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Neurodegeneration, the decline of nerve cells in the brain, is a common feature of neurodegenerative disorders (NDDs). Oxidative stress, a key factor in NDDs such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease can lead to neuronal cell death, mitochondria impairment, excitotoxicity, and Ca2+ stress. Environmental factors compromising stress response lead to cell damage, necessitating novel therapeutics for preventing or treating brain disorders in older individuals and an aging population. Synthetic medications offer symptomatic benefits but can have adverse effects. This research explores the potential of flavonoids derived from plants in treating NDDs. Flavonoids compounds, have been studied for their potential to enter the brain and treat NDDs. These compounds have diverse biological effects and are currently being explored for their potential in the treatment of central nervous system disorders. Flavonoids have various beneficial effects, including antiviral, anti-allergic, antiplatelet, anti-inflammatory, anti-tumor, anti-apoptotic, and antioxidant properties. Their potential to alleviate symptoms of NDDs is significant. [ABSTRACT FROM AUTHOR]

Rumex vesicarius L. Polygonaceae is a wildly grown plant in Egypt, North Africa, and Asia with wide traditional uses. Several studies reported its biological activities and richness in phytochemicals. This research addresses a comprehensive metabolic profiling of the flowers, leaves, stems, and roots via RP-HPLC-QTOF-MS and MS/MS with chemometrics. A total of 60 metabolites were observed and grouped into phenolic acids, flavonoids, phenols, terpenes, amino acids, fatty acids, organic acids, and sugars. Principal component analysis and hierarchal cluster analysis showed the segregation of different parts. Moreover, the antioxidant capacity was determined via several methods and agreed with the previous results. Additionally, an in silico approach of molecular docking of the predominant bioactive metabolites was employed against two antioxidant targets, NADPH oxidase and human peroxiredoxin 5 enzyme (PDB ID: 2CDU and 1HD2) receptors, alongside ADME predictions. The molecular modelling revealed that most of the approached molecules were specifically binding with the tested enzymes, achieving high binding affinities. The results confirmed that R. vesicarius stems and roots are rich sources of bioactive antioxidant components. To our knowledge, this is the first comprehensive metabolic profiling of R. vesicarius giving a prospect of its relevance in the development of new naturally based antioxidants. [ABSTRACT FROM AUTHOR]

Drug-induced liver injury (DILI) represents a significant clinical challenge characterized by hepatic dysfunction following exposure to diverse medications. Methotrexate (MTX) is a cornerstone in treating various cancers and autoimmune disorders. However, the clinical utility of MTX is overshadowed by its ability to induce hepatotoxicity. The current study aims to elucidate the hepatoprotective effect of the alcoholic extract of Egyptian Araucaria heterophylla resin (AHR) on MTX-induced liver injury in rats. AHR (100 and 200 mg/kg) significantly decreased hepatic markers (AST, ALT, and ALP), accompanied by an elevation in the antioxidant's markers (SOD, HO-1, and NQO1). AHR extract also significantly inhibited the TGF-β/NF-κB signaling pathway as well as the downstream cascade (IL-6, JAK, STAT-3, and cyclin D). The extract significantly reduced the expression of VEGF and p38 with an elevation in the BCL2 levels, in addition to a significant decrease in the IL-1β and TNF-α levels, with a prominent effect at a high dose (200 mg/kg). Using LC-HRMS/MS analysis, a total of 43 metabolites were tentatively identified, and diterpenes were the major class. This study presents AHR as a promising hepatoprotective agent through inhibition of the TGF-β/NF-κB and JAK/STAT3 pathways, besides its antioxidant and anti-inflammatory effects. [ABSTRACT FROM AUTHOR]

Researchers are actively exploring potential bioactive compounds to enhance the effectiveness of Lisuride (Lis) in treating Parkinson's disease (PD) over the long term, aiming to mitigate the serious side effects associated with its extended use. A recent study found that combining the dietary flavonoid Tiliroside (Til) with Lis has potential anti-Parkinson's benefits. The study showed significant improvements in PD symptoms induced by 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) when Til and Lis were given together, based on various behavioral tests. This combined treatment significantly improved motor function and protected dopaminergic neurons in rats with PD induced by MPTP. It also activated important molecular pathways related to cell survival and apoptosis control, as indicated by the increased pAkt/Akt ratio. Til and Lis together increased B-cell lymphoma 2 (Bcl-2), decreased caspase 3 activity, and prevented brain cell decay. Co-administration also reduced tumor necrosis factor alpha (TNF-α) and Interleukin-1 (IL-1). Antioxidant markers such as superoxide dismutase (SOD), catalase, and reduced glutathione significantly improved compared to the MPTP-induced control group. This study shows that using Til and Lis together effectively treats MPTP-induced PD in rats, yielding results comparable to an 8 mg/kg dose of levodopa, highlighting their potential as promising Parkinson's treatments. [ABSTRACT FROM AUTHOR]

Breast cancer is a deadly disease that affects countless women worldwide. The most conventional treatments for breast cancer, such as the administration of anticancer medications such as letrozole (LTZ), pose significant barriers due to the non-selective delivery and low bioavailability of cytotoxic drugs leading to serious adverse effects and multidrug resistance (MDR). Addressing these obstacles requires an innovative approach, and we propose a combined strategy that synergistically incorporates LTZ with berberine (BBR) into stabilised AuNPs coated with ascorbic acid (AA), known as LTZ-BBR@AA-AuNPs. The LTZ-BBR@AA-AuNPs, a novel combined drug delivery system, were carefully designed to maximise the entrapment of both LTZ and BBR. The resulting spherical nanoparticles exhibited remarkable efficiency in trapping these two compounds, with rates of 58% and 54%, respectively. In particular, the average hydrodynamic diameter of these nanoparticles was determined to be 81.23 ± 4.0 nm with a PDI value of only 0.286, indicating excellent uniformity between them. Furthermore, their zeta potential was observed to be −14.5 mV, suggesting high stability even under physiological conditions. The release profiles showed that after being incubated for about 24 h at pH levels ranging from acidic (pH = 5) to basic (pH = 7), the percentage released for both drugs ranged from 56–72%. This sustained and controlled drug release can reduce any negative side effects while improving therapeutic efficacy when administered directly to cancer. MDA-MB-231 cells treated with LTZ-BBR@AA-AuNPs for 48 h exhibited IC50 values of 2.04 ± 0.011 μg/mL, indicating potent cytotoxicity against cells. Furthermore, the nanoparticles demonstrated excellent stability throughout the duration of the treatment. [ABSTRACT FROM AUTHOR]

The objective of this study was to develop an innovative gallic-acid (GA) drug delivery system that could be administered transdermally, resulting in enhanced therapeutic benefits and minimal negative consequences. The method employed involved the preparation of poly(lactic-co-glycolic acid) (PLGA) nanoparticles loaded with GA through nanoprecipitation-denoted GA@PLGANPs. The results reveal that this strategy led to perfectly spherical, homogeneous, and negatively charged particles, which are suitable for administration via skin patches or ointments. A further analysis indicates that these GA@PLGANPs exhibit remarkable antioxidant activity as well as potent antibacterial effects against a diverse range of microorganisms, making them ideal candidates for numerous applications. Additionally, it has been observed that these nanoparticles can effectively mitigate oxidative stress while also significantly inhibiting microbial growth by exerting detrimental effects on bacterial cell walls or membranes. In conclusion, on the basis of the findings presented in this study, there is strong evidence supporting the potential use of GA@PLGANPs as an effective therapy option with reduced side effects compared to conventional drug delivery methods. [ABSTRACT FROM AUTHOR]

Combretaceae plants are used traditionally by many cultures, especially in Sudanese patients for the treatment of diverse ailments such as anti-inflammatory, antimicrobial, antitumor, and antioxidant disorders. Of these plants, the genus Combretum are traditional medicinal plants. Thus, they are formed from the non-polar or polar extracts of many isolated phytochemicals. Of these necessities, the use of Combretum extracts for their medicinal properties can be found in the earliest of myths and traditions used to document the plants' ability to treat diseases. Combretum glutinosum Perr. Ex Dc. is a common shrub native to the African continent, especially Sudan. Currently, there are no published data regarding its cytotoxic activity. Additionally, there are few chemical and biological reports of C. glutinosum. Therefore, the current study aimed to isolate the chemical bioactive compounds (1–6) from the ethyl acetate (EtOAc) extract of C. glutinosum. A new flavonoid compound, namely, glutosinumoside (4), was afforded, and five known compounds were obtained: three oleanane-glycosides (1–3) and two phenolic acids (5,6). The structures of the six compounds were determined by spectroscopic analysis, including one- and two-dimensional (1D and 2D) NMR, mass spectrometry, and chromatographic analysis. Moreover, an in vitro cytotoxic evaluation of the successive extracts and the bioactive EtOAc fractions of C. glutinosum against MCF7 (breast), HT29 (colon), HepG2 (liver), and MRC5 (normal lung) cell lines was performed. The isolated compounds showed comparable cytotoxic activities with the crude EtOH extract and doxorubicin against the tested cell lines. Compounds (1) and (6) exhibited the highest cytotoxicity against MCF7 (1.37 ± 0.21 and 1.48 ± 0.34 µg/mL, respectively) and HepG2 (3.30 ± 0.02 and 2.10 ± 0.22 µg/mL, respectively) in the MTT assay. In addition, compounds (1) and (3) demonstrated a significant upregulation of cancer's two important hallmarks (caspase 3 and bax genes) by inducing apoptosis and perturbing the MCF7 cell cycle. [ABSTRACT FROM AUTHOR]

Simultaneous estimation of rilpivirine (RLVN) and dolutegravir (DTGR) in bulk and tablet dosage forms via RP-HPLC-PDA with a Box–Behnken design (BBD) has been performed in this study to develop a fast, precise, timely and cost-saving method for estimating RLVN and DTGR in bulk and tablet dosage forms. The chromatographic conditions were optimized via the BBD, and the developed method was validated according to the ICH guidelines. Additionally, forced degradation studies were also conducted. RLVN and DTGR peaks were observed at retention times of 2.167 and 2.716 min, respectively, in a 6-min runtime. Kromasil 150 mm× 4.6 mm, 5 µm C 18 column was used. The flow rate of the mobile phase was 1.0 mL/min at a temperature of 30 °C. The mobile phase composition was a 0.1% OPA buffer and acetonitrile (ACN) in a 60:40 ratio. Elutes were measured at 260 nm (max) after being injected in a sample volume of 10 µL. The assay result of the marketed tablet was 99.19% and 99.09% for RLVN and DTGR, respectively. The results of forced degradation studies in different chemical environments conditions such as acid, base, dry heat, photo-stability, neutral, and oxidation conditions were observed for RLVN (5.96, 4.79, 3.27, 2.36, 0.99, and 4.35 in percentage degradation) and DTGR (5.67, 4.44, 4.09, 1.81, 0.43, and 4.28 in percentage degradation). The results of the validation parameters were within an acceptable range. The newly formed RP-HPLC-PDA method is novel, fast, precise, time-saving, and cost-effective. [ABSTRACT FROM AUTHOR]

Plants of the genus Echinop (Asteraceae) are traditional medicinal plants used to treat several GIT ailments, owing to their diverse bioactive secondary metabolites, including sesquiterpenoids, triterpenoids, phytosterols, phenolics, flavonoids, alkaloids, and essential oils. Echinops erinaceus Kit Tan is a wild perennial herb of the genus Echinops which is endemic to Oman, Saudi Arabia, and Yemen. Currently, there are no previous reports exploring its anti-ulcer and anti-inflammatory effects. Additionally, few reports have described the chemical profile of E. erinaceus Kit Tan. In the current study, the CHCl3 fraction of the aerial parts of the plant was subjected to chromatographic isolation and spectroscopic identification via 1D and 2D NMR, and MS. The plant afforded two new compounds, designated erinaceolic acid (E3) and erinaceoside (E5), in addition to five known compounds, namely taraxasterol acetate (E1), taraxasterol (E2), apigenin (E4), stigmasterol-3-O-β-D-glucoside (E6), and speranskoside (E7). The evaluation of the gastric ulcer protective activity of the total extract and successive fractions of E. erinaceus, using the in vivo ethanol-induced ulcer in rats model, revealed the significant effect of the tested extracts and fractions on the percentage of gastric ulcer protection and ulcer index (500 mg/kg) compared to antodine (20 mg/kg). The tested extracts and fractions also reduced the stomach contents of TNF-α and reduced IL-6 as compared to the untreated group. Histopathological examination of the gastric mucosal tissues of rats supportedprevious results. In addition, the main subfractions and their isolates were assessed for their in vitro anti-inflammatory activity against COX-2 and 15-LOX enzymes. The new compounds erinaceolic acid (E3) and speranskoside (E7) exhibited strong inhibition against COX-2 (3.41 and 2.62 µg/mL) and 15-LOX (10.05 and 5.51 µg/mL), respectively. A molecular docking study was performed to reveal the binding interaction modes of the most active compounds against the binding sites of COX-2 (PDB ID 3LN1) and 15-LOX (PDB ID 1LOX) proteins. Speranskoside (E7) showed a dual binding affinity better than that of the cocrystallized references, celecoxib and (2E)-3-(2-oct-1-yn-1-ylphenyl)acrylic acid (RS7) against both enzymes. This study shed a light on the potential use of E. erinaceus in the protection and treatment of gastric ulcers. [ABSTRACT FROM AUTHOR]

Wild plants are used by many cultures for the treatment of diverse ailments. However, they are formed from mixtures of many wanted and unwanted phytochemicals. Thus, there is a necessity to separate the bioactive compounds responsible for their biological activity. In this study, the chemical composition as well as antimicrobial and cytotoxic activities of Echinops erinaceus Kit Tan (Asteraceae) were investigated. This led to the isolation and identification of seven compounds, two of which are new (erinaceosin C3 and erinaceol C5), in addition to methyl oleate (C1) and ethyl oleate (C2), loliolide (C4), (E)-p-coumaric acid (C6), and 5,7,3',5'-tetrahydroxy flavanone (C7). The structures of the isolated compounds were elucidated by 1D, 2D NMR, and HR-ESI-MS. The methanol extract showed the highest antimicrobial activity among the tested extracts and fractions. The n-hexane and EtOAc extracts showed remarkable antimicrobial activity against B. subtilus, P. aeruginosa, E. coli, and C. albicans. A cytotoxicity-guided fractionation of the most bioactive chloroform extract resulted in the isolation of bioactive compounds C1/C2, which showed significant cytotoxicity against HCT-116 and CACO2 cell lines (IC50 24.95 and 19.74 µg/mL, respectively), followed by compounds C3 (IC50 82.82 and 76.70 µg/mL) and C5 (IC50 99.09 and 87.27 µg/mL), respectively. The antioxidant activity of the bioactive chloroform fractions was screened. Molecular docking was used to explain the results of the antimicrobial and anticancer activities against five protein targets, including DNA gyrase topoisomerase II, enoyl-acyl carrier protein reductase of S. aureus (FabI), dihydrofolate reductase (DHFR), β-catenin, and human P-glycoprotein (P-gp). [ABSTRACT FROM AUTHOR]

The emergence of various diseases during the COVID-19 pandemic made health workers more attentive, and one of the new pathogens is the black fungus (mucormycosis). As a result, millions of lives have already been lost. As a result of the mutation, the virus is constantly changing its traits, including the rate of disease transmission, virulence, pathogenesis, and clinical signs. A recent analysis revealed that some COVID-19 patients were also coinfected with a fungal disease called mucormycosis (black fungus). India has already categorized the COVID-19 patient black fungus outbreak as an epidemic. Only a few reports are observed in other countries. The immune system is weakened by COVID-19 medication, rendering it more prone to illnesses like black fungus (mucormycosis). COVID-19, which is caused by a B.1.617 strain of the SARS-CoV-2 virus, has been circulating in India since April 2021. Mucormycosis is a rare fungal infection induced by exposure to a fungus called mucormycete. The most typically implicated genera are Mucorrhyzuprhizopusdia and Cunninghamella. Mucormycosis is also known as zygomycosis. The main causes of infection are soil, dumping sites, ancient building walls, and other sources of infection (reservoir words "mucormycosis" and "zygomycosis" are occasionally interchanged). Zygomycota, on the other hand, has been identified as polyphyletic and is not currently included in fungal classification systems; also, zygomycosis includes Entomophthorales, but mucormycosis does not. This current review will be focused on the etiology and virulence factors of COVID-19/mucormycosis coinfections in COVID-19-associated mucormycosis patients, as well as their prevalence, diagnosis, and treatment. [ABSTRACT FROM AUTHOR]

Therapeutic strategies based upon enzyme inhibition have recently gained higher attention in treating hazardous ailments. Herein, the potential use of seventy-two antimicrobial alkaloids isolated from marine-derived fungi to fight COVID-19 infection via inhibition of SARS-CoV-2 lethal virus was performed using in silico analyses. Molecular modelling was performed to assess their enzyme inhibitory potential on the main protease SARS-CoV-2 MPro, 3-chymotrypsin-like protease SARS-CoV-2 3CLpro, and papain-like protease SARS-CoV-2 PLpro using Discovery Studio 4.5. Validation of the docking experiments was done by determination of RMSD (root mean square deviation) after redocking the superimposition of the cocrystalized ligands. Results showed that gymnastatin Z (72) showed the best fitting score in SARS-CoV-2 MPro and SARS-CoV-2 3CLpr active sites with ∆G equal −34.15 and −34.28 Kcal/mol, respectively. Meanwhile, scalusamide C (62) displayed the highest fitting within SARS-CoV-2 PLpro active sites (∆G = −26.91 Kcal/mol) followed by eutypellazine M (57). ADMET/TOPKAT prediction displayed that eutypellazine M and scalusamide C showed better pharmacokinetic and pharmacodynamic properties. Gymnastatin Z is safer showing better toxicity criteria and higher rat oral LD50 and rat chronic LOAEL (lowest observed adverse effect level). Chemometric analysis using principle component analysis (PCA) based on the binding energies observed for the compounds with respect to the three tested enzymes revealed the clustering of the compounds into different clusters. Eutypellazine M, scalusamide C, and gymnastatin Z appear in one cluster due to their closeness in activity. Thus, these compounds could serve as promising SARS-CoV-2 enzymes inhibitors that could help in alleviation of COVID-19 infection. Further investigations are recommended to confirm the results of molecular modelling. [ABSTRACT FROM AUTHOR]

Therapeutic strategies based upon enzyme inhibition have recently gained higher attention in treating hazardous ailments. Herein, the potential use of seventy-two antimicrobial alkaloids isolated from marine-derived fungi to fight COVID-19 infection via inhibition of SARS-CoV-2 lethal virus was performed using in silico analyses. Molecular modelling was performed to assess their enzyme inhibitory potential on the main protease SARS-CoV-2 MPro, 3-chymotrypsin-like protease SARS-CoV-2 3CLpro, and papain-like protease SARS-CoV-2 PLpro using Discovery Studio 4.5. Validation of the docking experiments was done by determination of RMSD (root mean square deviation) after redocking the superimposition of the cocrystalized ligands. Results showed that gymnastatin Z (72) showed the best fitting score in SARS-CoV-2 MPro and SARS-CoV-2 3CLpr active sites with ∆G equal −34.15 and −34.28 Kcal/mol, respectively. Meanwhile, scalusamide C (62) displayed the highest fitting within SARS-CoV-2 PLpro active sites (∆G = −26.91 Kcal/mol) followed by eutypellazine M (57). ADMET/TOPKAT prediction displayed that eutypellazine M and scalusamide C showed better pharmacokinetic and pharmacodynamic properties. Gymnastatin Z is safer showing better toxicity criteria and higher rat oral LD50 and rat chronic LOAEL (lowest observed adverse effect level). Chemometric analysis using principle component analysis (PCA) based on the binding energies observed for the compounds with respect to the three tested enzymes revealed the clustering of the compounds into different clusters. Eutypellazine M, scalusamide C, and gymnastatin Z appear in one cluster due to their closeness in activity. Thus, these compounds could serve as promising SARS-CoV-2 enzymes inhibitors that could help in alleviation of COVID-19 infection. Further investigations are recommended to confirm the results of molecular modelling. [ABSTRACT FROM AUTHOR]

Exploring the metabolic potency of fungi as camptothecin producers raises the hope of their usage as an industrial source of camptothecin, due to their short-life span and the feasibility of metabolic engineering. However, the tiny yield and loss of camptothecin productivity of fungi during storage and sub-culturing are challenges that counteract this approach. Marine fungi could be a novel source for camptothecin production, with higher yield and reliable metabolic sustainability. The marine fungal isolate Penicillium chrysogenum EFBL # OL597937.1 derived from the sponge "Cliona sp." has been morphologically identified and molecularly confirmed, based on the Internal Transcribed Spacer sequence, exhibiting the highest yield of camptothecin (110 μg/L). The molecular structure and chemical identity of P. chrysogenum derived camptothecin has been resolved by HPLC, FTIR and LC-MS/MS analyses, giving the same spectroscopic profiles and mass fragmentation patterns as authentic camptothecin. The extracted camptothecin displayed a strong anti-proliferative activity towards HEP-2 and HCT-116 (IC50 values 0.33–0.35 µM). The yield of camptothecin was maximized by nutritional optimization of P. chrysogenum with a Plackett-Burman design, and the productivity of camptothecin increased by 1.8 fold (200 µg/L), compared to control fungal cultures. Upon storage at 4 °C as slope culture for 8 months, the productivity of camptothecin for P. chrysogenum was reduced by 40% compared to the initial culture. Visual fading of the mycelial pigmentation of P. chrysogenum was observed during fungal storage, matched with loss of camptothecin productivity. Methylene chloride extracts of Cliona sp. had the potency to completely restore the camptothecin productivity of P. chrysogenum, ensuring the partial dependence of the expression of the camptothecin biosynthetic machinery of P. chrysogenum on the chemical signals derived from the sponge, or the associated microbial flora. This is the first report describing the feasibility of P. chrysogenum, endozoic of Cliona sp., for camptothecin production, along with reliable metabolic biosynthetic stability, which could be a new platform for scaling-up camptothecin production. [ABSTRACT FROM AUTHOR]