Supplying rats with halfa-bar and liquorice extracts ameliorate doxorubicin-induced nephrotic syndrome.

In the current work, we aimed to evaluate the protective effects of liquorice and halfa-bar extract against doxorubicin (DOX)-induced nephritic syndrome (NS) in rats. Twenty albino male rats were intraperitoneally injected with 50 mg/kg of DOX. The injected rats were supplied daily with 400 mg/kg of liquorice, halfa-bar extract, or their combination for 2 weeks. Our findings confirmed the induction of NS in rats indicated by alteration in Bowman's space, damaged in glomerular capsules, and tubules. Moreover, the levels of produced tumour necrosis factor-alpha (TNF-α) and interleukin-8 (IL-8) were increased, accompanied by decreasing levels of IL-4 and IL-10. Supplement NS-rats with liquorice and halfa-bar extracts restored the glomerular and tubules damage and adjusted the level of produced TNF-α and IL-8. Interestingly, both extracts can stimulate the expression profile of small proline-rich protein 2 F (sprr2f) and metalloproteinase-10 (MMP-10), which are responsible for repairing and regeneration mechanisms of renal syndromes.

Decoding the role of long non-coding RNAs in gallbladder cancer pathogenesis: A review focus on signaling pathways interplay.

Gallbladder cancer (GBC) is one of the most aggressive types of biliary tree cancers and the commonest despite its rarity. It is infrequently diagnosed at an early stage, further contributing to its poor prognosis and low survival rate. The lethal nature of the disease has underlined a crucial need to discern the underlying mechanisms of GBC carcinogenesis which are still largely unknown. However, with the continual evolution in the research of cancer biology and molecular genetics, studies have found that non-coding RNAs (ncRNAs) play an active role in the molecular pathophysiology of GBC development. Dysregulated long non-coding RNAs (lncRNAs) and their interaction with intracellular signaling pathways contribute to malignancy and disease development. LncRNAs, a subclass of ncRNAs with over 200 nucleotides, regulate gene expression at transcriptional, translational, and post-translational levels and especially as epigenetic modulators. Thus, their expression abnormalities have been linked to malignancy and therapeutic resistance. lnsRNAs have also been found in GBC patients' serum and tumor tissue biopsies, highlighting their potential as novel biomarkers and for targeted therapy. This review will examine the growing involvement of lncRNAs in GBC pathophysiology, including related signaling pathways and their wider clinical use.

Furofuranoid-Type Lignans and Related Phenolics from Anisacanthus virgularis (Salisb.) Nees with Promising Anticholinesterase and Anti-Ageing Properties: A Study Supported by Molecular Modelling.

Lignan phytomolecules demonstrate promising anti-Alzheimer activity by alleviating dementia and preserving nerve cells. The purpose of this work is to characterize the lignans of Anisacanthus virgularis and explore their potential anti-acetylcholinesterase and anti-ageing effects. Phytochemical investigation of A. virgularis aerial parts afforded a new furofuranoid-type lignan (1), four known structural analogues, namely pinoresinol (2), epipinoresinol (3), phillyrin (4), and pinoresinol 4-O-ß-d-glucoside (5), in addition to p-methoxy-trans-methyl cinnamate (6) and 1H-indole-3-carboxaldehyde (7). The structures were established from thorough spectroscopic analyses and comparisons with the literature. Assessment of the anticholinesterase activity of the lignans 1-5 displayed noticeable enzyme inhibition of 1 (IC50 = 85.03 ± 4.26 nM) and 5 (64.47 ± 2.75 nM) but lower activity of compounds 2-4 as compared to the reference drug donepezil. These findings were further emphasized by molecular docking of 1 and 5 with acetylcholinesterase (AChE). Rapid overlay chemical similarity (ROCS) and structure-activity relationships (SAR) analysis highlighted and rationalized the anti-AD capability of these compounds. Telomerase activation testing of the same isolates revealed 1.64-, 1.66-, and 1.72-fold activations in cells treated with compounds 1, 5, and 4, respectively, compared to untreated cells. Our findings may pave the way for further investigations into the development of anti-Alzheimer and/or anti-ageing drugs from furofuranoid-type lignans.

The potential relevance of long non-coding RNAs in colorectal cancer pathogenesis and treatment: A review focus on signaling pathways.

Colorectal cancer (CRC) is one of the most frequent cancers in incidence and mortality. Despite advances in cancer biology, molecular genetics, and targeted treatments, CRC prognosis and survival have not kept pace. This is usually due to advanced staging and metastases at diagnosis. Thus, great importance has been placed upon understanding the molecular pathophysiology behind the development of CRC, which has highlighted the significance of non-coding RNA's role and associated intracellular signaling pathways in the pathogenesis of the disease. According to recent studies, long non-coding RNAs (lncRNA), a subtype of ncRNAs whose length exceeds 200 nucleotides, have been found to have regulatory functions on multiple levels. Their actions at the transcription, post-transcriptional, translational levels, and epigenetic regulation have made them prime modulators of gene expression. Due to their role in cellular cancer hallmarks, their dysregulation has been linked to several illnesses, including cancer. Furthermore, their clinical relevance has expanded due to their possible detection in blood which has cemented them as potential future biomarkers and thus, potential targets for new therapy. This review will highlight the importance of lncRNAs and related signaling pathways in the development of CRC and their subsequent clinical applications.

A cyclic azapeptide ligand of the scavenger receptor CD36/SR-B2 reduces the atherosclerotic lesion progression and enhances plaque stability in apolipoprotein E-deficient mice.

Atherosclerosis is a chronic inflammatory disease of the arterial walls that develops at predisposed sites. As a major risk factor for adverse cardiovascular pathology, atherosclerosis can progress to myocardial infarction and stroke, due to the rupture of unstable atherosclerotic lesions. Macrophage uptake of modified lipoproteins and metabolic dysfunction contributes significantly to the initiation and development of atherosclerotic lesions. The cluster of differentiation 36 receptor [CD36 (SR-B2)] plays a key role in atherosclerotic lesion progression and acts as an efferocytic molecule in the resolution of advanced plaque. In previous studies, linear azapeptide CD36 ligands were shown to exhibit anti-atherosclerotic properties. In the present study, a novel potent and selective macrocyclic azapeptide CD36 ligand, MPE-298, has proven effective in protecting against atherosclerosis progression. Features of greater plaque stability were observed after 8 weeks of daily injections with the cyclic azapeptide in apolipoprotein E-deficient mice fed a high-fat high-cholesterol diet.

ESI-LC-MS/MS based comparative multivariate metabolomic and biological profiling with dynamic molecular docking of Gmelina arborea Roxb different organs.

A comprehensive study of leaves, flowers, fruits, bark, and seeds' extracts of Gmelina arborea Roxb was performed for first time to investigate their anti-inflammatory, anti-Alzheimer, and antidiabetic activities. A thorough comparative phytochemical investigation of the five organs was performed using Tandem ESI-LC-MS. The biological investigation, further aided by multivariate data analysis and molecular docking proved the highly significant potential of using G.arborea organs' extracts as medicinal agents. Chemometric analysis of the obtained data revealed 4 distinct clusters among different samples of the 5 G.arborea (GA)organs and also confirmed that each organ was chemically distinct from the others, except for fruits and seeds which were closely correlated. Compounds anticipated to be responsible for activity were identified by LC-MS/MS. To clarify the differential chemical biomarkers of G. arborea organs, an orthogonal partial least squares discriminant analysis (OPLS-DA) was constructed. Bark exhibited it's in vitro anti-inflammatory activity through down regulation of COX-1 pro-inflammatory markers while fruits and leaves affected mainly DPP4 the marker for diabetes, and flowers were the most potent against Alzheimer maker acetylcholine (ACE) esterase. The metabolomic profiling of the 5 extracts lead to the identification of 27 compounds in negative ion mode and the differences in chemical composition were correlated to difference in activity. Iridoid glycosides were the major class of identified compounds. Molecular docking proved the different affinities of our metabolite towards different targets. Gmelina arborea Roxb. is a very important plant both economically and medicinally.

Telomerase RNA component lncRNA as potential diagnostic biomarker promotes CRC cellular migration and apoptosis evasion via modulation of ß-catenin protein level.

Aim: Long non-coding RNA (LncRNA) telomerase RNA component (TERC) has telomerase-dependent and independent activity in numerous cancer types. The present study purposes to demonstrate the role of lncRNA TERC as a diagnostic serum biomarker in colorectal cancer (CRC) patients and the molecular mechanism of lncRNA TERC in inducing tumor in CRC cell lines. Materials and methods: PCR array was performed to examine lncRNAs dysregulated in CRC. LncRNA TERC expression level was evaluated in 70 CRC patients and 35 control subjects using RT-qPCR. Then transfection was performed to build down-expression models of lncRNA TERC. ROC curve analysis was applied to assess the diagnostic value of serum LncRNA CRC. In addition, RT-qPCR was used to detect expression level of lncRNA TERC and ß-catenin mRNA. Moreover, ELISA and Western blot were used to detect the level of ß-catenin protein in sera of CRC patients and cell lines. The biological functions such as cell growth and migration of CRC cells were assessed using a wound healing assay. Cell cycle analysis and apoptosis analysis were performed using flow cytometry. Results: The lncRNA TERC is overexpressed in the sera of CRC patients with high diagnostic and stage discrimination accuracy. Furthermore, lncRNA TERC expression was upregulated in CRC cell lines and lncRNA TERC silencing induced cell arrest and apoptosis and inhibited cell migration. Furthermore, inhibition of lncRNA TERC reduces ß-catenin protein levels. Conclusion: The lncRNA TERC could be considered as an early stages CRC diagnostic biomarker with a good ability to discriminate between CRC stages. lncRNA TERC induces CRC by promoting cell migration and evading apoptosis by elevating the level of ß-catenin protein.

Structural determination and anticholinesterase assay of C-glycosidic ellagitannins from Lawsonia inermis leaves: A study supported by DFT calculations and molecular docking.

An ellagitannin monomer, lythracin M (1), and a dimer, lythracin D (2), along with eight known monomers (3-10) were isolated from Lawsonia inermis (Lythraceae) leaves. Lythracin M (1) is a C-glycosidic ellagitannin with a flavogallonyl dilactone moiety that participates in the creation of a γ-lactone ring with the anomeric carbon of the glucose core. Lythracin D (2) was determined as an atropisomer of the reported lythcarin D. These newly discovered structures (1 and 2) were determined by intensive spectroscopic experiments and by comparing DFT-calculated 1H1H coupling, 1H NMR chemical shifts, and ECD data with experimental values. The anti-acetylcholinesterase assay of the compounds 1-10 revealed that the C-1 ellagitannin epimers [casuarinin (7; IC50 = 34 ± 2 nM) and stachyurin (8; IC50 = 56 ± 3 nM)], and the new dimer (2; IC50 = 61 ± 4 nM) possess enzyme inhibitory effects comparable to the reference drug (donepezil, IC50 = 44 ± 3 nM). Molecular docking of compounds 1-10 with AChE identified the free galloyl moiety as an important pharmacophore in the anticholinesterase activity of tannins.

Anti-androgenic potential of the fruit extracts of certain Egyptian Sabal species and their genetic variability studies: a metabolomic-molecular modeling approach.

This work aimed to evaluate the anti-androgenic activity of S. blackburniana Glazebrook, S. causiarum (O. F. Cook) Becc, and S. palmetto (Walter) Lodd. Ex Schult fruit extracts in rats using Hershberger assay. Furthermore, to annotate secondary metabolites using LC-HRMS technique, to investigate underlying mechanisms responsible for 5-α-reductase inhibitory activity in silico and to compare cytotoxic effects in vitro against human prostatic stromal myofibroblast (WPMY-1) and human benign prostatic hyperplasia (BPH-1) cell lines using MTT, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (spectrophotometrically). The results showed significant anti-androgenic implications with varying degrees, markedly decreased sex organ weights, reduction in testosterone and increase in LH and FSH serum levels. Genetic diversity study ensured the correct genotype and revealed outperformance of SCoT compared with CBDP markers to interpret polymorphism among selected species. S. blackburniana exhibited selective cytotoxic activity against BPH-1 compared to finasteride. Molecular docking of 59 dereplicated metabolites belonging to various chemical classes revealed that helasaoussazine, pinoresinol and tetra-O-caffeoylquinic acid are the top inhibitors of 5-α-reductase-2. Our study provides an insight into the anti-androgenic activity of selected species of Egyptian Sabal supported by docking study for the first time, demonstrates safety toward liver and kidney and highlights a new potential therapeutic candidate for anti-androgenic related disease such as benign prostatic hyperplasia.

Preclinical activity of fluvastatin-loaded self-nanoemulsifying delivery system against breast cancer models: Emphasis on apoptosis.

Statins trigger apoptotic cell death in some types of growing tumor cells in a cholesterol-lowering-independent manner. Self-nanoemulsifying delivery systems (SNEDs) are potentially effective for the suppression of breast cancer development. This study aims to investigate the potential anticancer activity of fluvastatin (FLV)-SNEDs in breast cancer while comparing it with FLV in vitro as well as in vivo exploiting/using MDA-MB-231 and Erhlich ascites carcinoma (EAC)-bearing mice, respectively. Biochemical analysis of liver and kidney functions, oxidative stress markers, and histopathological examinations of such tumor tissues were performed showing the potentiality of SNEDs as a nanocarrier for antitumor agents. FLV-SNEDs demonstrated more potent anticancer activity compared to FLV on MDA-MB-231 and hepatocellular carcinoma (HepG2) cells. In vivo experiments on the EAC-bearing mice model indicated that FLV and-to a greater extent-FLV-SNEDs ameliorated EAC-induced hepatotoxicity and nephrotoxicity. FLV or FLV-SNEDs evidently reduced the percent of Ki-67 +ve EAC cells by 57.5% and 86.5% in comparison to the vehicle-treated EAC group. In addition, FLV or FLV-SNEDs decreased Bcl-2 levels in serum and liver specimens. In contrast, FLV or FLV-SNEDs significantly activated the executioner caspase-3. Simultaneously, both FLV and FLV-SNEDs stimulated p53 signaling and modulated Bcl-2 protein levels in treated cells. Collectively, these results support the contribution of apoptotic cell death in mediating the anticancer activities of FLV and FLV-SNEDs against murine EAC model in vivo. This study provides new understandings of how FLV and FLV-SNEDs regulate EAC cell viability via upregulation of p53 signaling, and through modulation of cleaved caspase-3 as well as antiapoptotic Bcl-2 marker.

Cytotoxic potential of three Sabal species grown in Egypt: a metabolomic and docking-based study.

The phytochemical profiles of leaves and pollen grains' extracts of S. causiarum, S. palmetto and S. yapa were investigated and characterised by LC-HR-MS-based metabolomic analysis. Further, biomarker metabolites were determined using multivariate and clustering analysis. S. causiarum leaves extract along with both S. palmetto and S. yapa pollen grains extracts showed interesting in vitro cytotoxic activity using MTT assay against PC-3 cell lines. While, both S. yapa leaves and pollen grains-derived extracts and S. causiarum pollen grains-derived extracts were active against A-172 cell line. OPLS-DA models was generated, to putatively determine the most active cytotoxic metabolites, these models suggested that alkaloids, flavonoids and phenolic acids are the most important metabolites in the active extracts. In silico analysis (neural-networking-based activity prediction and docking studies) of these top-scoring metabolites further supported OPLS-DA models predictability. This study could be considered as primary step in the in-depth exploration of bioactive natural products from Sabal.

Cytotoxic and anti-diabetic potential, metabolic profiling and insilico studies of Syzygium cumini (L.) Skeels belonging to family Myrtaceae.

LC-HR-MS-coupled metabolic profiling of the methanol extracts from different parts of Syzygium cumini (L.), which was extensively identified via DNA fingerprinting, led to dereplication of 24 compounds. Cytotoxic investigation highlighted both extracts as the most potent, against both MCF-7 and MDA-231 Cell lines, with IC50 value of 5.86 ± 0.63 µg/ml and against HCT -116 cell line, with IC50 value of 1.24 ± 0.09 µg/ml, respectively. A molecular docking study was performed on the dereplicated compounds, which highlighted myricetin-3-glucoside (7), myricitrin (12), reynoutrin (15) and quercitrin (16) as the top scoring ligands within the protein active site (FIH-1). Interestingly, the extracts were significant against streptozotocin-induced diabetes in the order of flowers > seeds > leaves with BGL level of 98.9 ± 4.3, 123.2 ± 4.9 and 132.8 ± 5.9 mg/dl, respectively. The study highlights the health benefits of Syzygium cumini (L.) as a promising cytotoxic source.

Structure- and Ligand-Based in silico Studies towards the Repurposing of Marine Bioactive Compounds to Target SARS-CoV-2.

This work was a structured virtual screening for marine bioactive compounds with reported antiviral activities which were subjected to structure-based studies against SARS-CoV-2 co-crystallized proteins. The molecular docking of marine bioactive compounds against the main protease (Mpro, PDB ID: 6lu7 and 6y2f), the spike glycoprotein (PDB ID: 6vsb), and the RNA polymerase (PDB ID: 6m71) of SARS-CoV-2 was performed. Ligand-based approach with the inclusion of rapid overlay chemical structures (ROCS) was also addressed in order to examine the probability of these marine compounds sharing relevance and druggability with the reported drugs. Among the examined marine library, the highest scores in different virtual screening aspects were displayed by compounds with flavonoids core, acyl indole, and pyrrole carboxamide alkaloids. Moreover, a complete overlay with the co-crystallized ligands of Mpro was revealed by sceptrin and debromo-sceptrin. Thalassoilin (A-B) which was found in the Red Sea exhibited the highest binding and similarity outcomes among all target proteins. These data highlight the importance of marine natural metabolites in regard to further studies for discovering new drugs to combat the COVID-19 pandemic.

Chemometric-enhanced metabolic profiling of five Pinus species using HPLC-MS/MS spectrometry: Correlation to in vitro anti-aging, anti-Alzheimer and antidiabetic activities.

Detailed metabolic profiling of needles of five Pinus species was investigated using complementary HPLC-MS/MS techniques together with supervised and unsupervised chemometric tools. This resulted in putative identification of 44 compounds belonging to flavonoids, phenolics, lignans, diterpenes and fatty acids. Unsupervised principal component analysis showed that differences were maintained across the metabolites characteristic of each Pinus species, are mainly related to di-O-p-coumaroyltrifolin, p-coumaroyl quinic acid derivative, arachidonic acid, hydroxypalmitic acid, isopimaric acid and its derivative. A supervised Partial Least Squares regression analysis was performed to correlate HPLC-MS/MS profiles with the variation observed in the in vitro anticholinesterase, antiaging and anti-diabetic potential. All investigated Pinus extracts exerted their antiaging activity via increasing telomerase and TERT levels in normal human melanocytes cells compared to the control (untreated cells). Profound inhibition activities of acetylcholinesterase and dipeptidyl peptidase-4 were also observed with P. pinea and P. canariensis extracts having comparable antidiabetic activities to sitagliptin as a standard antidiabetic drug. Our findings suggested that pine needles are a good source of phenolics and diterpenoids that have possible health promoting activities in management and alleviation of diabetic conditions and Alzheimer disease.

New Adenosine Derivatives from Aizoon canariense L.: In Vitro Anticholinesterase, Antimicrobial, and Cytotoxic Evaluation of Its Extracts.

Aizoaceae is a large succulent family characterized by many psychoactive species. Aizoon canariense L., a wild neglected plant traditionally used in gastrointestinal ailments, has been the subject of a limited number of phytochemical and biological studies. Therefore, herein, we investigated the in vitro cytotoxic, antimicrobial, and anticholinesteraseactivity of the aerial parts of A. canariense L. and analyzed the phytochemical compositions of the lipoidal and alkaloidal fractions. Petroleum ether extract showed the presence of behenic and tricosylic acid, while an in-depth investigation of the alkaloidal fraction revealed the identification of new adenine based alkaloids (1-5), which were isolated and identified for the first time from Aizoon canariense L. Their structures were elucidated based on extensive spectroscopic analyses. The alkaloidal extract showed a powerful cytotoxic effect (IC50 14-28 µg/mL), with the best effect against colon carcinoma, followed by liver and breast carcinomas. The alkaloidal extract also had a potent effect against Candida albicans and Escherichia coli, with minimum inhibitory concentrations (MIC) values of 312.5 and 625 µg/mL. The in vitro anticholinesterase activity was potent, with IC50 < 200 ng/mL for the tested extracts compared with 27.29 ± 0.49 ng/mL for tacrine.

Bioactive constituents from Thunbergia erecta as potential anticholinesterase and anti-ageing agents: Experimental and in silico studies.

Acetylcholinesterase (AChE) inhibitor and telomerase reverse transcriptase (TERT) potentiator phytochemicals are highly targeted as anti-Alzheimerꞌs disease and as an anti-ageing process. A phytochemical study of Thunbergia erecta aerial parts resulted in the isolation of ten compounds (1-10). Their structures were identified based on spectral data and comparison with literature values. The activity of our pure isolates on AChE and TERT enzymes by documented in vitro assay methods were evaluated. The results indicated that apigenin (2), vanillic acid (4), and acacetin-7-O-ß-D-glucoside (7) exhibited potent inhibition of AChE (IC50 37.33, 30.80 and 49.57 ng/mL, respectively), compared to the standard drug donepezil (IC50 31.25 ng/mL). In the TERT enzyme assay, compound 7 triggered a 1.66­fold increase in telomerase activity at the concentration of 2.85 ng/ml. This is the first study that demonstrates that compound 7 isolated from T. erecta can lead to such telomerase activity relative to control cells. Virtual screening studies including docking, rapid overlay chemical structure (ROCS), and calculated structure-property relationships (SPR) were implemented in this work. Molecular docking studies supported the binding of compounds 2, 4, and 7 through hydrogen bonds (HBs) formation to essential amino acid residues namely ARG:24 A, SER:347 A, LYS:51 A, PHE:346 A, and GLY:345 A of acetylcholinesterase. ROCS and SPR analyses realized compound 2 as a possible treatment of Alzheimer's disease and as a lead compound for drug development process through applying semisynthetic modifications.

Green-synthesized zinc oxide nanoparticles, anti-Alzheimer potential and the metabolic profiling of Sabal blackburniana grown in Egypt supported by molecular modelling.

Nowadays, the biosynthesis of metal nanoparticles, particularly from plants, has been gaining interest. In the present work, the methanolic extracts of leaves, fruits, and the pollen grains of Sabal blackburniana were used for the green synthesis of ZnO nanoparticles, which were early detected by the formation of precipitate and further confirmed by UV-vis spectroscopy, transmission electron microscopy (TEM), X-ray diffraction (XRD), Fourier transform infra-red (FT-IR) spectroscopy and zeta potential (ZP) studies. TEM analysis has shown different shapes, predominantly irregular small spherical narrow particles included in hexagonal structures with size ranging from 2.23 to 49.56 nm. The XRD pattern confirmed that all synthesized ZnO nanoparticles have wurtzite hexagonal structure with crystalline nature. The average particle crystallite sizes were 47.21, 47.67 and 47.8 nm. The UV-visible spectra showed λ max in the range of 354-368 nm, which indicated the presence of ZnO nanoparticles. The FT-IR analysis identifies the characteristic functional groups present on the surface of ZnO nanoparticles. The ZP determination demonstrated that all representative selected synthesized ZnONPs exhibited acceptable ZP values of -30.8 to -45.9 mV, which indicated their good stability. In addition, the anti-Alzheimer potential of the selected extracts and ZnONPs was evaluated by assessing acetylcholinesterase inhibitory activity in vitro according to the improved Ellman method. The results indicated that the selected extracts have acetylcholinesterase inhibitory activity, and highlighted the promising inhibitory potential of green-synthesized ZnONPs using pollen grains, fruits and leaves extracts; they exhibited a potent inhibitory effect with IC50 values 63.78 ± 1.04651, 81.985 ± 3.075 and 117.95 ± 6.858 ng ml-1 respectively in comparison to donepezil as standard (IC50 = 50.7 ± 5.769 ng ml-1). Dereplication analysis of the selected extracts was performed using LC-MS; metabolic profiling revealed the presence of 41 compounds belonging to various chemical classes: flavonoids, steroidal saponins, terpenoids, alkaloids, lignans, sterols and fatty acids. Docking these dereplicated metabolites against the human AChE showed that the non-glycosylated flavonoid class of compounds was able to achieve interesting binding modes inside the AChE active site; they are suggested to be associated with the observed anti-AChE activity of Sabal extracts. This study is the first report to shed light on the acetylcholinesterase inhibitory activity of green-synthesized ZnO nanoparticles of S. blackburniana metabolites.

Lipid polymer hybrid nanocarriers as a combinatory platform for different anti-SARS-CoV-2 drugs supported by computational studies.

The COVID-19 pandemic caused by SARS-CoV-2 has demonstrated the potential of emergent pathogens to severely damage public health and global economies. As a consequence of the pandemic, millions of people have been forced into self-isolation, which has negatively affected the global economy. More efforts are needed to find new innovative approaches that could fundamentally change our understanding and management of this disaster. Herein, lipid polymer hybrid nanoparticles (LPH NPs) were utilized as a platform for the delivery of azithromycin or niclosamide in combination with piroxicam. The obtained systems were successfully loaded with both azithromycin and piroxicam (LPHAzi-Pir) with entrapment efficiencies (EE%) of 74.23 ± 8.14% and 51.52 ± 5.45%, respectively, or niclosamide and piroxicam (LPHNic-Pir) with respective EE% of 85.14 ± 3.47% and 48.75 ± 4.77%. The prepared LPH NPs had a core-shell nanostructure with particle size ≈ 125 nm and zeta potential ≈ -16.5 irrespective of drug payload. A dose-dependent cellular uptake of both LPH NPs was observed in human lung fibroblast cells. An enhanced in vitro antiviral efficacy of both LPHAzi-Pir and LPHNic-Pir was obtained over the mixed solution of the drugs. The LPH NPs of azithromycin or niclosamide with piroxicam displyed a promising capability to hinder the replication of SARS-CoV-2, with IC50 of 3.16 and 1.86 µM, respectively. These results provide a rationale for further in vivo pharmacological as well as toxicological studies to evaluate the potential activity of these drugs to combat the COVID-19 outbreak, especially the concept of combination therapy. Additionally, the molecular docking of macrolide bioactive compounds against papain-like protease (PDB ID:6wuu) was achieved. A ligand-based study, especially rapid overlay chemical structure (ROCS), was also examined to identify the general pharmacophoric features of these compounds and their similarity to reported anti-SARS-CoV-2 drugs. Molecular dynamic simulation was also implemented.

Rosuvastatin lyophilized tablets loaded with flexible chitosomes for improved drug bioavailability, anti-hyperlipidemic and anti-oxidant activity.

Rosuvastatin is a hypolipidemic drug of limited oral bioavailability. The aim was to develop rosuvastatin flexible chitosomes and loading into a pullulan-based tablet to improve the bioavailability and maximize the antihyperlipidemic and antioxidant activities. Chitosomes nanoparticles were developed and characterized. Pullulan-based lyophilized fast dissolving tablets were developed and evaluated. The tablets' outer and inner structures were morphologically investigated. In vivo disintegration of the prepared tablets was studied in healthy human volunteers. The pharmacokinetics, antihyperlipidemic, antioxidant, and biochemical markers activities were conducted after administration of the tablets into male Wister rats. Liver histopathology was also investigated. The prepared chitosomes illustrated an average particle size of 342.22 ± 2.90 nm, a zeta potential value of +28.87 ± 1.39 mV and a drug entrapment efficiency of 94.59 ± 1.62%. The developed tablets showed an acceptable quality control characteristics and in vivo disintegration time of 1.48 ± 0.439 min. Scanning electron microscopy revealed distinct porous surface and sponge-like inner structure. The chitosomes based tablets demonstrated higher relative bioavailability by more than 30% and 36% when compared with the corresponding pure rosuvastatin and the marketed drug tablets, respectively. Moreover, the chitosomes based tablets showed a significant improvement in the hepatic serum biomarkers and a dramatic decrease in the serum antioxidants in response to Poloxamer 407 intoxication. The prepared tablets did not exhibit marked histopathological changes in the hepatic tissues. Accordingly, the pullan-based lyophilized fast-dissolving tablets loaded with chitosomes nanoparticles could be considered as a promising drug formulation for enhancing rosuvastatin bioavailability and pharmacodynamics activity.

Enhancing the Hypolipidemic Effect of Simvastatin in Poloxamer-Induced Hyperlipidemic Rats via Liquisolid Approach: Pharmacokinetic and Pharmacodynamic Evaluation.

This study aimed to enhance the dissolution of simvastatin (SMV) through its formulation in liquisolid tablets (LSTs) to improve its bioavailability and hypolipidemic activity after oral administration. SMV-LSTs were optimized using Box-Behnken design to maximize the rate and extent of SMV dissolution. The optimized SMV-LST was evaluated for pharmacokinetic parameters and potential hypolipidemic activity on induced hyperlipidemic rats. The dissolution parameters revealed a shortening of mean dissolution time from 10.99 to 6.82 min, increasing of dissolution rate during the first 10 min from 1253.15 to 1667.31 µg/min, and enhancing of dissolution efficiency after 60 min from 71.92 to 86.93% for SMV-LSTs versus the commercial SMV tablets. The obtained data reflected an improvement in the relative bioavailability of SMV with 148.232% which was confirmed by the significant reduction of the levels of circulating total cholesterol, triglycerides that reached the normal level after 12 h. In particular, the optimized SMV-LSTs reduced serum low-density lipoproteins (LDL) by 44.6% which was significantly different from the commercial SMV tablets. In contrast, the level of serum high-density lipoprotein (HDL) was significantly augmented after 4 h in rats treated with the optimized SMV-LSTs by 47.6%. Finally, the optimized SMV-LSTs showed a significant lower atherosclerotic index value which could maximize its potential in decreasing the risk of coronary disease and atherosclerosis. Overall enhancement in pharmacokinetics and pharmacodynamics in comparison with the commercial tablets confers the potential of the liquisolid approach as a promising alternative for improved oral bioavailability, hypolipidemic, and cardioprotective effects of SMV. Graphical abstract.