T. pulcherrima stem extract against CACO2 cell line (IC50 2.6 µg/mL). Metabolic profiling of the ten extracts using liquid chromatography-high-resolution mass spectrometry for dereplication purposes led to annotation of forty compounds belonging to different chemical classes. Among the annotated compounds, irridoids represent the major class. Principle component analysis (PCA) was applied to test the similarity and variability among the tested species and the score plot showed similar chemical profiling between the leaves and stems of both T. pulcherrima and T. pallida L. and unique chemical profiling among T. rosea (Bertol.) DC., T. argentea Britton, and T. guayacan (Seem.) Hemsl. leaf extracts and the stem extract of T. rosea (Bertol.) DC. Additionally, a molecular correlation analysis was used to annotate the bioactive cytotoxic metabolites in the extracts and correlate between their chemical and biological profiles.

Anti-Inflammatory and Antioxidant Activities of Terpene- and Polyphenol-Rich Premna odorata Leaves on Alcohol-Inflamed Female Wistar Albino Rat Liver.

Premna odorata Blanco (Lamiaceae) is an ethnomedicinal plant native to different tropical regions. Although some reports addressed their anti-inflammatory, cytotoxic, and antituberculotic effects, their hepatoprotective potential is yet to be discovered. Accordingly, this study investigated the crude extract and different fractions of the plant leaves; metabolic profiling using liquid chromatography/high-resolution electrospray ionization mass spectroscopy (LC-HRESIMS) analysis, in silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties for the dereplicated metabolite via online PreADMET program, ROS scavenger activity on the Hep G2 human liver cancer cell line, and the possible hepatic cellular treatment effects in alcohol-inflamed liver female Wistar albino rats. Metabolic profiling dereplicated a total of 28 metabolites from the crude extract and its various fractions. In silico ADMET and ROS scavenger activity screening suggested plant metabolites are of potential bioactivity. In vivo hepatic treatment with crude, defatted crude, and n-hexane leave extracts suggested all extracts significantly improved liver damage, which was indicated by the reduction of elevated serum levels of bilirubin, AST, ALT, ALP, CRP, TNF-α, ICAM-1, VCAM-1, and MDA. The reduced levels of GSH and TAC were normalized during the study. Histological examinations of liver tissue showed collagen fiber distribution nearly back to its normal pattern. The anti-inflammatory and antioxidant potentials of Premna odorata extracts could be partly related to the combined effects of these phytochemicals or their synergistic interactions.

Silencing of tissue factor by antisense deoxyoligonucleotide mitigates thioacetamide-induced liver injury.

BACKGROUND: Retinoid receptors (RRs), RAR-α and RXR-α, work as transcription factors that regulate cell growth, differentiation, survival, and death. Hepatic stellate cells (HSCs) store retinoid and release its RRs as lipid droplets upon their activation. PURPOSE: We test the hypothesis that loss of retinoid receptors RAR-α and RXR-α from HSCs is dependent on tissue factor (TF) during thioacetamide (TAA)-induced liver injury. METHODS: Liver toxicity markers, TF, fibrin, cleaved caspase-3, and cyclin D1 as well as histopathology were investigated. RESULTS: Increased TF, fibrin, cleaved caspase-3, and cyclin D1 protein expression is seen in zone of central vein after TAA injection compared with vehicle-treated mice. A strong downregulation of RAR-α and RXR-α is seen in TAA-induced liver injury. In addition, histopathological obliteration and pericentral expression of cleaved caspase 3 and cyclin D1 are observed after TAA injection compared with the normal vehicle-treated mice. No changes have been seen in TAA/TF-sense (SC) in whole parameters compared with TAA-treated animals. TAA/TF-antisense (AS)-treated mice show normal expression of all parameters and normal histopathological features when compared with the control mice. In conclusion, this study declares that the strong downregulation of RAR-α and RXR-α may cause liver injury and particularly activation of HSCs in TAA-induced toxicity. TF-AS treatment not only downregulates TF protein expression but also alleviates loss of liver RAR-α and RXR-α and suppresses the activated apoptosis signals in TAA-induced liver toxicity. Finally, TF and RAR-α/RXR-α are important regulatory molecules in TAA induced acute liver injury.

Cytotoxic Activity and Metabolic Profiling of Fifteen Euphorbia Species.

Euphorbia is a large genus of flowering plants with a great diversity in metabolic pattern. Testing the cytotoxic potential of fifteen Euphorbia species revealed highest activity of E. officinarum L. against CACO2 cell line (IC50 7.2 µM) and of E. lactea Haw. against HepG2 and MCF-7 cell lines (IC50 5.2 and 5.1 µM, respectively). Additionally, metabolic profiling of the fifteen tested species, using LC-HRMS, for dereplication purposes, led to the annotation of 44 natural compounds. Among the annotated compounds, diterpenoids represent the major class. Dereplication approach and multivariate data analysis are adopted in order to annotate the compounds responsible for the detected cytotoxic activity. Results of PCA come in a great accordance with results of biological testing, which emphasized the cytotoxic properties of E. lactea Haw. A similarity correlation network showed that the two compounds with the molecular formula C16H18O8 and C20H30O10, are responsible for cytotoxic activity against MCF-7 and HepG2 cell lines. Similarly, the compound with molecular formula C18H35NO correlates with cytotoxic activity against CACO2.