Wound healing potential of Cystoseira/mesenchymal stem cells in immunosuppressed rats supported by overwhelming immuno-inflammatory crosstalk.

Wound healing, one of the most intricate and dynamic processes of the body, maintains skin integrity following trauma. One of the main issues that still exists is impaired wound healing, particularly for immunosuppressed patients. Recently, natural products from marine environments have been employed in wound-repairing activities. This work investigates the mesenchymal stem cells in the combined capacity of the bone marrow (BMMSC) for wound healing and Cystoseira sp. Algae extract in immunosuppressed rats. High-resolution liquid chromatography / MS investigation of Cystoseira extract revealed the prevalence of fatty acids that have wound-soothing potential. From constructed PPI network for wound healing and further analysis through molecular docking and molecular dynamics (MD) simulation experiments suggested that cystalgerone metabolite may be responsible for the wound healing-promoting effect of Cystoseira extract. According to the CD marker characterization of the BMMSC, 98.21% of them expressed CD90, and 97.1% expressed CD105. Sixteen d after immunity suppression (by 40 mg/kg hydrocortisone daily), an incision was made in the dorsal skin of the rat. The treatments were applied for 16 d and samples were taken from the tested groups on the 8th, 14th, and 16th days. The BMMSCs / Cystoseira group showed significantly improved wound closure, thickness, density of new layers, and skin elasticity than the control group (p < 0.001). The BMMSCs / Cystoseira combination significantly reduced the oxidative indicators, pro-inflammatory cytokines, and immune markers, according to the RT-PCR gene expression study. In order to delve deeper into the complex interconnections among wound healing-related biological targets and pinpoint key factors in this complex process, we engaged in network pharmacology and computational research. Subsequently, we conducted a comprehensive computational analysis, including reverse docking, free energy (ΔG) computation, and molecular dynamics simulations, on the molecular structures of the annotated compounds. The purpose of this investigation was to identify potential new targets for these chemicals as well as any potential interactions they may have with different signaling pathways related to the wound healing process. Our research indicates that the primary compounds of Cystoseira holds potential wound healing therapeutic activity. Although more safety testing and clinical studies are required, the combination has great potential for regenerative medicine and could be a revolutionary advance in the healing of the wounds of immunosuppressed patients.

Antiplasmodial potential of phytochemicals from Citrus aurantifolia peels: a comprehensive in vitro and in silico study.

Phytochemical investigation of Key lime (Citrus aurantifolia L., F. Rutaceae) peels afforded six metabolites, known as methyl isolimonate acetate (1), limonin (2), luteolin (3), 3`-hydroxygenkwanin (4), myricetin (5), and europetin (6). The structures of the isolated compounds were assigned by 1D NMR. In the case of limonin (2), further 1- and 2D NMR experiments were done to further confirm the structure of this most active metabolite. The antiplasmodial properties of the obtained compounds against the pathogenic NF54 strain of Plasmodium falciparum were assessed in vitro. According to antiplasmodial screening, only limonin (2), luteolin (3), and myricetin (5) were effective (IC50 values of 0.2, 3.4, and 5.9 µM, respectively). We explored the antiplasmodial potential of phytochemicals from C. aurantifolia peels using a stepwise in silico-based analysis. We first identified the unique proteins of P. falciparum that have no homolog in the human proteome, and then performed inverse docking, ΔGBinding calculation, and molecular dynamics simulation to predict the binding affinity and stability of the isolated compounds with these proteins. We found that limonin (2), luteolin (3), and myricetin (5) could interact with 20S a proteasome, choline kinase, and phosphocholine cytidylyltransferase, respectively, which are important enzymes for the survival and growth of the parasite. According to our findings, phytochemicals from C. aurantifolia peels can be considered as potential leads for the development of new safe and effective antiplasmodial agents.

Apium extract alleviates indomethacin-induced gastric ulcers in rats via modulating the VEGF and IK-κB/NF-κB p65 signaling pathway: insights from in silico and in vivo investigations.

BACKGROUND: Gastric ulcers represent a worldwide health problem, characterized by erosions that affect the mucous membrane of the stomach and may even reach the muscular layer, leading to serious complications. Numerous natural products have been assessed as anti-ulcerogenic agents, and have been considered as new approaches for treatment or prevention of gastric ulcers. The present research investigated the preventive benefits of Apium graveolens L. (Apiaceae), known as celery, seed extract towards indomethacin-induced ulceration of the stomach in rats. METHODS: Metabolomic profiling, employing liquid chromatography coupled to high-resolution electrospray ionization mass spectrometry (LC-HR-ESI-MS), was implemented with the aim of investigating the chemical profile of the seeds. Histopathological analysis of gastric tissues, as well as assessment of numerous inflammatory cytokines and oxidative stress indicators, confirmed the in vivo evaluation. RESULTS: The prior treatment with A. graveolens seed extract resulted in a substantial reduction in the ulcer index when compared to the indomethacin group, indicating an improvement in stomach mucosal injury. Moreover, the gastroprotective effect was demonstrated through examination of the oxidative stress biomarkers which was significantly attenuated upon pre-treatment with A. graveolens seed extract. Vascular endothelial growth factor (VEGF), a fundamental angiogenic factor that stimulates angiogenesis, was markedly inhibited by indomethacin. A. graveolens seed extract restored this diminished level of VEGF. The dramatic reductions in NF-κB protein levels indicate a considerable attenuation of the indomethacin-induced IKκB/NF-κB p65 signaling cascade. These activities were also correlated to the tentatively featured secondary metabolites including, phenolic acids, coumarins and flavonoids, previously evidenced to exert potent anti-inflammatory and antioxidant activities. According to our network pharmacology study, the identified metabolites annotated 379 unique genes, among which only 17 genes were related to gastric ulcer. The PTGS2, MMP2 and PTGS1 were the top annotated genes related to gastric ulcer. The top biological pathway was the VEGF signaling pathway. CONCLUSION: A. graveolens seed extract possesses significant anti-ulcer activity, similar to famotidine, against gastric lesions induced by indomethacin in rats. It is worth highlighting that the extract overcomes the negative effects of conventional chemical anti-secretory drugs because it does not lower stomach acidity.

New cytotoxic dammarane type saponins from Ziziphus spina-christi.

Cancer is the world's second-leading cause of death. Drug development efforts frequently focus on medicinal plants since they are a valuable source of anticancer medications. A phytochemical investigation of the edible Ziziphus spina-christi (F. Rhamnaceae) leaf extract afforded two new dammarane type saponins identified as christinin E and F (1, 2), along with the known compound christinin A (3). Different cancer cell lines, such as lung cancer (A549), glioblastoma (U87), breast cancer (MDA-MB-231), and colorectal carcinoma (CT-26) cell lines, were used to investigate the extracted compounds' cytotoxic properties. Our findings showed significant effects on all the tested cell lines at varying concentrations (1, 5, 10, and 20 µg/mL). The three compounds exhibited potent activity at low concentrations (< 10 µg/mL), as evidenced by their low IC50 values. To further investigate the complex relationships between these identified cancer-relevant biological targets and to identify critical targets in the pathogenesis of the disease, we turned to network pharmacology and in silico-based investigations. Following this, in silico-based analysis (e.g., inverse docking, ΔG calculation, and molecular dynamics simulation) was performed on the structures of the isolated compounds to identify additional potential targets for these compounds and their likely interactions with various signalling pathways relevant to this disease. Based on our findings, Z. spina-christi's compounds showed promise as potential anti-cancer therapeutic leads in the future.

Nutritional Composition and Anti-Type 2 Diabetes Mellitus Potential of Femur Bone Extracts from Bovine, Chicken, Sheep, and Goat: Phytochemical and In Vivo Studies.

Nutritional deficits in one's diet have been established as the key risk factor for T2DM in recent years. Nutritional therapy has been demonstrated to be useful in treating T2DM. The current study was carried out to assess the nutritional composition of bovine (12 months), chicken (4 months), sheep (13 months), and goat (9 months) femur bone extracts, as well as their potential therapeutic effects on T2DM regression in a Wistar albino rat model (500 mg/kg b.wt.). The proximate composition of the different extracts, their fatty acid composition, their amino acids, and their mineral contents were identified. In vivo data indicated considerably improved T2DM rats, as seen by lower serum levels of TL, TG, TC, ALT, AST, ALP, bilirubin, creatinine, urea, IL-6, TNF-α, sICAM-1, sVCAM-1, and MDA. Low levels of HDL-C, GSH, and total proteins were restored during this study. Histological investigations of liver and pancreatic tissue revealed that the distribution of collagen fibers was nearly normal. The bovine extract, on the other hand, was the most active, followed by the sheep, goat, and finally chicken extract. This research could result in the creation of a simple, noninvasive, low-cost, and reliable method for T2DM control, paving the way for potential early therapeutic applications in T2DM control.

Egyptian mandarin peel oil's anti-scabies potential via downregulation-of-inflammatory/immune-cross-talk: GC-MS and PPI network studies.

The current study investigated the scabicidal potential of Egyptian mandarin peel oil (Citrus reticulata Blanco, F. Rutaceae) against sarcoptic mange-in-rabbits. Analysis of the oil's GC-MS identified a total of 20 compounds, accounting for 98.91% of all compounds found. Mandarin peel oil topical application improved all signs of infection, causing a scabicidal effect three days later, whereas in vitro application caused complete mite mortality one day later. In comparison to ivermectin, histopathological analysis showed that the epidermis' inflammatory-infiltration/hyperkeratosis-had disappeared. In addition to TIMP-1, the results of the mRNA gene expression analysis showed upregulation of I-CAM-1-and-KGF and downregulation of ILs-1, 6, 10, VEGF, MMP-9, and MCP-1. The scabies network was constructed and subjected to a comprehensive bioinformatic evaluation. TNF-, IL-1B, and IL-6, the top three hub protein-coding genes, have been identified as key therapeutic targets for scabies. From molecular docking data, compounds 15 and 16 acquired sufficient affinity towards the three screened proteins, particularly both possessing higher affinity towards the IL-6 receptor. Interestingly, it achieved a higher binding energy score than the ligand of the docked protein rather than displaying proper binding interactions like those of the ligand. Meanwhile, geraniol (15) showed the highest affinity towards the GST protein, suggesting its contribution to the acaricidal effect of the extract. The subsequent, MD simulations revealed that geraniol can achieve stable binding inside the binding site of both GST and IL-6. Our findings collectively revealed the scabicidal ability of mandarin peel extract for the first time, paving the way for an efficient, economical, and environmentally friendly herbal alternative for treating rabbits with Sarcoptes mange.

Wound Restorative Power of Halimeda macroloba/ Mesenchymal Stem Cells in Immunocompromised Rats via Downregulating Inflammatory/Immune Cross Talk.

Impaired skin wound healing is still a major challenge, especially with immunocompromised patients who express delayed healing and are susceptible to infections. Injection of rat-derived bone marrow mesenchymal stem cells (BMMSCs) via the tail vein accelerates cutaneous wound healing via their paracrine activity. The present work aimed to investigate the combined wound-healing potential of BMMSCs and Halimeda macroloba algae extract in immunocompromised rats. High-resolution liquid chromatography-mass spectrometry (HR-LC-MS) investigation of the extract revealed the presence of variant phytochemicals, mostly phenolics, and terpenoids, known for their angiogenic, collagen-stimulating, anti-inflammatory, and antioxidant properties. The BMMSCs were isolated and characterized for CD markers, where they showed a positive expression of CD90 by 98.21% and CD105 by 97.1%. Twelve days after inducing immunocompromise (40 mg/kg hydrocortisone daily), a circular excision was created in the dorsal skin of rats and the treatments were continued for 16 days. The studied groups were sampled on days 4, 8, 12, and 16 after wounding. The gross/histopathological results revealed that the wound closure (99%), thickness, density of new epidermis and dermis, and skin elasticity in the healed wounds were considerably higher in the BMMSCs/Halimeda group than the control group (p < 0.05). RT-PCR gene expression analysis revealed that the BMMSCs/Halimeda extract combination had perfectly attenuated oxidative stress, proinflammatory cytokines, and NF-KB activation at day 16 of wounding. The combination holds promise for regenerative medicine, representing a revolutionary step in the wound healing of immunocompromised patients, with still a need for safety assessments and further clinical trials.

Anti-Alzheimer Potential of a New (+)-Pinitol Glycoside Isolated from Tamarindus indica Pulp: In Vivo and In Silico Evaluations.

Tamarindus indica Linn (tamarind, F. Leguminosae) is one of the most widely consumed edible fruits in the world. Phytochemical investigation of tamarind pulp n-butanol fraction yielded one new (+)-pinitol glycoside compound 1 (25% w/w), and 1D, 2D NMR, and HRESIMS investigation were used to confirm the new compound's structure. (+)-Pinitol glycoside showed anti-Alzheimer potential that was confirmed in prophylactic and treatment groups by decreasing time for the T-maze test; decreased TAO, brain and serum AChE, MDA, tau protein levels, and ß amyloid peptide protein levels; and increasing GPX, SOD levels, and in vivo regression of the neurodegenerative features of Alzheimer's dementia in an aluminum-intoxicated rat model. The reported molecular targets for human Alzheimer's disease were then used in a network pharmacology investigation to examine their complex interactions and identify the key targets in the disease pathogenesis. An in silico-based analysis (molecular docking, binding free energy calculation (ΔGBinding), and molecular dynamics simulation) was performed to identify the potential targets for compound 1. The findings of this study may lead to the development of dietary supplements for the treatment of Alzheimer's disease.

Abelmoschus eculentus Seed Extract Exhibits In Vitro and In Vivo Anti-Alzheimer's Potential Supported by Metabolomic and Computational Investigation.

Abelmoschus esculentus Linn. (okra, F. Malvaceae) is a fruit widely consumed all over the world. In our study, the anti-Alzheimer's potential of A. esculentus was evaluated. An in vitro DPPH free radical assay on A. esculentus seed's total extract and AChE inhibition potential screening indicated a significant anti-Alzheimer's activity of the extract, which was confirmed through an in vivo study in an aluminum-intoxicated rat model. Additionally, in vivo results demonstrated significant improvement in Alzheimer's rats, which was confirmed by improving T-maze, beam balance tests, lower serum levels of AChE, norepinephrine, glycated end products, IL-6, and MDA. The levels of dopamine, BDNF, GSH, and TAC returned to normal values during the study. Moreover, histological investigations of brain tissue revealed that the destruction in collagen fiber nearly returns back to the normal pattern. Metabolomic analysis of the ethanolic extract of A. esculentus seeds via LC-HR-ESI-MS dereplicated ten compounds. A network pharmacology study displayed the relation between identified compounds and 136 genes, among which 84 genes related to Alzheimer's disorders, and focused on AChE, APP, BACE1, MAPT and TNF genes with interactions to all Alzheimer's disorders. Consequently, the results revealed in our study grant potential dietary elements for the management of Alzheimer's disorders.

Nutraceutical Effect of Resveratrol on the Mammary Gland: Focusing on the NF-κb /Nrf2 Signaling Pathways.

The aim of this study is to evaluate the defensive role of resveratrol, which is antagonistic to the oxidative stress and inflammation that is prompted by LPS in mammary tissue of female mice. Thirty adult mice were distributed into three groups (n = 10) control (CON), lipopolysaccharides at 2.5 mg/kg (LPS), and lipopolysaccharides at 2.5 mg/kg with 2 mg/kg of resveratrol (RES + LPS). The treatments were applied for 15 consecutive days. Spectrophotometry was used to quantify ROS in the blood, and proinflammatory cytokines concentrations were determined through radioimmunoassay. NF-κB, Jnk, IL-1ß, Erk, IL-6, Nrf2 and TNF-α were quantified by RT-qPCR, and Western blots were used to quantifyP65 and pP65 protein intensities. MDA production was considerably increased, and the activity of T-AOC declined in the LPS treatment in comparison with the CON group but was significantly reversed in the RES + LPS group. Proinflammatory cytokines production and the genes responsible for inflammation and oxidative stress also showed higher mRNA and pP65 protein intensity in the LPS group, while Nrf2 showed a remarkable decline in mRNA expression in the LPS versus the CON group. All these mRNA intensities were reversed in the RES + LPS group. There were no remarkable changes in P65 protein intensity observed between the CON, LPS, and RES + LPS groups. In conclusion, resveratrol acts as a protective agent to modulate cellular inflammation and oxidative stress caused by LPS in mammary tissue of female mice.

Antibacterial efficacy of synthesized silver nanoparticles of Microbacterium proteolyticum LA2(R) and Streptomyces rochei LA2(O) against biofilm forming meningitis causing microbes.

Actinobacteria obtained from the least explored Indian regions were studied for their ability to suppress meningitis-causing bacteria in nanoparticle form. Drug-resistant bacteria and long-term treatment with different medications make meningitis control complicated. Thus, new meningitis drugs are required to combat MDR bacteria. In this study, secondary metabolites isolated from actinomycetes strains, Microbacterium proteolyticum LA2(R) and Streptomyces rochei LA2(O), were employed to synthesize silver nanoparticles (AgNPs) at 37 °C for seven days incubation. UV-Vis spectroscopy, TEM, FTIR, and HPLC studies were used for the confirmation of the synthesis of AgNPs. Furthermore, these NPs demonstrated antibacterial and antibiofilm activities against meningitis-causing bacteria. The average size of LA2(R) and LA2(O) isolated secondary metabolites mediated AgNPs was observed to be 27 ± 1and 29 ± 2 nm by TEM analysis. FTIR study of RAgNPs and OAgNPs revealed that presence of peaks with positions of 1637.17 cm1 and 1636.10 cm1 for C=O amide group appearances in the amide I linkage. These NPs were effective against bacterial pathogens such as S. pneumoniae, H. influenzae, and N. meningitidis and confirmed by their MICs, i.e., 109.4, 120.60, and 138.80 µg/ml of RAgNPs and 105.80, 114.40 and 129.06 µg/ml of OAgNPs, respectively. Additionally, the production of biofilms is impeded by these nanoparticles on S. pneumoniae, H. influenzae, and N. meningitidis by 73.14%, 71.89% and 64.81%, respectively. These findings confirm the potential role of synthesized AgNPs against biofilm forming meningitis causing Multidrug resistance (MDR) microbes.

The Protective and Therapeutic Anti-Alzheimer Potential of Olea europaea L. cv. Picual: An In Silico and In Vivo Study.

LC-HRESIMS metabolomic profiling of Olea europaea L. cv. Picual (OEP) (Saudi Arabian olive cultivar, F. Oleacea) revealed 18 compounds. Using pharmacology networking to specify the targets of the identified compounds with a relationship to Alzheimer's disease, it was possible to identify the VEGFA, AChE, and DRD2 genes as the top correlated genes to Alzheimer's disease with 8, 8, and 6 interactions in the same order. The mechanism of action on cellular components, biological processes, and molecular functions was determined by gene enrichment analysis. A biological pathway comparison revealed 13 shared pathways between the identified genes and Alzheimer protein genes (beta-amyloid band tau proteins). The suggested extract's anti-Alzheimer potential in silico screening was confirmed through in vivo investigation in regressing the neurodegenerative features of Alzheimer's dementia in an aluminum-intoxicated rat model (protective and therapeutic effects, 100 mg/kg b.w.). In vivo results suggested that OEP extract significantly improved Alzheimer's rats, which was indicated by the crude extract's ability to improve T-maze performance; lower elevated serum levels of AChE, AB peptide, and Ph/T ratio; and normalize the reduced level of TAC during the study. The results presented in this study may provide potential dietary supplements for the management of Alzheimer's disease.

Scabicidal Potential of Coconut Seed Extract in Rabbits via Downregulating Inflammatory/Immune Cross Talk: A Comprehensive Phytochemical/GC-MS and In Silico Proof.

Scabies is an invasive skin condition caused by Sarcoptes scabiei mites. The present study investigates the antiscabies potential of coconut seed extract (CSE) in rabbits. GC-MS analysis of the seed oil identified 17 known compounds, while CSE phytochemical investigation afforded 4 known ones. The topical application of seed extract improved all signs of infection, and the improvement started 3 days post application. However, in vitro application of the extract caused 99% mortality of mites 1 day post application. Histopathological examination revealed the absence of inflammatory infiltration and hyperkeratosis of the epidermis, compared with ivermectin-treated groups which revealed less improvement. The mRNA gene expression results revealed a suppression of IL-1ß, IL-6, IL-10, MMP-9, VEGF, and MCP-1, and an upregulation of I-CAM-1, KGF as well as TIMP-1. The docking analysis emphasized a strong binding of gondoic acid with IL-1ß, IL-6, and VEGF with high binding scores of -5.817, -5.291, and -8.362 kcal/mol, respectively, and a high binding affinity of 3″(1‴-O-ß-D-glucopyranosyl)-sucrose with GST with -7.24 kcal/mol. Accordingly, and for the first time, our results highlighted the scabicidal potential of coconut seed extract, which opens the gate for an efficient, cost-effective as well as herbal-based alternative for the control of scabies in rabbits.