α-Glucosidase, butyrylcholinesterase and acetylcholinesterase inhibitory activities of phenolic compounds from Carthamus tinctorius L. flowers: In silico and in vitro studies.

Chemical investigation of Carthamus tinctorius L. flowers resulted in isolation of seven metabolites that were identified as; p-Hydroxybenzoic acid (1), trans hydroxy cinnamic acid (2), kaempferol-6-C-glucoside (3), astragalin (4), cartormin (5), kaempferol-3-O-rutinoside (6), and kaempferol-3-O-sophoroside (7). Virtual screening of the isolated compounds against human intestinal α-glucosidase, acetylcholinesterase, and butyrylcholinesterase was carried out. Additionally, the antioxidant activity of the bioactive compounds was assessed. Compounds 1 and 5 exhibited moderate binding affinities to acetylcholinesterase (binding energy -5.33 and -4.18 kcal/mol, respectively), compared to donepezil (-83.33kcal/mol). Compounds 1-7 demonstrated weak affinity to butyrylcholinesterase. Compounds 2 and 4 displayed moderate binding affinity to human intestinal α-glucosidase,compared to Acarbose (reference compound), meanwhile compound 2 exhibited lower affinity. Molecular dynamic studies revealed that compound 4 formed a stable complex with the binding site throughout a 100 ns simulation period. The in-vitro results were consistent with the virtual experimental results, as compounds 1 and 5 showed mild inhibitory effects on acetylcholinesterase (IC50s 150.6 and 168.7 µM, respectively). Compound 4 exhibited moderate α-glucosidase inhibition with an IC50 of 93.71 µM. The bioactive compounds also demonstrated notable antioxidant activity in ABTS [2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)], ORAC (oxygen radical-absorbance capacity), and metal chelation assays, suggesting their potential in improving dementia in Alzheimer's disease (AD) and mitigating hyperglycemia.

RETRACTED: Alhakamy et al. Development and Optimization of Luliconazole Spanlastics to Augment the Antifungal Activity against Candida albicans. Pharmaceutics 2021, 13, 977.

The journal retracts the article, "Development and Optimization of Luliconazole Spanlastics to Augment the Antifungal Activity against Candida albicans" [...].

Cepabiflas B and C as Novel Anti-Inflammatory and Anti-Apoptotic Agents against Endotoxin-Induced Acute Kidney and Hepatic Injury in Mice: Impact on Bax/Bcl2 and Nrf2/NF-κB Signalling Pathways.

Cepabiflas B and C (CBs) are flavonoid dimers separated from Allium cepa. They demonstrated antioxidant and α-glucosidase and protein tyrosine phosphatase 1B inhibition capacities. However, their anti-inflammatory activities and their effects on endotoxemia are unknown. The current study aimed at exploring the protective activities of CBs on lipopolysaccharide (LPS)-induced kidney and liver damage in mice and investigating the possible molecular mechanisms. Mice were orally treated with a low (40 mg/kg) or high (60 mg/kg) dose of CBs for five days prior to a single intraperitoneal injection of LPS (10 mg/kg). Samples of serum and hepatic and kidney tissues were collected 24 h after the LPS challenge. Changes in serum indices of hepatic and renal injury, pathological changes, molecular biological parameters, and proteins/genes related to inflammation and apoptosis of these organs were estimated. LPS injection resulted in deleterious injury to both organs as indicated by elevation of serum ALT, AST, creatinine, and BUN. The deteriorated histopathology of hepatic and renal tissues confirmed the biochemical indices. CBs treated groups showed a reduction in these parameters and improved histopathological injurious effects of LPS. LPS-induced hepatorenal injury was linked to elevated oxidative stress as indicated by high levels of MDA, 4-HNE, as well as repressed antioxidants (TAC, SOD, and GSH) in hepatic and kidney tissues. This was accompanied with suppressed Nrf2/HO-1 activity. Additionally, there was a remarkable inflammatory response in both organs as NF-κB signalling was activated and high levels of downstream cytokines were produced following the LPS challenge. Apoptotic changes were observed as the level and gene expression of Bax and caspase-3 were elevated along with declined level and gene expression of Bcl2. Interestingly, CBs reversed all these molecular and genetic changes and restricted oxidative inflammatory and apoptotic parameters after LPS-injection. Collectedly, our findings suggested the marked anti-inflammatory and anti-apoptotic activity of CBs which encouraged its use as a new candidate for septic patients.

SIRT1/Nrf2/NF-κB Signaling Mediates Anti-Inflammatory and Anti-Apoptotic Activities of Oleanolic Acid in a Mouse Model of Acute Hepatorenal Damage.

Background and objectives: Oleanolic acid (OA) is a penta-cyclic triterpene with diverse bioactivities such as anticarcinogenic, antiviral, antimicrobial, hepatoprotective, anti-atherosclerotic, hypolipidemic, and gastroprotective. However, its effects on hepatorenal damage remain unclear. The protective activity of OA, separated from Viscum schimperi (Loranthaceae), against TAA (thioacetamide)-produced acute hepatic and renal damage was explored. Materials and Methods: Mice were treated with OA for 7 days before TAA (200 mg/kg, i.p.). Serum indices of hepatorenal injury, pathological lesions, molecular biological indexes, and inflammatory/apoptotic genes were estimated. Results: The tissues of both organs were greatly affected by the TAA injection. That was evident through increased serum markers of hepato-renal injury as well as remarkable histopathological lesions. TAA-induced injury was associated with oxidative and inflammatory responses in both organs as there was an elevation of oxidative stress parameters (4-HNE (4-hydroxy-nonenal), MDA (malondialdehyde), NOx (nitric oxide)), decline of antioxidants (reduced glutathione (GSH), superoxide dismutase (SOD), and total antioxidant capacity (TAC)), and an increase in the gene expression/level of inflammatory mediators (interleukins (1ß&6)). The inflammatory response was linked to a significant activation of NF-κB (nuclear-factor kappa-B)/TNF-α (tumor-necrosis factor-alpha) signaling. The inflammatory response in both organs was accompanied by apoptotic changes, including a rise in the gene expression and level of apoptotic parameters (caspase-3 and Bax) along with a decline in Bcl-2 (anti-apoptotic parameter) gene expression and level. These pathogenic events were found to be closely related to the suppression of the antioxidant signaling pathway, Nrf2 (nuclear-factor erythroid 2-related factor-2)/SIRT1 (sirtuin-1)/HO-1 (heme-oxygenase 1). On the other hand, OA significantly ameliorated TAA-induced injury in both organs. On the other hand, OA counterpoised the inflammatory response as it ameliorated NF-κB/TNF-α signaling and cytokine release. OA enhanced Nrf2/SIRT1/HO-1 signaling and counteracted apoptotic damage. Conclusions: OA showed anti-inflammation and antiapoptotic capacities that effectively suppressed TAA-induced acute hepatorenal damage.

Hepatoprotective Effect of Silver Nanoparticles at Two Different Particle Sizes: Comparative Study with and without Silymarin.

Silver nanoparticles have been used for numerous therapeutic purposes because of their increased biodegradability and bioavailability, yet their toxicity remains questionable as they are known to interact easily with biological systems because of their small size. This study aimed to investigate and compare the effect of silver nanoparticles' particle size in terms of their potential hazard, as well as their potential protective effect in an LPS-induced hepatotoxicity model. Liver slices were obtained from Sprague Dawley adult male rats, and the thickness of the slices was optimized to 150 µm. Under regulated physiological circumstances, freshly cut liver slices were divided into six different groups; GP1: normal, GP2: LPS (control), GP3: LPS + AgNpL (positive control), GP4: LPS + silymarin (standard treatment), GP5: LPS + AgNpS + silymarin (treatment I), GP6: LPS + AgNpL + silymarin (treatment II). After 24 h of incubation, the plates were gently removed, and the supernatant and tissue homogenate were all collected and then subjected to the following biochemical parameters: Cox2, NO, IL-6, and TNF-α. The LPS elicited marked hepatic tissue injury manifested by elevated cytokines and proinflammatory markers. Both small silver nanoparticles and large silver nanoparticles efficiently attenuated LPS hepatotoxicity, mainly via preserving the cytokines' level and diminishing the inflammatory pathways. In conclusion, large silver nanoparticles exhibited effective hepatoprotective capabilities over small silver nanoparticles.

Cucurbitacin E glucoside alleviates concanavalin A-induced hepatitis through enhancing SIRT1/Nrf2/HO-1 and inhibiting NF-ĸB/NLRP3 signaling pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Cucurbitacins are highly oxygenated tetracyclic triterpenoids, that represent the major metabolites reported from C. colocynthis (L.) Schrad.. Cucurbitacin E glucoside (CuE) is a tetracyclic triterpene glycoside separated from Cucurbitaceae plants. CuE has potent anti-inflammatory, immunomodulatory, and anti-tumor properties. AIM OF THE STUDY: The current study aimed at examining the hepatoprotective effect of CuE against concanavalin A (Con A)-produced hepatitis. MATERIALS AND METHODS: Mice were intravenously administered Con A (15 mg/kg) to induce AIH. CuE was orally administered at two different doses for five days preceding Con A injection. RESULTS: The results revealed that CuE pretreatment markedly attenuated the serum indices of hepatotoxicity and the severity of hepatic lesions. CuE depressed Con A-provoked increment in CD4+ T-cells in hepatic tissue. The antioxidant activity of CuE was evident through its ability to decrease markers of Con A-induced oxidative stress (malondialdehyde, 4-hydroxyenonanal, and protein carbonyl) and intensified the antioxidants in the hepatic tissue (SOD, GSH, and TAC). CuE increased mRNA expression of SIRT1 and Nrf2 as well as its binding capacity. Subsequently, CuE augmented mRNA expression of Nrf2 targeted genes as NQO1, GCL, and HO-1 and recovered its normal level. CuE inhibited the activation of NF-κB/downstream pro-inflammatory mediators signaling. Furthermore, CuE attenuated the mRNA expression of NLRP3 and its associated genes. CONCLUSION: Collectively, these results demonstrated the remarkable hepatoprotective potential of CuE towards Con A-induced AIH which was mediated via suppression of oxidative stress, enhancing SIRT1/Nrf2/HO-1, and prohibition of the NF-κB/NLRP3 signaling. CuE could be a candidate for hepatitis patients.

Mokko Lactone Alleviates Doxorubicin-Induced Cardiotoxicity in Rats via Antioxidant, Anti-Inflammatory, and Antiapoptotic Activities.

Doxorubicin (DOX), a commonly utilized anthracycline antibiotic, suffers deleterious side effects such as cardiotoxicity. Mokko lactone (ML) is a naturally occurring guainolide sesquiterpene with established antioxidant and anti-inflammatory actions. This study aimed at investigating the protective effects of ML in a DOX-induced cardiotoxicity model in rats. Our results indicated that ML exerted protection against cardiotoxicity induced by DOX as indicated by ameliorating the rise in serum troponin and creatine kinase-MB levels and lactate dehydrogenase activity. Histological assessment showed that ML provided protection against pathological alterations in heart architecture. Furthermore, treatment with ML significantly ameliorated DOX-induced accumulation of malondialdehyde and protein carbonyl, depletion of glutathione, and exhaustion of superoxide dismutase and catalase. ML's antioxidant effects were accompanied by increased nuclear translocation of NF-E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) expression. Moreover, ML exhibited significant anti-inflammatory activities as evidenced by lowered nuclear factor κB, interleukin-6, and tumor necrosis factor-α expression. ML also caused significant antiapoptotic actions manifested by modulation in mRNA expression of Bax, Bcl-2, and caspase-3. This suggests that ML prevents heart injury induced by DOX via its antioxidant, anti-inflammatory, and antiapoptotic activities.

Enhancing the Antifungal Activity and Ophthalmic Transport of Fluconazole from PEGylated Polycaprolactone Loaded Nanoparticles.

Fungal eye infections are caused mainly by an eye injury and can result in serious eye damage. Fluconazole (FLZ), a broad-spectrum antifungal agent, is a poorly soluble drug with a risk of hepatotoxicity. This work aimed to investigate the antifungal activity, ocular irritation, and transport of FLZ-loaded poly (ε-caprolactone) nanoparticles using a rabbit eye model. Three formulation factors affecting the nanoparticle's size, zeta potential, and entrapment efficiency were optimized utilizing the Box-Behnken design. Morphological characteristics and antifungal activity of the optimized nanoparticles were studied. The optimized nanoparticles were loaded into thermosensitive in situ hydrogel and hydroxypropylmethylcellulose (HPMC) hydrogel ophthalmic formulations. The rheological behavior, in vitro release and in vivo corneal transport were investigated. Results revealed that the percentage of poly (ε-caprolactone) in the nanoparticle matrix, polymer addition rate, and mixing speed significantly affected the particle size, zeta potential, and entrapment efficiency. The optimized nanoparticles were spherical in shape and show an average size of 145 nm, a zeta potential of -28.23 mV, and a FLZ entrapment efficiency of 98.2%. The antifungal activity of FLZ-loaded nanoparticles was significantly higher than the pure drug. The developed ophthalmic formulations exhibited a pseudoplastic flow, prolonged the drug release and were found to be non-irritating to the cornea. The prepared FLZ pegylated nanoparticles were able to reach the posterior eye segment without eye irritation. As a result, the developed thermosensitive in situ hydrogel formulation loaded with FLZ polymeric nanoparticles is a promising drug delivery strategy for treating deep fungal eye infections.

Optimized D-α-tocopherol polyethylene glycol succinate/phospholipid self-assembled mixed micelles: A promising lipid-based nanoplatform for augmenting the antifungal activity of fluconazole.

Fluconazole (FLZ) is the most widely used antifungal agent for treating cutaneous candidiasis. Although oral FLZ has been proved to be effective, the incidence of side effects necessitates the development of an effective formulation that could surpass the pitfalls associated with systemic availability. Accordingly, this research aimed at developing a self-assembled mixed micelles topical delivery system to enhance the topical delivery of the drug. Self-assembled mixed micelles were developed using D-α-tocopheryl polyethylene glycol 1000 succinate and phospholipids and optimized using Box-Behnken design. The optimized formulation with minimized size was then tested in vivo for the antifungal activity against C. albicans in immunocompromised mice. Treatment with the optimized formulation led to decreased peripheral erythema as well as lesions due to fungal infection in comparison to raw FLZ loaded gel. Therefore, the developed formulation was found to be a promising vehicle for the treatment of cutaneous candidiasis.

Malva parviflora Leaves Mucilage: An Eco-Friendly and Sustainable Biopolymer with Antioxidant Properties.

Malva parviflora L. is an edible and medicinal herb containing mucilaginous cells in its leaves. Mucilage obtained from M. parviflora leaves (MLM) was extracted in distilled water (1:10 w/v) at 70 °C followed by precipitation with alcohol. Preliminary phytochemical tests were performed to assess the purity of the extracted mucilage. Results showed that the yield of mucilage was 7.50%, and it was free from starch, alkaloids, glycosides, saponins, steroids, lipids and heavy metals. MLM had 16.19% carbohydrates, 13.55% proteins and 4.76% amino acids, which indicate its high nutritional value. Physicochemical investigations showed that MLM is neutral and water-soluble, having 5.84% moisture content, 15.60% ash content, 12.33 swelling index, 2.57 g/g water-holding capacity and 2.03 g/g oil-binding capacity. The functional properties, including emulsion capacity, emulsion stability, foaming capacity and stability increased with increased concentrations. Micromeritic properties, such as bulk density, tapped density, Carr's index, Hausner ratio, and angle of repose, were found to be 0.69 g/cm3, 0.84 g/cm3, 17.86%, 1.22 and 28.5, respectively. Scanning electron microscopy (SEM) showed that MLM is an amorphous powder possessing particles of varying size and shape; meanwhile, rheological studies revealed the pseudoplastic behavior of MLM. The thermal transition process of MLM revealed by a differential scanning calorimetry (DSC) thermogram, occurring at a reasonable enthalpy change (∆H), reflects its good thermal stability. The presence of functional groups characteristic of polysaccharides was ascertained by the infrared (IR) and gas chromatography/mass spectrometry (GC/MS) analyses. GC revealed the presence of five neutral monosaccharides; namely, galactose, rhamnose, arabinose, glucose and mannose, showing 51.09, 10.24, 8.90, 1.80 and 0.90 mg/g of MLM, respectively. Meanwhile, galacturonic acid is the only detected acidic monosaccharide, forming 15.06 mg/g of MLM. It showed noticeable antioxidant activity against the DPPH (1,1-diphenyl-2-picrylhydrazyl) radical with an IC50 value of 154.27 µg/mL. It also prevented oxidative damage to DNA caused by the Fenton reagent, as visualized in gel documentation system. The sun protection factor was found to be 10.93 ± 0.15 at 400 µg/mL. Thus, MLM can be used in food, cosmetic and pharmaceutical industry and as a therapeutic agent due to its unique properties.

Umuhengerin Neuroprotective Effects in Streptozotocin-Induced Alzheimer's Disease Mouse Model via Targeting Nrf2 and NF-Kß Signaling Cascades.

Alzheimer's disease (AD) is the most common type of dementia and is characterized by advanced cognitive deterioration, deposition of Aß (amyloid-beta), and the formation of neurofibrillary tangles. Administration of streptozotocin (STZ) via the intracerebroventricular (ICV) route is a reliable model resembling sporadic AD (SAD) associated neuropathological changes. The present study was undertaken to explore the neuroprotective effects of the methoxy flavonoid, umuhengerin, in an STZ-induced SAD mouse model as a potential therapy for AD. Mice were injected once with STZ (3 mg/kg, ICV), followed by daily administration of umuhengerin (orally, 30 mg/kg) or the positive control donepezil (orally, 2.5 mg/kg) for 21 days. The pharmacological activity of umuhengerin was assessed through estimation of oxidative stress and inflammatory markers via mouse ELISA kits, Western blot analysis, and brain histopathological examination. Morris water maze test was also conducted to investigate umuhengerin-induced cognitive enhancement. The results showed that umuhengerin attenuated STZ-produced neuroinflammation and oxidative stress with a notable rise in the expression of Nrf2 (nuclear factor erythroid 2-related factor 2). In contrast, it downregulated Keap-1 (Kelch-like ECH associated protein 1), as well as elevated brain contents of GSH (reduced glutathione) and HO-1 (heme oxygenase-1). STZ-injected animals receiving umuhengerin showed marked downregulation of the nuclear factor kappa beta (NF-Kßp65) and noticeable increment in the expression of its inhibitor kappa beta alpha protein (IKßα), as well as prominent reduction in malondialdehyde (MDA), H2O2 (hydrogen peroxide), and TNF-α (tumor-necrosis factor-alpha) contents. Β-secretase protein expression and acetylcholinesterase (AchE) activity were also diminished upon umuhengerin injection in the STZ group, leading to decreased Aß formation and cognitive improvement, respectively. In conclusion, umuhengerin neuroprotective effects were comparable to the standard drug donepezil; thus, it could be an alternative approach for AD management.

Mangostanaxanthone IV Ameliorates Streptozotocin-Induced Neuro-Inflammation, Amyloid Deposition, and Tau Hyperphosphorylation via Modulating PI3K/Akt/GSK-3ß Pathway.

Alzheimer's disease (AD), a progressive neurodegenerative disorder, is characterized by amyloid deposition and neurofibrillary tangles formation owing to tau protein hyperphosphorylation. Intra-cerebroventricular (ICV) administration of streptozotocin (STZ) has been widely used as a model of sporadic AD as it mimics many neuro-pathological changes witnessed in this form of AD. In the present study, mangostanaxanthone IV (MX-IV)-induced neuro-protective effects in the ICV-STZ mouse model were investigated. STZ (3 mg/kg, ICV) was injected once, followed by either MX-IV (30 mg/kg/day, oral) or donepezil (2.5 mg/kg/day, oral) for 21 days. Treatment with MX-IV diminished ICV-STZ-induced oxidative stress, neuro-inflammation, and apoptosis which was reflected by a significant reduction in malondialdehyde (MDA), hydrogen peroxide (H2O2), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) brain contents contrary to increased glutathione (GSH) content. Moreover, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase content and cleaved caspase-3 activity were reduced together with a marked decrement in amyloid plaques number and phosphorylated tau expression via PI3K/Akt/GSK-3ß pathway modulation, leading to obvious enhancement in neuronal survival and cognition. Therefore, MX-IV is deemed as a prosperous nominee for AD management with obvious neuro-protective effects that were comparable to the standard drug donepezil.

Mokko Lactone Attenuates Doxorubicin-Induced Hepatotoxicity in Rats: Emphasis on Sirt-1/FOXO1/NF-κB Axis.

Doxorubicin (DOX), a common chemotherapeutic agent, suffers serious adverse effects including hepatotoxicity. Mokko lactone (ML) is a guainolide sesquiterpene with promising biological activities. The study aimed to evaluate the protection offered by ML against hepatotoxicity induced by DOX in rats. Our data indicated ML exhibited protective effects as evidenced by ameliorating the rise in serum activities of alanine transaminase, aspartate transaminase and alkaline phosphatase. This was confirmed histologically as ML prevented DOX-induced pathological alteration in liver architecture. Further, ML administration significantly prevented malondialdehyde accumulation, glutathione depletion and superoxide dismutase and catalase exhaustion. Antioxidant action of ML was associated with enhanced expression of the nuclear translocation of NF-E2-related factor 2 (Nrf2) and a lower expression of forkhead box protein O1 (FOXO1). Also, ML showed potent anti-inflammatory activities highlighted by decreased expression of interleukin 6, tumor necrosis factor α and nuclear factor κB (NF-κB). The anti-apoptotic effects of ML were associated with decreased Bax and enhanced Bcl-2 mRNA expression in liver tissues. ML caused a significant up-regulation in the expression of silent information regulator 1 (Sirt-1). Therefore, it can be concluded that ML prevents liver injury caused by DOX. This could partially be due to the ML regulatory activities on Sirt-1/FOXO1/NF-κB axis.

Bright Side of Fusarium oxysporum: Secondary Metabolites Bioactivities and Industrial Relevance in Biotechnology and Nanotechnology.

Fungi have been assured to be one of the wealthiest pools of bio-metabolites with remarkable potential for discovering new drugs. The pathogenic fungi, Fusarium oxysporum affects many valuable trees and crops all over the world, producing wilt. This fungus is a source of different enzymes that have variable industrial and biotechnological applications. Additionally, it is widely employed for the synthesis of different types of metal nanoparticles with various biotechnological, pharmaceutical, industrial, and medicinal applications. Moreover, it possesses a mysterious capacity to produce a wide array of metabolites with a broad spectrum of bioactivities such as alkaloids, jasmonates, anthranilates, cyclic peptides, cyclic depsipeptides, xanthones, quinones, and terpenoids. Therefore, this review will cover the previously reported data on F. oxysporum, especially its metabolites and their bioactivities, as well as industrial relevance in biotechnology and nanotechnology in the period from 1967 to 2021. In this work, 180 metabolites have been listed and 203 references have been cited.

Terretonin as a New Protective Agent against Sepsis-Induced Acute Lung Injury: Impact on SIRT1/Nrf2/NF-κBp65/NLRP3 Signaling.

Endophytic fungi are proving to be an excellent source of chemical entities with unique structures and varied bioactivities. Terretonin (TE) and its structurally related derivatives are a class of meroterpenoids, possessing the same unique tetracyclic core skeleton, which have been reported from the Aspergillus genus. This study was carried out to assess the potential protective effects of TE separated from the endophytic fungus A. terreus against LPS (lipopolysaccharide)-induced ALI (acute lung injury) in mice. The results revealed that TE alleviated pulmonary edema as it lowered both the W/D lung ratio and protein content. The inflammatory response represented by inflammatory cell infiltration into the lung tissues was greatly repressed by TE. That was supported by the improved histopathological results and also by the reduced level of myeloperoxidase in the lung. TE showed a potent antioxidant activity as it attenuated lipid peroxidative markers (malondialdehyde, 4-hydroxynonenal, and protein carbonyl) and enhanced endogenous antioxidants (reduced glutathione, superoxide dismutase, and catalase) in lung tissues. Similarly, TE increased the mRNA expression of SIRT1, Nrf2, and its genes (HO-1, NQO1, and GCLm). On the other hand, TE restrained the activation of NF-κB (nuclear factor-κB) in the lung. Consequently, TE depressed the pro-inflammatory cytokines: nitric oxide (NOx), TNF-α (tumor necrosis factor-α), and interleukins (IL-6 and -1ß). Additionally, TE inhibited NLRP3 signaling and interrupted apoptosis by decreasing the levels of proapoptotic markers (Bax and caspase-3) and increasing the level of an anti-apoptotic marker (Bcl-2). In conclusion, TE had a remarkable protective potential on LPS-induced lung damage via antioxidant and anti-inflammatory mechanisms. This finding encourages further investigations on this promising candidate.

Optimization of Hyaluronate-Based Liposomes to Augment the Oral Delivery and the Bioavailability of Berberine.

Various perspectives had been utilized to enhance the poor intestinal permeability and bioavailability of drugs with low water solubility. Berberine (Brb) is a unique molecule that possesses multiple therapeutic activities such as antimicrobial, anti-inflammatory, antioxidant and anti-hyperglycemic effects. To improve Brb permeability and bioavailability, this study presents a newly developed formulation, namely Brb hyaluronate-based liposomes, prepared by using film hydration method and characterized by dynamic light scattering measurements, entrapment efficiency percentage (EE%), transmission electron microscope (TEM), in vitro drug release and physical stability. The bioavailability of the selected formulations was assessed in vivo after oral administration to rats. The results revealed an enhanced effect of hyaluronic acid on the entrapment efficiency, reaching 78.1 ± 0.1% with mean size 520.7 ± 19.9 nm. Sustained release of Brb was recorded up to 24 h in comparison to Brb solution. Physical stability was maintained for three months at refrigeration temperature. Results of pharmacokinetics studies indicated the potential of the liposomal formulation to increase the oral bioavailability of Brb and to accelerate its entry into the bloodstream. The obtained results are accredited to the lipophilic nature of the prepared system, resembling the structural features of bio-membrane, in addition to their small size that enhances intestinal penetration.

Fungal Depsides-Naturally Inspiring Molecules: Biosynthesis, Structural Characterization, and Biological Activities.

Fungi represent a huge reservoir of structurally diverse bio-metabolites. Although there has been a marked increase in the number of isolated fungal metabolites over the past years, many hidden metabolites still need to be discovered. Depsides are a group of polyketides consisting of two or more ester-linked hydroxybenzoic acid moieties. They possess valuable bioactive properties, such as anticancer, antidiabetic, antibacterial, antiviral, anti-inflammatory, antifungal, antifouling, and antioxidant qualities, as well as various human enzyme-inhibitory activities. This review provides an overview of the reported data on fungal depsides, including their sources, biosynthesis, physical and spectral data, and bioactivities in the period from 1975 to 2020. Overall, 110 metabolites and more than 122 references are confirmed. This is the first review of these multi-faceted metabolites from fungi.

Thonningia sanguinea Extract: Antioxidant and Cytotoxic Activities Supported by Chemical Composition and Molecular Docking Simulations.

The current study was designed to investigate the antioxidant and cytotoxic activities of Thonningia sanguinea whole-plant extract. The total phenolic content was determined using Folin-Ciocalteu reagent and found to be 980.1 mg/g, calculated as gallic acid equivalents. The antioxidant capacity was estimated for the crude extract and the phenolic portion of T. sanguinea, whereupon both revealed a dose-dependent scavenging rate of DPPH• with EC50 values of 36.33 and 11.14 µg/mL, respectively. Chemical profiling of the plant extract was achieved by LC-ESI-TOF-MS/MS analysis, where 17 compounds were assigned, including ten compounds detected in the negative mode and seven detected in the positive mode. The phenolic portion exhibited promising cytotoxic activity against MCF-7 and HepG2 cells, with IC50 values of 16.67 and 13.51 µg/mL, respectively. Phenolic extract treatment caused apoptosis in MCF-7 cells, with total apoptotic cell death 18.45-fold higher compared to untreated controls, arresting the cell cycle at G2/M by increasing the G2 population by 39.7%, compared to 19.35% for the control. The apoptotic investigation was further validated by the upregulation of proapoptotic genes of P53, Bax, and caspases-3,8 9, and the downregulation of Bcl-2 as the anti-apoptotic gene. Bcl-2 inhibition was also virtualized by good binding interactions through a molecular docking study. Taken together, phenolic extract exhibited promising cytotoxic activity in MCF-7 cells through apoptosis induction and antioxidant activation, so further fractionation studies are recommended for the phenolic extract for specifying the most active compound to be developed as a novel anti-cancer agent.

Development and Optimization of Luliconazole Spanlastics to Augment the Antifungal Activity against Candida albicans.

Luliconazole is a new topical imidazole antifungal drug for the treatment of skin infections. It has low solubility and poor skin penetration which limits its therapeutic applications. In order to improve its therapeutic efficacy, spanlastics nanoformulation was developed and optimized using a combined mixture-process variable design (CMPV). The optimized formulation was converted into a hydrogel formula to enhance skin penetration and increase the efficacy in experimental cutaneous Candida albicans infections in Swiss mice wounds. The optimized formulation was generated at percentages of Span and Tween of 48% and 52%, respectively, and a sonication time of 6.6 min. The software predicted that the proposed formulation would achieve a particle size of 50 nm with a desirability of 0.997. The entrapment of luliconazole within the spanlastics carrier showed significant (p < 0.0001) antifungal efficacy in the immunocompromised Candida-infected Swiss mice without causing any irritation, when compared to the luliconazole treated groups. The microscopic observation showed almost complete removal of the fungal colonies on the skin of the infected animals (0.2 ± 0.05 log CFU), whereas the control animals had 0.2 ± 0.05 log CFU. Therefore, luliconazole spanlastics could be an effective formulation with improved topical delivery for antifungal activity against C. albicans.

Repurposing of Some Natural Product Isolates as SARS-COV-2 Main Protease Inhibitors via In Vitro Cell Free and Cell-Based Antiviral Assessments and Molecular Modeling Approaches.

The emergence of the SARS-CoV-2 pandemic has prompted scientists to search for an efficient antiviral medicine to overcome the rapid spread and the marked increase in the number of patients worldwide. In this regard natural products could be a potential source of substances active against coronavirus infections. A systematic computer-aided virtual screening approach was carried out using commercially available natural products found on the Zinc Database in addition to an in-house compound library to identify potential natural product inhibitors of SARS-CoV-2 main protease (MPRO). The top eighteen hits from the screening were selected for in vitro evaluation on the viral protease (SARS-CoV-2 MPRO). Five compounds (naringenin, 2,3',4,5',6-pentahydroxybenzophenone, apigenin-7-O-glucoside, sennoside B, and acetoside) displayed high activity against the viral protein. Acteoside showed similar activity to the positive control GC376. The most potent compounds were tested in vitro on SARS-CoV-2 Egyptian strain where only naringenin showed moderate anti-SARS-CoV-2 activity at non-cytotoxic micromolar concentrations in vitro with a significant selectivity index (CC50/IC50 = 178.748/28.347 = 6.3). Moreover; a common feature pharmacophore model was generated to explain the requirements for enzyme inhibition by this diverse group of active ligands. These results pave a path for future repurposing and development of natural products to aid in the battle against COVID-19.