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.

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.

Membrane-bound sn-1,2-diacylglycerols explain the dissociation of hepatic insulin resistance from hepatic steatosis in MTTP knockout mice.

Microsomal triglyceride transfer protein (MTTP) deficiency results in a syndrome of hypolipidemia and accelerated NAFLD. Animal models of decreased hepatic MTTP activity have revealed an unexplained dissociation between hepatic steatosis and hepatic insulin resistance. Here, we performed comprehensive metabolic phenotyping of liver-specific MTTP knockout (L-Mttp-/-) mice and age-weight matched wild-type control mice. Young (10-12-week-old) L-Mttp-/- mice exhibited hepatic steatosis and increased DAG content; however, the increase in hepatic DAG content was partitioned to the lipid droplet and was not increased in the plasma membrane. Young L-Mttp-/- mice also manifested normal hepatic insulin sensitivity, as assessed by hyperinsulinemic-euglycemic clamps, no PKCε activation, and normal hepatic insulin signaling from the insulin receptor through AKT Ser/Thr kinase. In contrast, aged (10-month-old) L-Mttp-/- mice exhibited glucose intolerance and hepatic insulin resistance along with an increase in hepatic plasma membrane sn-1,2-DAG content and PKCε activation. Treatment with a functionally liver-targeted mitochondrial uncoupler protected the aged L-Mttp-/- mice against the development of hepatic steatosis, increased plasma membrane sn-1,2-DAG content, PKCε activation, and hepatic insulin resistance. Furthermore, increased hepatic insulin sensitivity in the aged controlled-release mitochondrial protonophore-treated L-Mttp-/- mice was not associated with any reductions in hepatic ceramide content. Taken together, these data demonstrate that differences in the intracellular compartmentation of sn-1,2-DAGs in the lipid droplet versus plasma membrane explains the dissociation of NAFLD/lipid-induced hepatic insulin resistance in young L-Mttp-/- mice as well as the development of lipid-induced hepatic insulin resistance in aged L-Mttp-/- mice.

Lipid transfer proteins in the assembly of apoB-containing lipoproteins.

A better understanding of intracellular lipoprotein assembly may help identify proteins with important roles in lipid disorders. apoB-containing lipoproteins (B-lps) are macromolecular lipid and protein micelles that act as specialized transport vehicles for hydrophobic lipids. They are assembled predominantly in enterocytes and hepatocytes to transport dietary and endogenous fat, respectively, to different tissues. Assembly occurs in the endoplasmic reticulum (ER) and is dependent on lipid resynthesis in the ER and on a chaperone, namely, microsomal triglyceride transfer protein (MTTP). Precursors for lipid synthesis are obtained from extracellular sources and from cytoplasmic lipid droplets. MTTP is the major and essential lipid transfer protein that transfers phospholipids and triacylglycerols to nascent apoB for the assembly of lipoproteins. Assembly is aided by cell death-inducing DFF45-like effector B and by phospholipid transfer protein, which may facilitate additional deposition of triacylglycerols and phospholipids, respectively, to apoB. Here, we summarize the current understanding of the different steps in the assembly of B-lps and discuss the role of lipid transfer proteins in these steps to help identify new clinical targets for lipid-associated disorders, such as heart disease.

Kidney triglyceride accumulation in the fasted mouse is dependent upon serum free fatty acids.

Lipid accumulation is a pathological feature of every type of kidney injury. Despite this striking histological feature, physiological accumulation of lipids in the kidney is poorly understood. We studied whether the accumulation of lipids in the fasted kidney are derived from lipoproteins or NEFAs. With overnight fasting, kidneys accumulated triglyceride, but had reduced levels of ceramide and glycosphingolipid species. Fasting led to a nearly 5-fold increase in kidney uptake of plasma [14C]oleic acid. Increasing circulating NEFAs using a ß adrenergic receptor agonist caused a 15-fold greater accumulation of lipid in the kidney, while mice with reduced NEFAs due to adipose tissue deficiency of adipose triglyceride lipase had reduced triglycerides. Cluster of differentiation (Cd)36 mRNA increased 2-fold, and angiopoietin-like 4 (Angptl4), an LPL inhibitor, increased 10-fold. Fasting-induced kidney lipid accumulation was not affected by inhibition of LPL with poloxamer 407 or by use of mice with induced genetic LPL deletion. Despite the increase in CD36 expression with fasting, genetic loss of CD36 did not alter fatty acid uptake or triglyceride accumulation. Our data demonstrate that fasting-induced triglyceride accumulation in the kidney correlates with the plasma concentrations of NEFAs, but is not due to uptake of lipoprotein lipids and does not involve the fatty acid transporter, CD36.

MicroRNAs regulating apolipoprotein B-containing lipoprotein production.

MicroRNAs (miRs) are small, non-coding RNAs that regulate gene expression and have been implicated in many pathological conditions. Significant progress has been made to unveil their role in lipid metabolism. This review aims at summarizing the role of different miRs that regulate hepatic assembly and secretion of apolipoprotein B (apoB)-containing lipoproteins. Overproduction and/or impaired clearance of these lipoproteins from circulation increase plasma concentrations of lipids enhancing risk for cardiovascular disease. So far, three miRs, miR-122, miR-34a, and miR-30c have been shown to modulate hepatic production of apoB-containing low density lipoproteins. In this review, we will first provide a brief overview of lipid metabolism and apoB-containing lipoprotein assembly to orient readers to different steps that have been shown to be regulated by miRs. Then, we will discuss the role of each miR on plasma lipids and atherosclerotic burden. Furthermore, we will summarize mechanistic studies explaining how these miRs regulate hepatic lipid synthesis, fatty acid oxidation, and lipoprotein secretion. Finally, we will briefly highlight the potential use of each miR as a therapeutic drug for treating cardiovascular diseases. This article is part of a Special Issue entitled: MicroRNAs and lipid/energy metabolism and related diseases edited by Carlos Fernández-Hernando and Yajaira Suárez.

Circadian regulation of intestinal lipid absorption by apolipoprotein AIV involves forkhead transcription factors A2 and O1 and microsomal triglyceride transfer protein.

We have shown previously that Clock, microsomal triglyceride transfer protein (MTP), and nocturnin are involved in the circadian regulation of intestinal lipid absorption. Here, we clarified the role of apolipoprotein AIV (apoAIV) in the diurnal regulation of plasma lipids and intestinal lipid absorption in mice. Plasma triglyceride in apoAIV(-/-) mice showed diurnal variations similar to apoAIV(+/+) mice; however, the increases in plasma triglyceride at night were significantly lower in these mice. ApoAIV(-/-) mice absorbed fewer lipids at night and showed blunted response to daytime feeding. To explain reasons for these lower responses, we measured MTP expression; intestinal MTP was low at night, and its induction after food entrainment was less in apoAIV(-/-) mice. Conversely, apoAIV overexpression increased MTP mRNA in hepatoma cells, indicating transcriptional regulation. Mechanistic studies revealed that sequences between -204/-775 bp in the MTP promoter respond to apoAIV and that apoAIV enhances expression of FoxA2 and FoxO1 transcription factors and their binding to the identified cis elements in the MTP promoter at night. Knockdown of FoxA2 and FoxO1 abolished apoAIV-mediated MTP induction. Similarly, knockdown of apoAIV in differentiated Caco-2 cells reduced MTP, FoxA2, and FoxO1 mRNA levels, cellular MTP activity, and media apoB. Moreover, FoxA2 and FoxO1 expression showed diurnal variations, and their expression was significantly lower in apoAIV(-/-) mice. These data indicate that apoAIV modulates diurnal changes in lipid absorption by regulating forkhead transcription factors and MTP and that inhibition of apoAIV expression might reduce plasma lipids.

Icariin inhibits cisplatin-induced ovarian toxicity via modulating NF-κB and PTEN/AKT/mTOR/AMPK axis.

Cisplatin (CP) is a highly effective broad-spectrum chemotherapeutic agent for several solid tumors. However, its clinical use is associated with ovarian toxicity. Icariin (ICA) is a bioactive flavonoid of Epimedium brevicornum with reported protective activities against inflammation, oxidative stress and ovarian failure. This study aimed to explore the protective effects of ICA against CP-associated ovarian toxicity in rats. Rats were randomized into five groups and treated for 17 days: control, ICA (10 mg/kg/day, for 17 days. p.o.), CP (6 mg/kg, i.p. on days 7 and 14), CP + ICA (CP 6 mg/kg i.p. on days 7 and 14 and ICA 5 mg/kg p.o. daily), and CP + ICA (CP 6 mg/kg i.p. on days 7 and 14 and ICA 10 mg/kg p.o. daily). Our results indicated that ICA effectively improved ovarian reserve as indicated by attenuating CP-induced histolopathological changes and enhancing serum anti-müllerian hormone (AMH). Furthermore, co-administration of ICA with CP showed restoration of the oxidant-anti-oxidant balance in ovarian tissues, evidenced by decreased malondialdehyde (MDA) concentrations and elevated superoxide dismutase (SOD) and catalase (CAT) activities. Also, ICA suppressed ovarian inflammation as evidenced by down-regulation of the expression of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and nuclear factor kappa B (NF-κB). ICA inhibited ovarian apoptosis in CP-treated rats by down-regulation of CASP3 and Bax and up-regulation of Bcl-2 mRNA expression. Further, ICA enhanced PTEN, p-AKT, p-mTOR, and p-AMPKα expression. In conclusion, ICA possesses a protective activity against CP-induced ovarian toxicity in rats by exhibiting antioxidant, antiinflammatory, anti-apoptotic activities and modulating NF-κB expression and PTEN/AKT/mTOR/AMPK axis in ovarian tissues.

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.

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.

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.

The Antifungal and Ocular Permeation of Ketoconazole from Ophthalmic Formulations Containing Trans-Ethosomes Nanoparticles.

Ketoconazole (KET), a synthetic imidazole broad-spectrum antifungal agent, is characterized by its poor aqueous solubility and high molecular weight, which might hamper its corneal permeation. The aim was to develop an ophthalmic formulation loaded with optimized trans-ethosomal vesicles to enhance KET ocular permeation, antifungal activity, rapid drug drainage, and short elimination half-life. Four formulation factors affecting the vesicles' size, zeta potential, entrapment efficiency, and flexibility of the trans-ethosomes formulations were optimized. The optimum formulation was characterized, and their morphological and antifungal activity were studied. Different ophthalmic formulations loaded with the optimized vesicles were prepared and characterized. The ocular irritation and in vivo corneal permeation were investigated. Results revealed that the drug-to-phospholipid-molar ratio, the percentage of edge activator, the percentage of ethanol, and the percentage of stearyl amine significantly affect the characteristics of the vesicles. The optimized vesicles were spherical and showed an average size of 151.34 ± 8.73 nm, a zeta potential value of +34.82 ± 2.64 mV, an entrapment efficiency of 94.97 ± 5.41%, and flexibility of 95.44 ± 4.33%. The antifungal activity of KET was significantly improved following treatment with the optimized vesicles. The developed in situ gel formulations were found to be nonirritating to the cornea. The trans-ethosomes vesicles were able to penetrate deeper into the posterior eye segment without any toxic effects. Accordingly, the in situ developed gel formulation loaded with KET trans-ethosomes vesicles represents a promising ocular delivery system for the treatment of deep fungal eye infections.

Summary of Natural Products Ameliorate Concanavalin A-Induced Liver Injury: Structures, Sources, Pharmacological Effects, and Mechanisms of Action.

Liver diseases represent a threat to human health and are a significant cause of mortality and morbidity worldwide. Autoimmune hepatitis (AIH) is a progressive and chronic hepatic inflammatory disease, which may lead to severe complications. Concanavalin A (Con A)-induced hepatic injury is regarded as an appropriate experimental model for investigating the pathology and mechanisms involved in liver injury mediated by immune cells as well as T cell-related liver disease. Despite the advances in modern medicine, the only available strategies to treat AIH, include the use of steroids either solely or with immunosuppressant drugs. Unfortunately, this currently available treatment is associated with significant side-effects. Therefore, there is an urgent need for safe and effective drugs to replace and/or supplement those in current use. Natural products have been utilized for treating liver disorders and have become a promising therapy for various liver disorders. In this review, the natural compounds and herbal formulations as well as extracts and/or fractions with protection against liver injury caused by Con A and the underlying possible mechanism(s) of action are reviewed. A total of 53 compounds from different structural classes are discussed and over 97 references are cited. The goal of this review is to attract the interest of pharmacologists, natural product researchers, and synthetic chemists for discovering novel drug candidates for treating immune-mediated liver injury.

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.

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.

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.