Phytochemical analysis, and antioxidant and hepatoprotective activities of Chamaerops humilis L. leaves; a focus on xanthine oxidase.

Chamaerops humilis L. is clumping palm of the family Arecaceae with promising health-promoting effects. Parts of this species are utilized as food and employed in folk medicine to treat several disorders. This study investigated the phytochemical constituents of C. humilis leaves and their antioxidant and xanthine (XO) inhibitory activities in vitro and in acetaminophen (APAP)-induced hepatotoxicity in rats. Eleven compounds were isolated from C. humilis ethanolic extract (CHEE). CHEE and the butanol, n-hexane, and dichloromethane fractions exhibited in vitro radical scavenging and XO inhibitory efficacy. The computational findings revealed the tendency of the isolated compounds towards the active site of XO. In vivo, CHEE ameliorated liver function markers (ALT, AST, ALP, and albumin) and prevented tissue injury induced by APAP in rats. CHEE suppressed hepatic XO, decreased serum uric acid and liver MDA, and enhanced GSH, SOD, and catalase in APAP-treated rats. CHEE ameliorated serum TNF-α and IL-1ß in APAP-treated rats. Thus, C. humilis is rich in beneficial phytochemicals that possess binding affinity towards XO. C. humilis exhibited potent in vitro antioxidant and XO inhibitory activities, and prevented APAP hepatotoxicity by attenuating tissue injury, oxidative stress and inflammation.

Targeting antimalarial metabolites from the actinomycetes associated with the Red Sea sponge Callyspongia siphonella using a metabolomic method.

Malaria is a persistent illness that is still a public health issue. On the other hand, marine organisms are considered a rich source of anti­infective drugs and other medically significant compounds. Herein, we reported the isolation of the actinomycete associated with the Red Sea sponge Callyspongia siphonella. Using "one strain many compounds" (OSMAC) approach, a suitable strain was identified and then sub-cultured in three different media (M1, ISP2 and OLIGO). The extracts were evaluated for their in-vitro antimalarial activity against Plasmodium falciparum strain and subsequently analyzed by Liquid chromatography coupled with high-resolution mass spectrometry (LC-HR-MS). In addition, MetaboAnalyst 5.0 was used to statistically analyze the LC-MS data. Finally, Molecular docking was carried out for the dereplicated metabolites against lysyl-tRNA synthetase (PfKRS1). The phylogenetic study of the 16S rRNA sequence of the actinomycete isolate revealed its affiliation to Streptomyces genus. Antimalarial screening revealed that ISP2 media is the most active against Plasmodium falciparum strain. Based on LC-HR-MS based metabolomics and multivariate analyses, the static cultures of the media, ISP2 (ISP2-S) and M1 (M1-S), are the optimal media for metabolites production. OPLS-DA suggested that quinone derivatives are abundant in the extracts with the highest antimalarial activity. Fifteen compounds were identified where eight of these metabolites were correlated to the observed antimalarial activity of the active extracts. According to molecular docking experiments, saframycin Y3 and juglomycin E showed the greatest binding energy scores (-6.2 and -5.13) to lysyl-tRNA synthetase (PfKRS1), respectively. Using metabolomics and molecular docking investigation, the quinones, saframycin Y3 (5) and juglomycin E (1) were identified as promising antimalarial therapeutic candidates. Our approach can be used as a first evaluation stage in natural product drug development, facilitating the separation of chosen metabolites, particularly biologically active ones.

Development and Evaluation of a Self-Nanoemulsifying Drug Delivery System for Sinapic Acid with Improved Antiviral Efficacy against SARS-CoV-2.

This study aimed to develop a self-nanoemulsifying drug delivery system (SNE) for sinapic acid (SA) to improve its solubility and antiviral activity. Optimal components for the SA-SNE formulation were selected, including Labrafil as the oil, Cremophor EL as the surfactant, and Transcutol as the co-surfactant. The formulation was optimized using surface response design, and the optimized SA-SNE formulation exhibited a small globule size of 83.6 nm, high solubility up to 127.1 ± 3.3, and a 100% transmittance. In vitro release studies demonstrated rapid and high SA release from the formulation. Pharmacokinetic analysis showed improved bioavailability by 2.43 times, and the optimized SA-SNE formulation exhibited potent antiviral activity against SARS-CoV-2. The developed SA-SNE formulation can enhance SA's therapeutic efficacy by improving its solubility, bioavailability, and antiviral activity. Further in silico, modeling, and Gaussian accelerated molecular dynamics (GaMD)-based studies revealed that SA could interact with and inhibit the viral main protease (Mpro). This research contributes to developing effective drug delivery systems for poorly soluble drugs like SA, opening new possibilities for their application via nebulization in SARS-CoV-2 therapy.

Modulation of mi-RNA25/Ox-LDL/NOX4 signaling pathway by polyphenolic compound Hydroxytyrosol as a new avenue to alleviate cisplatin-induced acute kidney injury, a mechanistic study in rats.

Acute kidney injury (AKI) caused by Cis is considered one of the most severe adverse effects, which restricts its use and efficacy. This study seeks to examine the potential reno-protective impact of phenolic compound Hydroxytyrosol (HT) against Cis-induced AKI and the possible involvement of the mi-RNA25/Ox-LDL/NOX4 pathway elucidating the probable implicated molecular mechanisms. Forty rats were placed into 5 groups. Group I received saline only. Group II received Cis only. Group III, IV, and V received 20, 50, and 100 mg/kg b.w, of HT, respectively, with Cis delivery. NOX4, Ox-LDL, and gene expression of mi-RNA 25, TNF-α, and HO-1 in renal tissue were detected. HT showed reno-protective effect and significantly upregulated mi-RNA 25 and HO-1 as well as decreased the expression of NOX4, Ox-LDL, and TNF-α. In conclusion, HT may be promising in the fight against Cis-induced AKI through modulation of mi-RNA25/Ox-LDL/NOX4 pathway.

Aloin A inhibits SARS CoV-2 replication by targeting its binding with ACE2 - Evidence from modeling-supported molecular dynamics simulation.

The current study aimed to expand on the recently published results and assess the inhibitory efficacy of aloin A against SARS CoV-2. In vitro testing of aloin A against SARS CoV-2 proteases (i.e., MPro and PLPro) showed weak to moderate activity (IC50 = 68.56 ± 1.13 µM and 24.77 ± 1.57 µM, respectively). However, aloin A was able to inhibit the replication of SARS CoV-2 in Vero E6 cells efficiently with an IC50 of 0.095 ± 0.022 µM. Depending on the reported poor permeability of aloin A alongside its insignificant protease inhibitory activities presented in this study, we ran a number of extensive virtual screenings and physics-based simulations to determine the compound's potential mode of action. As a result, RBD-ACE2 was identified as a key target for aloin A. Results from 600 ns-long molecular dynamics (MD) simulation experiments pointed to aloin A's role as an RBD-ACE2 destabilizer. Therefore, the results of this work may pave the way for further development of this scaffold and the eventual production of innovative anti-SARS CoV-2 medicines with several mechanisms of action.Communicated by Ramaswamy H. Sarma.

Phthalazone tethered 1,2,3-triazole conjugates: In silico molecular docking studies, synthesis, in vitro antiproliferative, and kinase inhibitory activities.

New phthalazone tethered 1,2,3-triazole derivatives 12-21 were synthesized utilizing the Cu(I)-catalyzed click reactions of alkyne-functionalized phthalazone 1 with functionalized azides 2-11. The new phthalazone-1,2,3-triazoles structures 12-21 were confirmed by different spectroscopic tools, like IR; 1H, 13C, 2D HMBC and 2D ROESY NMR; EI MS, and elemental analysis. The antiproliferative efficacy of the molecular hybrids 12-21 against four cancer cell lines was evaluated, including colorectal cancer, hepatoblastoma, prostate cancer, breast adenocarcinoma, and the normal cell line WI38. The antiproliferative assessment of derivatives 12-21 showed potent activity of compounds 16, 18, and 21 compared to the anticancer drug doxorubicin. Compound 16 showed selectivity (SI) towardthe tested cell lines ranging from 3.35 to 8.84 when compared to Dox., that showed SI ranged from 0.75 to 1.61. Derivatives 16, 18 and 21 were assessed towards VEGFR-2 inhibitory activity and result in that derivative 16 showed the potent activity (IC50 = 0.123 µM) in comparison with sorafenib (IC50 = 0.116 µM). Compound 16 caused an interference with the cell cycle distribution of MCF7 and increased the percentage of cells in S phase by 1.37-fold. In silico molecular docking of the effective derivatives 16, 18, and 21 against vascular endothelial growth factor receptor-2 (VEGFR-2) confirmed the formation of stable protein-ligand interactions within the pocket.

Screening and Molecular Docking of Bioactive Metabolites of the Red Sea Sponge Callyspongia siphonella as Potential Antimicrobial Agents.

Marine sponges create a wide range of bioactive secondary metabolites, as documented throughout the year. Several bioactive secondary metabolites were isolated from different members of Callyspongia siphonella species. This study aimed for isolation and structural elucidation of major metabolites in order to investigate their diverse bioactivities such as antimicrobial and anti-biofilm activities. Afterwards, a molecular docking study was conducted, searching for the possible mechanistic pathway of the most bioactive metabolites. Extraction, fractionation, and metabolomics analysis of different fractions was performed in order to obtain complete chemical profile. Moreover, in vitro assessment of different bioactivities was performed, using recent techniques. Additionally, purification, structural elucidation of high features using recent chromatographic and spectroscopic techniques was established. Finally, AutoDock Vina software was used for the Pharmacophore-based docking-based analysis. As a result, DCM (dichloromethane) fraction exerted the best antibacterial activity using disc diffusion method; particularly against S. aureus with an inhibition zone of 6.6 mm. Compound 11 displayed a considerable activity against both MRSA (Methicillin-resistant Staphyllococcus aureus) and Staphyllococcus aureus with inhibition ratios of 50.37 and 60.90%, respectively. Concerning anti-biofilm activity, compounds 1 and 2 displayed powerful activity with inhibition ratios ranging from 39.37% to 70.98%. Pharmacophore-based docking-based analysis suggested elongation factor G (EF-G) to be a probable target for compound 11 (siphonellinol C) that showed the best in vitro antibacterial activity, offering unexplored potential for new drugs and treatment candidates.

Metabolomic Profiling, In Vitro Antimalarial Investigation and In Silico Modeling of the Marine Actinobacterium Strain Rhodococcus sp. UR111 Associated with the Soft Coral Nephthea sp.

Malaria is a persistent illness with a great public health concern. To combat this fatal disease, developing effective antimalarial medications has become a necessity. In the present study, we described the actinomycetes associated with the Red Sea soft coral Nephthea sp. and isolated a strain that was sub-cultured in three different media (M1, ISP2, and OLIGO). Actinomycete isolate's phylogenetic analysis of the 16S rRNA gene revealed that it belongs to the genus Rhodococcus. In vitro screening of the antimalarial activity for three extracts against Plasmodium falciparum was carried out. Non-targeted metabolomics for the chemical characterization of the isolated actinomycete species UA111 derived extracts were employed using high-resolution liquid chromatography-mass spectrometry (LC-HR-MS) for dereplication purposes. Additionally, statistical analysis of the vast LC-MS data was performed using MetaboAnalyst 5.0. Finally, an in silico analysis was conducted to investigate the potential chemical compounds that could be the source of the antimalarial potential. The results revealed that ISP2 media extract is the most effective against Plasmodium falciparum, according to antimalarial screening (IC50 8.5 µg/mL), in contrast, OLIGO media extract was inactive. LC-HRMS-based metabolomics identified a range of metabolites, mainly alkaloids, from the genus Rhodococcus. On the other hand, multivariate analysis showed chemical diversity between the analyzed samples, with ISP2 extract being optimal. The docking analysis was able to anticipate the various patterns of interaction of the annotated compounds with three malarial protein targets (P. falciparum kinase, P. falciparum cytochrome bc1 complex, and P. falciparum lysyl-tRNA synthetase). Among all of the test compounds, perlolyrine (11) and 3097-B2 (12) displayed the best docking profiles. In conclusion, this work demonstrated the value of the established method for the metabolic profiling of marine actinomycetes using the data from liquid chromatography-mass spectrometry (LC-MS), which helps to streamline the difficult isolation stages required for their chemical characterization. In addition, the antimalarial efficacy of this strain has intriguing implications for future pharmaceutical development.

Garcinia cambogia Phenolics as Potent Anti-COVID-19 Agents: Phytochemical Profiling, Biological Activities, and Molecular Docking.

COVID-19 is a disease caused by the coronavirus SARS-CoV-2 and became a pandemic in a critically short time. Phenolic secondary metabolites attracted much attention from the pharmaceutical industries for their easily accessible natural sources and proven antiviral activity. In our mission, a metabolomics study of the Garcinia cambogia Roxb. fruit rind was performed using LC-HRESIMS to investigate its chemical profile, especially the polar aspects, followed by a detailed phytochemical analysis, which led to the isolation of eight known compounds. Using spectrometric techniques, the isolated compounds were identified as quercetin, amentoflavone, vitexin, rutin, naringin, catechin, p-coumaric, and gallic acids. The antiviral activities of the isolated compounds were investigated using two assays; the 3CL-Mpro enzyme showed that naringin had a potent effect with IC50 16.62 µg/mL, followed by catechin and gallic acid (IC50 26.2, 30.35 µg/mL, respectively), while the direct antiviral inhibition effect of naringin confirmed the potency with an EC50 of 0.0169 µM. To show the molecular interaction, in situ molecular docking was carried out using a COVID-19 protease enzyme. Both biological effects and docking studies showed the hydrophobic interactions with Gln 189 or Glu 166, per the predicated binding pose of the isolated naringin.

Partial Synthetic PPARƳ Derivative Ameliorates Aorta Injury in Experimental Diabetic Rats Mediated by Activation of miR-126-5p Pi3k/AKT/PDK 1/mTOR Expression.

Type 2 diabetes mellitus (T2D) is a world wild health care issue marked by insulin resistance, a risk factor for the metabolic disorder that exaggerates endothelial dysfunction, increasing the risk of cardiovascular complications. Peroxisome proliferator-activated receptor PPAR) agonists have therapeutically mitigated hyperlipidemia and hyperglycemia in T2D patients. Therefore, we aimed to experimentally investigate the efficacy of newly designed synthetic PPARα/Ƴ partial agonists on a High-Fat Diet (HFD)/streptozotocin (STZ)-induced T2D. Female Wistar rats (200 ± 25 g body weight) were divided into four groups. The experimental groups were fed the HFD for three consecutive weeks before STZ injection (45 mg/kg/i.p) to induce T2D. Standard reference PPARƳ agonist pioglitazone and the partial synthetic PPARƳ (PIO; 20 mg/kg/BW, orally) were administered orally for 2 weeks after 72 h of STZ injection. The aorta tissue was isolated for biological ELISA, qRT-PCR, and Western blotting investigations for vascular inflammatory endothelial mediators endothelin-1 (ET-1), intracellular adhesion molecule 1 (ICAM-1), E-selectin, and anti-inflammatory vasoactive intestinal polypeptide (VIP), as well as microRNA126-5p and p-AKT/p-Pi3k/p-PDK-1/p-mTOR, endothelial Nitric Oxide Synthase (eNOS) immunohistochemical staining all are coupled with and histopathological examination. Our results revealed that HFD/STZ-induced T2D increased fasting blood glucose, ET-1, ICAM-1, E-selectin, and VIP levels, while decreasing the expression of both microRNA126-5p and p-AKT/p-Pi3k/p-PDK-1/p-mTOR phosphorylation. In contrast, the partial synthetic PPARƳ derivative evidenced a vascular alteration significantly more than reference PIO via decreasing (ET-1), ICAM-1, E-selectin, and VIP, along with increased expression of microRNA126-5p and p-AKT/p-Pi3k/p-PDK-1/p-mTOR. In conclusion, the partial synthetic PPARƳ derivative significantly affected HFD/STZ-induced T2D with vascular complications in the rat aorta.

Cecropin A Improves the Antibacterial Activity of Hen Egg White Lysozyme against Challenging Salmonella enterica Serovars.

The prevalence of multidrug-resistant Salmonella enterica among animal- and plant-derived food products threatens global healthcare and economic sectors. Hen egg white lysozyme is widely exploited as a food preservative against Gram-positive pathogens. Nevertheless, its limited penetration of the outer membrane renders it ineffective against Gram-negative bacteria. Herein, we present a safe and effective approach to facilitate HEWL access to peptidoglycan layers using cecropin A. In silico analysis of cecropin A peptide revealed an amphipathic α-helical peptide with potential outer membrane permeabilizing activity through its interaction with both hydrophobic and ionic stabilizing forces. Evaluation of HEWL/cecropin A combination showed a cecropin A dose-dependent bacterial count reduction up to 4.16 and 3.18 ± 0.26 log units against Salmonella enterica ATCC 35664 at the logarithmic and stationary growth phases, respectively. Moreover, the combination displayed antibacterial activity of 2.1 ± 0.31 and ~1 log-unit reductions against Salmonella enterica serovars Kentucky, Typhimurium, and Enteritidis, respectively, whereas Hato and Shangani were found irresponsive. The cytotoxicity assay revealed compatibility of cecropin A with oral epithelial cells. These observations suggest HEWL/cecropin A combination as an effective and safe alternative to lysozyme against Salmonella enterica.

¹H-NMR Metabolic Profiling, Antioxidant Activity, and Docking Study of Common Medicinal Plant-Derived Honey.

The purpose of this investigation was to determine ¹H-NMR profiling and antioxidant activity of the most common types of honey, namely, citrus honey (HC1) (Morcott tangerine L. and Jaffa orange L.), marjoram honey (HM1) (Origanum majorana L.), and clover honey (HT1) (Trifolium alexandrinum L.), compared to their secondary metabolites (HC2, HM2, HT2, respectively). By using a ¹H-NMR-based metabolomic technique, PCA, and PLS-DA multivariate analysis, we found that HC2, HM2, HC1, and HM1 were clustered together. However, HT1 and HT2 were quite far from these and each other. This indicated that HC1, HM1, HC2, and HM2 have similar chemical compositions, while HT1 and HT2 were unique in their chemical profiles. Antioxidation potentials were determined colorimetrically for scavenging activities against DPPH, ABTS, ORAC, 5-LOX, and metal chelating activity in all honey extract samples and their secondary metabolites. Our results revealed that HC2 and HM2 possessed more antioxidant activities than HT2 in vitro. HC2 demonstrated the highest antioxidant effect in all assays, followed by HM2 (DPPH assay: IC50 2.91, 10.7 µg/mL; ABTS assay: 431.2, 210.24 at 50 ug/mL Trolox equivalent; ORAC assay: 259.5, 234.8 at 50 ug/mL Trolox equivalent; 5-LOX screening assay/IC50: 2.293, 6.136 ug/mL; and metal chelating activity at 50 ug/mL: 73.34526%, 63.75881% inhibition). We suggest that the presence of some secondary metabolites in HC and HM, such as hesperetin, linalool, and caffeic acid, increased the antioxidant activity in citrus and marjoram compared to clover honey.

LC/MS Profiling and Gold Nanoparticle Formulation of Major Metabolites from Origanum majorana as Antibacterial and Antioxidant Potentialities.

Origanum majoranum L. is a Lamiaceae medicinal plant with culinary and ethnomedical applications. Its biological and phytochemical profiles have been extensively researched. Accordingly, this study aimed to investigate the chemical composition and the antibacterial and antioxidant properties of O. majoranum high features, as well as to search for techniques for activity optimization. A metabolomics study of the crude extract of O. majoranum using liquid chromatography-high-resolution electrospray ionization mass spectrometry (LC ± HR ± ESI ± MS) was conducted. Five fractions (petroleum ether, dichloromethane, ethyl acetate, n-butanol, and aqueous) were derived from the total extract of the aerial parts. Different chromatographic methods and NMR analysis were utilized to purify and identify the isolated phenolics (high features). Moreover, the antimicrobial, antibiofilm, and antioxidant activity of phenolics were performed. Results showed that metabolomic profiling of the crude extract of O. majoranum aerial parts revealed the presence of a variety of phytochemicals, predominantly phenolics, resulting in the isolation and identification of seven high-feature compounds comprising two phenolic acids, rosmarinic and caffeic acids, one phenolic diterpene, 7-methoxyepirosmanol, in addition to four flavonoids, quercetin, hesperitin, hesperidin, and luteolin. On the other hand, 7-methoxyepirosmanol (OM1) displayed the most antimicrobial and antioxidant potential. Such a phenolic principal activity improvement seems to be established after loading on gold nanoparticles.

Chitosan Silver and Gold Nanoparticle Formation Using Endophytic Fungi as Powerful Antimicrobial and Anti-Biofilm Potentialities.

Nanotechnology is emerging as a new technology with encouraging innovations. Global antibiotic use has grown enormously, with antibiotic resistance increasing by about 80 percent. In view of this alarming situation, intensive research has been carried out into biogenic nanoparticles and their antibacterial, antifungal, and antitumor activities. Many methods are available to enhance stability and dispersion via peroration of conjugate with a polymer, such as chitosan, and other bioactive natural products. Two marine fungi were isolated and identified as Aspergillus sp. and Alternaria sp. via sequencing of the 16S rRNA gene. In this work, these strains were used to form the conjugation of biogenic silver nanoparticles (AgNPs) from Aspergillus sp. Silv2 extract and gold nanoparticles (AuNPs) from Alternaria sp. Gol2 extracts with chitosan to prepare chitosan-AgNPs and chitosan-AuNP conjugates. A variety of imaging and analytical methods, such as UV-vis, X-ray powder diffraction (XRD), FTIR spectroscopy, transmission electron microscopy (TEM), and scanning electron microscopy (SEM) were utilized to characterize biogenic nanoparticles and conjugates. The biosynthesized Ag and Au nanoparticles along with the prepared conjugates were evaluated for their antimicrobial effects on Gram-negative and Gram-positive bacterial isolates, including Escherichia coli and Staphylococcus aureus. Both chitosan-AgNP and AuNP showed powerful antimicrobial activities compared to the control. On the other hand, chitosan-AgNP conjugation had better antibacterial ctivity than chitosan-AuNPs, which exhibited moderate activity against S. aureus and very low activity against E. coli. Furthermore, the antibiofilm potentials of the prepared conjugates were tested against four biofilm-forming bacteria, including P. aeruginosa, B. subtilis, E. coli, and S. aureus. The obtained results indicate that the chitosan-AgNP showed a promising anti-biofilm activities on all strains, especially S. aureus, while chitosan-AuNP conjugates showed moderate anti-biofilm against B. subtilis and weak activities against the other three strains. These results showed the superiority of chitosan-AgNP as a promising antibacterial as well as biofilm formation inhibitors.

Radiolabeling, biological distribution, docking and ADME studies of 99mTc-Ros as a promising natural tumor tracer.

Rosmarinic acid (Ros) is one of phenolic metabolites with powerful potency as an anticancer agent, with different mechanisms to diminish the cancer cells. This current study represents radiolabeling of Ros with 99mTc using SnCl2 in pH4 for 15 min at 60 °C, The yield up to 92.2%. Biological evaluation in normal and cancer mice revealed the localization of the tracer in tumor tissue. Furthermore, docking and ADME (Absorption, Distribution, Metabolism, and Excretion) studies were performed, The resulted data clarifies the use of Ros as a promissing natural tracer.

Pioglitazone Synthetic Analogue Ameliorates Streptozotocin-Induced Diabetes Mellitus through Modulation of ACE 2/Angiotensin 1-7 via PI3K/AKT/mTOR Signaling Pathway.

The renin angiotensin aldosterone system has a localized key regulatory action, especially in liver and body circulation. Furthermore, it accomplishes a significant role in the downregulation of the PI3K/AKT/mTOR signaling pathway that is involved in type II diabetes mellitus pathogenesis. The current study aimed to evaluate the effect of a synthetic pioglitazone analogue (benzenesulfonamide derivative) compared to the standard pioglitazone hypoglycemic drug on enhancing liver insulin sensitivity via ACE 2/Ang (1-7)/PI3K/AKT/mTOR in experimental STZ-induced diabetes. After the model was established, rats were distributed into the normal control group, diabetic group, pioglitazone group (20 mg/kg), and a benzenesulfonamide derivative group (20 mg/kg), with the last 2 groups receiving oral treatment for 14 consecutive days. Our results suggested enhancing liver insulin sensitivity against the ACE2/Ang (1-7)/PI3K/AKT/mTOR pathway. Moreover, the synthetic compound produced a reduction in blood glucose levels, restored hyperinsulinemia back to normal, and enhanced liver glycogen deposition. In addition, it up regulated the ACE2/Ang (1-7)/PI3K/AKT/mTOR signaling pathway via increasing insulin receptor substrate 1 and 2 sensitivity to insulin, while it increased glucose transporter 2 expression in the rat pancreas. The study findings imply that the hypoglycemic effect of the benzenesulfonamide derivative is due to enhancing liver sensitivity to regulate blood glucose level via the ACE2/Ang (1-7)/PI3K/AKT/mTOR pathway.

The Chemical Profiling, Docking Study, and Antimicrobial and Antibiofilm Activities of the Endophytic fungi Aspergillus sp. AP5.

Growing data suggest that Aspergillus niger, an endophytic fungus, is a rich source of natural compounds with a wide range of biological properties. This study aimed to examine the antimicrobial and antibiofilm capabilities of the Phragmites australis-derived endophyte against a set of pathogenic bacteria and fungi. The endophytic fungus Aspergillus sp. AP5 was isolated from the leaves of P. australis. The chemical profile of the fungal crude extract was identified by spectroscopic analysis using LC-HRESIMS. The fungal-derived extract was evaluated for its antimicrobial activity towards a set of pathogenic bacterial and fungal strains including Staphylococcus aureus, Pseudomonas aeruginosa, Proteus vulgaris, Klebsiella sp., Candida albicans, and Aspergillus niger. Moreover, antibiofilm activity toward four resistant biofilm-forming bacteria was also evaluated. Additionally, a neural-networking pharmacophore-based visual screening predicted the most probable bioactive compounds in the obtained extract. The AP5-EtOAc extract was found to have potent antibacterial activities against S. aureus, E. coli, and Klebsiella sp., while it exhibited low antibacterial activity toward P. Vulgaris and P. aeruginosa and displayed anticandidal activity. The AP5-EtOAc extract had significant antibiofilm activity in S. aureus, followed by P. aeruginosa. The active metabolites' antifungal and/or antibacterial activities may be due to targeting the fungal CYP 51 and/or the bacterial Gyr-B.

In Silico-Based Discovery of Natural Anthraquinones with Potential against Multidrug-Resistant E. coli.

E. coli is a Gram-negative bacterium that causes different human infections. Additionally, it resists common antibiotics due to its outer protective membrane. Natural products have been proven to be efficient antibiotics. However, plant natural products are far less explored in this regard. Accordingly, over 16,000 structures covering almost all African medicinal plants in AfroDb in a structural-based virtual screening were used to find efficient anti-E. coli candidates. These drug-like structures were docked into the active sites of two important molecular targets (i.e., E. coli's Ddl-B and Gyr-B). The top-scoring hits (i.e., got docking scores < -10 kcal/mol) produced in the initial virtual screening (0.15% of the database structures for Ddl-B and 0.17% of the database structures for Gyr-B in the database) were further refined using molecular dynamic simulation-based binding free energy (ΔG) calculation. Anthraquinones were found to prevail among the retrieved hits. Accordingly, readily available anthraquinone derivatives (10 hits) were selected, prepared, and tested in vitro against Ddl-B, Gyr-B, multidrug-resistant (MDR) E. coli, MRSA, and VRSA. A number of the tested derivatives demonstrated strong micromolar enzyme inhibition and antibacterial activity against E. coli, MRSA, and VRSA, with MIC values ranging from 2 to 64 µg/mL. Moreover, both E. coli's Ddl-B and Gyr-B were inhibited by emodin and chrysophanol with IC50 values comparable to the reference inhibitors (IC50 = 216 ± 5.6, 236 ± 8.9 and 0.81 ± 0.3, 1.5 ± 0.5 µM for Ddl-B and Gyr-B, respectively). All of the active antibacterial anthraquinone hits showed low to moderate cellular cytotoxicity (CC50 > 50 µM) against human normal fibroblasts (WI-38). Furthermore, molecular dynamic simulation (MDS) experiments were carried out to reveal the binding modes of these inhibitors inside the active site of each enzyme. The findings presented in this study are regarded as a significant step toward developing novel antibacterial agents against MDR strains.

Development and Greenness Assessment of HPLC Method for Studying the Pharmacokinetics of Co-Administered Metformin and Papaya Extract.

Foods with medical value have been proven to be beneficial, and they are extensively employed since they integrate two essential elements: food and medication. Accordingly, diabetic patients can benefit from papaya because the fruit is low in sugar and high in antioxidants. An RP-HPLC method was designed for studying the pharmacokinetics of metformin (MET) when concurrently administered with papaya extract. A mobile phase of 0.5 mM of KH2PO4 solution and methanol (65:35, v/v), pH = 5 ± 0.2 using aqueous phosphoric acid and NaOH, and guaifenesin (GUF) were used as an internal standard. To perform non-compartmental pharmacokinetic analysis, the Pharmacokinetic program (PK Solver) was used. The method's greenness was analyzed using two tools: the Analytical GREEnness calculator and the RGB additive color model. Taking papaya with MET improved the rate of absorption substantially (time for reaching maximum concentration (Tmax) significantly decreased by 75% while maximum plasma concentration (Cmax) increased by 7.33%). The extent of absorption reduced by 22.90%. Furthermore, the amount of medication distributed increased (30.83 L for MET concurrently used with papaya extract versus 24.25 L for MET used alone) and the clearance rate rose by roughly 13.50%. The results of the greenness assessment indicated that the method is environmentally friendly. Taking papaya with MET changed the pharmacokinetics of the drug dramatically. Hence, this combination will be particularly effective in maintaining quick blood glucose control.