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.

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.

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.

Effect of substituting hydroponic barley forage with or without enzymes on performance of growing rabbits.

This study aims to evaluate the effect of hydroponic barley (HB) by substituting control diet with 25% HB with or without enzymes on rabbit performance, nutrient digestibility, and economic efficiency. A total number of 60 growing male HyPlus rabbits (average body weight 669 ± 12 g, 30 days of age) were utilized in the present study. The rabbits were randomly assigned to three groups (n = 20 rabbits per group). The first group served as a control (C). The other two groups were fed the control diet substituted with 25% hydroponic barley HB (group CHB), and the control diet substituted with 25% HB added with 0.5 g/kg enzymes (CHBE). The experiment lasted for 56 days. The results revealed that daily body weight gain improved (P < 0.05) by 18.64% and 23.94%, and feed conversion ratio improved by 3.74% and 17.91% than control, respectively, during 30-86 days of age in CHB and CHBE groups. The economic efficiency was improved (P < 0.05) by 32.17% and 39.60% in CHB and CHBE diets, respectively, compared to control; and nutrient digestibility, and mineral retention of growing rabbits were also improved (P < 0.05) by substituting HB with or without enzymes compared to control diet. Overall, the best rabbit performances were observed in both CHB and CHBE groups. In conclusion, these results suggest that substituting 25% of concentrated control diet by hydroponic barley with or without enzymes have positive effects in a sustainable way on growth performance, nutrient digestibility, and economic efficiency of growing rabbits.

Anti-Inflammatory and Antioxidant Properties of Malapterurus electricus Skin Fish Methanolic Extract in Arthritic Rats: Therapeutic and Protective Effects.

The protective and therapeutic anti-inflammatory and antioxidant potency of Malapterurus electricus (F. Malapteruridae) skin fish methanolic extract (FE) (300 mg/kg.b.wt/day for 7 days, orally) was tested in monosodium urate(MSU)-induced arthritic Wistar albino male rats' joints. Serum uric acid, TNF-α, IL-1ß, NF-𝜅B, MDA, GSH, catalase, SOD, and glutathione reductase levels were all measured. According to the findings, FE significantly reduced uric acid levels and ankle swelling in both protective and therapeutic groups. Furthermore, it has anti-inflammatory effects by downregulating inflammatory cytokines, primarily through decreased oxidative stress and increased antioxidant status. All the aforementioned lesions were significantly improved in protected and treated rats with FE, according to histopathological findings. iNOS immunostaining revealed that protected and treated arthritic rats with FE had weak positive immune-reactive cells. Phytochemical analysis revealed that FE was high in fatty and amino acids. The most abundant compounds were vaccenic (24.52%), 9-octadecenoic (11.66%), palmitic (34.66%), stearic acids (14.63%), glycine (0.813 mg/100 mg), and alanine (1.645 mg/100 mg). Extensive molecular modelling and dynamics simulation experiments revealed that compound 4 has the potential to target and inhibit COX isoforms with a higher affinity for COX-2. As a result, we contend that FE could be a promising protective and therapeutic option for arthritis, aiding in the prevention and progression of this chronic inflammatory disease.

Bioassay-Guided Isolation, Metabolic Profiling, and Docking Studies of Hyaluronidase Inhibitors from Ravenala madagascariensis.

Hyaluronidase enzyme (HAase) has a role in the dissolution or disintegration of hyaluronic acid (HA) and in maintaining the heathy state of skin. Bioassay-guided fractionation of Ravenala madagascariensis (Sonn.) organ extracts (leaf, flower, stem, and root) testing for hyaluronidase inhibition was performed followed by metabolic profiling using LC-HRMS. Additionally, a hyaluronidase docking study was achieved using Molecular Operating Environment (MOE). Results showed that the crude hydroalcoholic (70% EtOH) extract of the leaves as well as its n-butanol (n-BuOH) partition showed higher HAase activity with 64.3% inhibition. Metabolic analysis of R. madagascariensis resulted in the identification of 19 phenolic compounds ranging from different chemical classes (flavone glycosides, flavonol glycosides, and flavanol aglycones). Bioassay-guided purification of the leaf n-BuOH partition led to the isolation of seven compounds that were identified as narcissin, rutin, epiafzelechin, epicatechin, isorhamnetin 7-O-glucoside, kaempferol, and isorhamnetin-7-O-rutinoside. The docking study showed that narcissin, rutin, and quercetin 3-O-glucoside all interact with HAase through hydrogen bonding with the Asp111, Gln271, and/or Glu113 residues. Our results highlight Ravenala madagascariensis and its flavonoids as promising hyaluronidase inhibitors in natural cosmetology preparations for skin care.

Carnitine palmitoyltransferase 1A functions to repress FoxO transcription factors to allow cell cycle progression in ovarian cancer.

Cancer cells rely on hyperactive de novo lipid synthesis for maintaining malignancy. Recent studies suggest involvement in cancer of fatty acid oxidation, a process functionally opposite to lipogenesis. A mechanistic link from lipid catabolism to oncogenic processes is yet to be established. Carnitine palmitoyltransferase 1 (CPT1) is a rate-limiting enzyme of fatty acid ß-oxidation (FAO) that catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine, thereby shuttling fatty acids into the mitochondrial matrix for ß-oxidation. In the present study, we demonstrated that CPT1A was highly expressed in most ovarian cancer cell lines and primary ovarian serous carcinomas. Overexpression of CPT1A correlated with a poor overall survival of ovarian cancer patients. Inactivation of CPT1A decreased cellular ATP levels and induced cell cycle arrest at G0/G1, suggesting that ovarian cancer cells depend on or are addicted to CPT1A-mediated FAO for cell cycle progression. CPT1A deficiency also suppressed anchorage-independent growth and formation of xenografts from ovarian cancer cell lines. The cyclin-dependent kinase inhibitor p21WAF1 (p21) was identified as most consistently and robustly induced cell cycle regulator upon inactivation of CPT1A. Furthermore, p21 was transcriptionally upregulated by the FoxO transcription factors, which were in turn phosphorylated and activated by AMP-activated protein kinase and the mitogen-activated protein kinases JNK and p38. Our results established the oncogenic relevance of CPT1A and a mechanistic link from lipid catabolism to cell cycle regulation, suggesting that CPT1A could be a prognostic biomarker and rational target for therapeutic intervention of cancer.

Lysophosphatidic Acid Up-Regulates Hexokinase II and Glycolysis to Promote Proliferation of Ovarian Cancer Cells.

Lysophosphatidic acid (LPA), a blood-borne lipid mediator, is present in elevated concentrations in ascites of ovarian cancer patients and other malignant effusions. LPA is a potent mitogen in cancer cells. The mechanism linking LPA signal to cancer cell proliferation is not well understood. Little is known about whether LPA affects glucose metabolism to accommodate rapid proliferation of cancer cells. Here we describe that in ovarian cancer cells, LPA enhances glycolytic rate and lactate efflux. A real time PCR-based miniarray showed that hexokinase II (HK2) was the most dramatically induced glycolytic gene to promote glycolysis in LPA-treated cells. Analysis of the human HK2 gene promoter identified the sterol regulatory element-binding protein as the primary mediator of LPA-induced HK2 transcription. The effects of LPA on HK2 and glycolysis rely on LPA2, an LPA receptor subtype overexpressed in ovarian cancer and many other malignancies. We further examined the general role of growth factor-induced glycolysis in cell proliferation. Like LPA, epidermal growth factor (EGF) elicited robust glycolytic and proliferative responses in ovarian cancer cells. Insulin-like growth factor 1 (IGF-1) and insulin, however, potently stimulated cell proliferation but only modestly induced glycolysis. Consistent with their differential effects on glycolysis, LPA and EGF-dependent cell proliferation was highly sensitive to glycolytic inhibition while the growth-promoting effect of IGF-1 or insulin was more resistant. These results indicate that LPA- and EGF-induced cell proliferation selectively involves up-regulation of HK2 and glycolytic metabolism. The work is the first to implicate LPA signaling in promotion of glucose metabolism in cancer cells.