Biosynthesis of Hesperetin, Homoeriodictyol, and Homohesperetin in a Transcriptomics-Driven Engineered Strain of Streptomyces albidoflavus.

Flavonoids exhibit various bioactivities including anti-oxidant, anti-tumor, anti-inflammatory, and anti-viral properties. Methylated flavonoids are particularly significant due to their enhanced oral bioavailability, improved intestinal absorption, and greater stability. The heterologous production of plant flavonoids in bacterial factories involves the need for enough biosynthetic precursors to allow for high production levels. These biosynthetic precursors are malonyl-CoA and l-tyrosine. In this work, to enhance flavonoid biosynthesis in Streptomyces albidoflavus, we conducted a transcriptomics study for the identification of candidate genes involved in l-tyrosine catabolism. The hypothesis was that the bacterial metabolic machinery would detect an excess of this amino acid if supplemented with the conventional culture medium and would activate the genes involved in its catabolism towards energy production. Then, by inactivating those overexpressed genes (under an excess of l-tyrosine), it would be possible to increase the intracellular pools of this precursor amino acid and eventually the final flavonoid titers in this bacterial factory. The RNAseq data analysis in the S. albidoflavus wild-type strain highlighted the hppD gene encoding 4-hydroxyphenylpyruvate dioxygenase as a promising target for knock-out, exhibiting a 23.2-fold change (FC) in expression upon l-tyrosine supplementation in comparison to control cultivation conditions. The subsequent knock-out of the hppD gene in S. albidoflavus resulted in a 1.66-fold increase in the naringenin titer, indicating enhanced flavonoid biosynthesis. Leveraging the improved strain of S. albidoflavus, we successfully synthesized the methylated flavanones hesperetin, homoeriodictyol, and homohesperetin, achieving titers of 2.52 mg/L, 1.34 mg/L, and 0.43 mg/L, respectively. In addition, the dimethoxy flavanone homohesperetin was produced as a byproduct of the endogenous metabolism of S. albidoflavus. To our knowledge, this is the first time that hppD deletion was utilized as a strategy to augment the biosynthesis of flavonoids. Furthermore, this is the first report where hesperetin and homoeriodictyol have been synthesized from l-tyrosine as a precursor. Therefore, transcriptomics is, in this case, a successful approach for the identification of catabolism reactions affecting key precursors during flavonoid biosynthesis, allowing the generation of enhanced production strains.

Effect of hesperidin on blood pressure and lipid profile: A systematic review and meta-analysis of randomized controlled trials.

The cardioprotective activity of hesperidin has been well demonstrated in several clinical studies. Also, there is a meta-analysis published on this topic in 2019. However, considering the recently published clinical studies, there is a scope for performing a systematic review and meta-analysis of hesperidin to determine its beneficial effect in alleviating alterations in cardiovascular parameters. In this study, the literature search was performed using online databases such as PubMed and Google Scholar till April 2023 involving randomized controlled studies conducted on hesperidin against various cardiovascular disorders including metabolic disorders in healthy/diseased individuals compared to the placebo/control. Based on the inclusion and exclusion criteria, nine clinical studies involving 2414 subjects were included. The meta-analysis revealed that hesperidin has significantly reduced the low-density lipoprotein (LDL) (IV: -0.55 (-0.94 to -0.16) at 95% CI, p = 0.005, I2 = 70%), total cholesterol (TC) (IV: -61 (-0.82 to -0.41) at 95% CI, p < 0.00001, I2 = 69%), and triglycerides (TG) (IV: -0.21 (-0.40 to -0.02) at 95% CI, p = 0.03, I2 = 12%). However, there were no statistically significant changes in the systolic blood pressure (IV: -0.29 (-2.21 to 1.63) at 95% CI, p = 0.77, I2 = 60%), diastolic blood pressure (IV: 0.79 (-0.74 to 2.31) at 95% CI, p = 0.31, I2 = 49%), and high-density lipoprotein (IV: 0.04 (-0.25 to 0.34) at 95% CI, p = 0.78, I2 = 56%) in the hesperidin treatment compared to the placebo/control. In conclusion, the outcomes of this meta-analysis suggest that hesperidin administration could benefit patients with CVD by reducing LDL, TC, and TG. Further high-quality studies are needed to firmly establish the clinical efficacy of hesperidin for its benefits in treating cardiovascular conditions.

Effect of hesperidin on growth, photosynthesis, antioxidant systems and uptake of cadmium, copper, chromium and zinc by Celosia argentea plants.

Rapid industrialization and extensive agricultural practices are the major causes of soil heavy metal contamination, which needs urgent attention to safeguard the soils from contamination. However, the phytotoxic effects of excessive metals in plants are the primary obstacle to efficient phytoextraction. The present study evaluated the effects of hesperidin (HSP) on metals (Cu, Cd, Cr, Zn) phytoextraction by hyperaccumulator (Celosia argentea L.) plants. For this purpose, HSP, a flavonoid compound with strong antioxidant potential to assist metal phytoextraction was used under metal stress in plants. Celosia argentea plants suffered significant (P ≤ 0.001) oxidative damage due to the colossal accumulation of metals (Cu, Cd, Cr, Zn). However, HSP supplementation notably (P ≤ 0.001) abated ROS generation (O2•‒, •OH, H2O2), lipoxygenase activity, methylglyoxal production, and relative membrane permeability that clearly indicated HSP-mediated decline in oxidative injury in plants. Exogenous HSP improved (P ≤ 0.001) the production of non-protein thiol, phytochelatins, osmolytes, and antioxidant compounds. Further, HSP enhanced (P ≤ 0.001) H2S and NO endogenous production, which might have improved the GSH: GSSG ratio. Consequently, HSP-treated C. argentea plants had higher biomass alongside elevated metal accumulation mirrored as profound modifications in translocation factor (TF), bioaccumulation coefficient (BAC), and bioconcentration factor (BCF). In this context, HSP significantly enhanced TF of Cr (P ≤ 0.001), Cd (P ≤ 0.001), and Zn (P ≤ 0.01), while BAC of Cr (P ≤ 0.001), Cd (P ≤ 0.001), and Zn (P ≤ 0.001). Further, BCF was significant (P ≤ 0.05) only in plants grown under Cr-spiked soil. Overall, HSP has the potential for phytoremediation of metals by C. argentea, which might be a suitable strategy for metal-polluted soils.

Hesperetin promotes diabetic wound healing by inhibiting ferroptosis through the activation of SIRT3.

Hesperetin (HST) is a flavonoid compound naturally occurring in citrus fruits and is widespread in various traditional medicinal herbs such as grapefruit peel, orange peel, and tangerine peel. These plant materials are commonly used in traditional Chinese medicine to prepare herbal remedies. The study aimed to investigate the potential molecular mechanisms through which HST reduces ferroptosis in human umbilical vein endothelial cells (HUVECs) and promotes angiogenesis and wound healing. We employed network pharmacology to predict the downstream targets affected by HST. The expression of markers related to ferroptosis was assessed through Western blot (WB) and polymerase chain reaction. Intracellular levels of ferroptosis-related metabolism were examined using glutathione/oxidized glutathione (GSH/GSSG) and malondialdehyde (MDA) assay kits. Mitochondrial status and iron levels within the cells were investigated through staining with Mitosox, FerroOrange, and JC1 staining. Potential downstream direct targets of HST were identified using molecular docking. Additionally, wound healing and neovascularization within the wound site were analyzed using various methods including HE staining, Masson's staining, immunohistochemistry, and Doppler hemodynamics assessment. HST effectively inhibits the elevated levels of intracellular ferroptosis stimulated by ERASTIN. Furthermore, we observed that HST achieves this inhibition of ferroptosis by activating SIRT3. In a diabetic rat wound model, HST significantly promotes wound healing, reducing levels of tissue ferroptosis, consistent with our in vitro findings. This study demonstrates that HST can inhibit the progression of ferroptosis and protect the physiological function of HUVECs by activating SIRT3. HST holds promise as a natural compound for promoting diabetic wound healing.

Hesperidin Protects Against High-Fat Diet-Induced Lipotoxicity in Rats by Inhibiting Pyroptosis.

It is currently thought that excess fatty acid-induced lipotoxicity in hepatocytes is a critical initiator in the development of nonalcoholic fatty liver disease (NAFLD). Lipotoxicity can induce hepatocyte death; thus, reducing lipotoxicity is one of the most effective therapeutic methods to combat NAFLD. Abundant evidence has shown that hesperidin (HSP), a type of flavanone mainly found in citrus fruits, is able to ameliorate NAFLD, but the molecular mechanisms are unclear. We previously reported that pyroptosis contributed to NAFLD development and that inhibiting pyroptosis contributed to blunting the progression of NAFLD in rat models. Therefore, we questioned whether HSP could contribute to ameliorating NAFLD by modulating pyroptosis. In this study, a high-fat diet (HFD) induced dyslipidemia and hepatic lipotoxicity in rats, and HSP supplementation ameliorated dyslipidemia and insulin resistance. In addition, the HFD also caused pyroptosis in the liver and pancreas, while HSP supplementation ameliorated pyroptosis. In vitro, we found that HSP ameliorated palmitic acid-induced lipotoxicity and pyroptosis in HepG2 and INS-1E cells. In conclusion, we showed for the first time that HSP has a protective effect against liver and pancreas damage in terms of pyroptosis and provides a novel mechanism for the protective effects of HSP on NAFLD.

Revealing anti-fungal potential of plant-derived bioactive therapeutics in targeting secreted aspartyl proteinase (SAP) of Candida albicans: a molecular dynamics approach.

Candida species have established themselves as a major source of nosocomial infections. Increased expression of secreted aspartyl proteinases (SAP5) plays a crucial role in the pathogenesis of Candida species. Phytotherapeutics continue to serve as a viable resource for discovering novel antifungal agents. Hence the main aim of the present investigation is to explore the possible inhibitory role of the selected bioactive molecules against the SAP5 enzyme of C. albicans using in silico approach. Molecular docking and dynamic simulations were utilized to predict the binding affinity of the lead molecules using the AutoDock and Gromacs in-silico screening tools. Results of preliminary docking simulations show that the compounds hesperidin, vitexin, berberine, adhatodine, piperine, and chlorogenic acid exhibit significant interactions with the core catalytic residues of the target protein. The best binding ligands (hesperidin, vitexin, fluconazole) were subjected to molecular dynamics (MD) and essential dynamics of the trajectories. Results of the MD simulation confirm that the ligand-protein complexes became more stable from 20 ns until 100 ns. The calculated residue-level contributions to the interaction energy along a steady simulation trajectory of all three hits (hesperidin (-132.720 kJ/mol), vitexin (-83.963 kJ/mol) and fluconazole (-98.864 kJ/mol)) ensure greater stability of the leads near the catalytic region. Essential dynamics of PCA and DCCM analysis signifies that the binding of hesperidin and vitexin created a more structurally stable environment in the protein target. The overall outcomes of this study clearly emphasize that the bioactive therapeutics found in medicinal herbs may have remarkable scope in managing Candida infection.

Neuroprotective Potential of Hesperidin as Therapeutic Agent in the Treatment of Brain Disorders: Preclinical Evidence-based Review.

Neurodegenerative disorders (NDs) are progressive morbidities that represent a serious health issue in the aging world population. There is a contemporary upsurge in worldwide interest in the area of traditional remedies and phytomedicines are widely accepted by researchers due to their health-promoted effects and fewer side effects. Hesperidin, a flavanone glycoside present in the peels of citrus fruits, possesses various biological activities including anti-inflammatory and antioxidant actions. In various preclinical studies, hesperidin has provided significant protective actions in a variety of brain disorders such as Alzheimer's disease, epilepsy, Parkinson's disease, multiple sclerosis, depression, neuropathic pain, etc. as well as their underlying mechanisms. The findings indicate that the neuroprotective effects of hesperidin are mediated by modulating antioxidant defence activities and neural growth factors, diminishing apoptotic and neuro-inflammatory pathways. This review focuses on the potential role of hesperidin in managing and treating diverse brain disorders.

Enhanced oral delivery of hesperidin-loaded sulfobutylether-ß-cyclodextrin/chitosan nanoparticles for augmenting its hypoglycemic activity: in vitro-in vivo assessment study.

Hesperidin (Hsd), a bioactive phytomedicine, experienced an antidiabetic activity versus both Type 1 and Type 2 Diabetes mellitus. However, its intrinsic poor solubility and bioavailability is a key challenging obstacle reflecting its oral delivery. From such perspective, the purpose of the current study was to prepare and evaluate Hsd-loaded sulfobutylether-ß-cyclodextrin/chitosan nanoparticles (Hsd/CD/CS NPs) for improving the hypoglycemic activity of the orally administered Hsd. Hsd was first complexed with sulfobutylether-ß-cyclodextrin (SBE-ß-CD) and the complex (CX) was found to be formed with percent complexation efficiency and percent process efficiency of 50.53 ± 1.46 and 84.52 ± 3.16%, respectively. Also, solid state characterization of the complex ensured the inclusion of Hsd inside the cavity of SBE-ß-CD. Then, Hsd/CD/CS NPs were prepared using the ionic gelation technique. The prepared NPs were fully characterized to select the most promising one (F1) with a homogenous particle size of 455.7 ± 9.04 nm, a positive zeta potential of + 32.28 ± 1.12 mV, and an entrapment efficiency of 77.46 ± 0.39%. The optimal formula (F1) was subjected to further investigation of in vitro release, ex vivo intestinal permeation, stability, cytotoxicity, and in vivo hypoglycemic activity. The results of the release and permeation studies of F1 manifested a modulated pattern between Hsd and CX. The preferential stability of F1 was observed at 4 ± 1 °C. Also, the biocompatibility of F1 with oral epithelial cell line (OEC) was retained up to a concentration of 100 µg/mL. After oral administration of F1, a noteworthy synergistic hypoglycemic effect was recorded with decreased blood glucose level until the end of the experiment. In conclusion, Hsd/CD/CS NPs could be regarded as a hopeful oral delivery system of Hsd with enhanced antidiabetic activity.

Selection and evaluation of quality markers for the regulation of PXR-CYP3A4/FXR-LXRα by Exocarpium Citri Grandis for the treatment of hyperlipidaemia with dispelling blood stasis and removing phlegm.

Hyperlipidaemia is described as "excessive phlegm" and "blood stasis" in the classic theory of traditional Chinese medicine. Exocarpium Citri Grandis has the effect of dispelling blood stasis and removing phlegm, which can better meet the treatment needs of this disease. However, there is still a lack of focus and depth in the study of the chemical composition of this medicine, and the correlation between the study of relevant medicinal substances and the efficacy of dispelling stasis and removing phlegm is insufficient. To address this issue, this study was carried out to validate the overall efficacy and identify and determine the chemical composition of Exocarpium Citri Grandis. The regulatory mechanism of the PXR-CYP3A4/FXR-LXRα pathway and its active ingredients were screened, and a pharmacokinetic study of active ingredients was performed. The obtained multidimensional data were statistically analysed and comprehensively evaluated. The quality marker of Exocarpium Citri Grandis in the treatment of hyperlipidaemia based on the PXR-CYP3A4/FXR-LXRα mechanism to exert the efficacy of dispelling blood stasis and removing phlegm was finally determined. Based on the above experiments, we identified 27 compounds from the ethanol extract of Exocarpium Citri Grandis. Among them, naringenin, meranzin hydrate, apigenin, caffeic acid phenethyl ester, anacardiin, hesperidin and naringin can significantly regulate all or part of the targets in the PXR-CYP3A4/FXR-LXRα pathway. It also has suitable content and pharmacokinetic characteristics in vivo. In conclusion, this study established quality markers to characterize the efficacy of Exocarpium Citri Grandis in dispelling blood stasis and removing phlegm, which provides a scientific basis for the targeted evaluation of the hypolipidaemic activity of this medicinal plant.

Exploring the Pharmacological Potential of Onosma riedliana: Phenolic Compounds and Their Biological Activities.

Onosma riedliana Binzet & Orcan, a traditionally used plant species, has been explored for its therapeutic potential in this study. The work presented here is the first report on the phenolic profile and biological activity of this species. Three extracts of varying polarity were prepared, with the methanolic extract containing the highest phenolic content (97.62 ± 0.20 mgGAE/g). Key phenolic compounds identified included pinoresinol, hesperidin, 4-hydroxybenzoic acid, and p-coumaric acid. The methanolic extract exhibited exceptional antioxidant properties, rivaling Trolox as a positive control, primarily attributed to hesperidin and luteolin. Moreover, the ethyl acetate extract demonstrated remarkable inhibition of cholinesterase and tyrosinase enzymes, while the methanolic extract displayed potent activity against carbohydrate hydrolytic enzymes, α-amylase and α-glucosidase. Again, phenolic compounds were shown to be responsible for the inhibition of cholinesterases and tyrosinase, but not for α-amylase and α-glucosidase. These findings underscore Onosma riedliana's potential for incorporation into diverse pharmaceutical formulations, given its multifaceted bioactivity.

Detailed Phytochemical Evaluation of a Locally Endemic Species (Campanula baskilensis) by LC-MS/MS and Its In-Depth Antioxidant and Enzyme Inhibitory Activities.

The importance of bioactive plant species in the scientific world is increasing day by day. The relationship between health and traditional-modern life, promotes the creation of new value-added natural products. This is the first research to conduct a bioactivity and chemical composition analysis of Campanula baskilensis species, which belongs to the medicinally important genus Campanula L (Campanulaceae). The aim of the current study is to quantitatively investigate the phytochemical contents of aerial and root parts of different C. baskilensis extracts (ethanol, methanol, and water) by LC-MS/MS and to evaluate their total phenolic and flavonoid contents, antioxidant and enzyme inhibitory activities. Remarkably, LC-MS/MS results revealed that, high amounts of quinic acid (53.6 mg/g aerial-MeOH extract), fumaric acid (6.3 mg/g aerial-H2 O extract, 2.5 mg/g root-H2 O extract), protocatechuic acid (11.4 mg/g aerial-H2 O extract), vanillic acid (1.4 mg/g aerial-EtOH extract), quercetin-3-O-rutinoside (rutin) (2.3 mg/g aerial-EtOH extract), hesperetin 7-rutinoside (hesperidin) (2.0 mg/g aerial-EtOH extract), kaempferol-3-O-rutinoside (nicotiflorin) (5.5 mg/g aerial-EtOH extract) were detected in the extracts of the species. Considering the bioactivity tests performed on C. baskilensis extracts, aerial-H2 O extract showed significant activity in all antioxidant assays. However, ethanol extracts of root and aerial parts exhibited the highest activities in all enzyme inhibitory tests.

Ameliorative and Neuroprotective Effect of Core-Shell Type Se@Au Conjugated Hesperidin Nanoparticles in Diabetes-Induced Cognitive Impairment.

Diabetes mellitus is the most chronic metabolic ailment characterized by insulin deficiency leading to aberrant cognitive dysfunction in later stages. Hesperidin is a bioflavonoid, having different pharmacological activities, but its poor water solubility and short plasma half-life restrict its applications in the clinical field. So, the hesperidin was conjugated with gold, selenium, and core-shell bimetallic nanoparticles of gold and selenium. Different spectroscopic methods characterized the synthesized monometallic and bimetallic nanoparticles. The rats were injected with streptozotocin to induce cognitive dysfunction, followed by administering HSP, HSP-Au NPs, HSP-Se NPs, and Se@Au-HSP NPs daily for 21 days. Then, the neurobehavioral studies, oxidative stress parameters, AChE and nitrite levels, the content of amyloid-ß42, and inflammatory mediators were accessed to evaluate the effect of the nanoparticles against the STZ rat model. The results showed a significant increase in oxidative stress, AChE activity, amyloid-ß42, nitrite levels, and neuroinflammation by upregulating the inflammatory cytokines in the streptozotocin-administered rat brain. The HSP, HSP-Au NPs, HSP-Se NPs, and Se@Au-HSP NPs effectively reversed all these effects of streptozotocin. However, the bimetallic nanoparticle Se@Au-HSP NPs revealed better neuroprotective action than HSP-Au NPs and HSP-Se NPs. Hesperidin-conjugated bimetallic nanoparticles improved learning and memory in the STZ rat model and may be an alternative approach for neurodegenerative diseases, including Alzheimer's disease.

Hesperidin, a Bioflavonoid in Cancer Therapy: A Review for a Mechanism of Action through the Modulation of Cell Signaling Pathways.

Cancer represents one of the most frequent causes of death in the world. The current therapeutic options, including radiation therapy and chemotherapy, have various adverse effects on patients' health. In this vista, the bioactive ingredient of natural products plays a vital role in disease management via the inhibition and activation of biological processes such as oxidative stress, inflammation, and cell signaling molecules. Although natural products are not a substitute for medicine, they can be effective adjuvants or a type of supporting therapy. Hesperidin, a flavonoid commonly found in citrus fruits, with its potential antioxidant, anti-inflammatory, and hepatoprotective properties, and cardio-preventive factor for disease prevention, is well-known. Furthermore, its anticancer potential has been suggested to be a promising alternative in cancer treatment or management through the modulation of signal transduction pathways, which includes apoptosis, cell cycle, angiogenesis, ERK/MAPK, signal transducer, and the activator of transcription and other cell signaling molecules. Moreover, its role in the synergistic effects with anticancer drugs and other natural compounds has been described properly. The present article describes how hesperidin affects various cancers by modulating the various cell signaling pathways.

Study on the mechanism of Shuganzhi Tablet against nonalcoholic fatty liver disease and lipid regulation effects of its main substances in vitro.

ETHNOPHARMACOLOGICAL RELEVANCE: Shuganzhi Tablet (SGZT) originates from a famous traditional Chinese herbal formula Chaihu Decoction which can be applied to treat liver diseases, however, the pharmacodynamic mechanism of SGZT needs to be evaluated. AIM OF THIS STUDY: To study the mechanism of SGZT in the treatment of non-alcoholic fatty liver disease (NAFLD), and screen out its effective ingredients. MATERIALS AND METHODS: In this study, firstly, the main components of SGZT were analyzed qualitatively. And a rat model of NAFLD was established by feeding high-fat diet. Serum biochemical indexes and liver pathological analysis were used to evaluate the pharmacodynamic effect of SGZT in the treatment of NAFLD. In order to explore the pharmacodynamic mechanism, proteomics and metabolomics analysis were used. Western blotting was used to verify the expression of important differential proteins. And L02 cells were treated with free fatty acids (FFA) and the main substances of SGZT to establish the cell model of NAFLD in vitro and to reveal the pharmacodynamic substance of SGZT. RESULTS: Twelve components were detected in SGZT, and according to the results of serum biochemical indexes and liver pathological analysis, SGZT could effectively treat NAFLD. Combined with the results of bioinformatics analysis, we found that 133 differentially expressed proteins were reversed in liver samples of rats treated with SGZT. The important proteins in PPAR signaling pathway, steroid biosynthesis, cholesterol metabolism and fatty acid metabolism were mainly regulated to maintain cholesterol homeostasis and improve lipid metabolism. SGZT also affected various metabolites in rat liver, including eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and taurine. In addition, the main components contained in SGZT (hesperidin, polydatin, naringin, emodin, specnuezhenide, saikosaponin A) and a metabolite (resveratrol) could significantly reduce FFA-induced intracellular lipid accumulation. CONCLUSION: SGZT effectively treated NAFLD, and PPAR-γ, Acsl4, Plin2 and Fads1 may be the main targets of SGZT. And Fads1-EPA/DHA-PPAR-γ may be the potential pharmacodynamic pathway. Cell experiments in vitro revealed that the main components of SGZT and their metabolites, such as hesperidin, polydatin, naringin, emodin, specnuezhenide, saikosaponin A and resveratrol may be the main components of its efficacy. Further research is needed to reveal and validate the pharmacodynamic mechanism.

Mechanism underlying Fanmugua () leaf multicomponent synergistic therapy for anemia: data mining based on hematopoietic network.

OBJECTIVE: To investigate the underlying mechanism of Fanmugua (Fructus Caricae) Leaf (CPL) multicomponent synergistic therapy for anemia. METHODS: The components were identified in the literature. Six databases were searched for targets of CPL. Enrichment analysis was used to determine the targets associated with anemia and in bone marrow. Based on the Kyoto Encyclopedia of Genes and Genomes database, pathways and targets related to hematopoiesis were obtained. The key targets were obtained by protein-protein interaction analysis. Molecular docking was used to analyze the binding ability of key targets and active components. Bone marrow cells were used as an experimental model to verify the drug efficacy. RESULTS: A total of 139 components and 1868 targets of CPL were retrieved from the literature. By disease enrichment analysis, 543 targets for hemorrhagic anemia, 223 targets for aplastic anemia, and 126 targets for sickle cell anemia were obtained. Target organ enrichment yielded 27, 29, and 20 targets of bone marrow. Based on KEGG pathway enrichment, a total of 47 shared hematopoietic pathways and 42 related targets were found. The key targets were vascular endothelial growth factor A (VEGFA), interleukin 10 (IL-10), platelet-endothelial cell adhesion molecule-1 (PECAM1), C-C motif chemokine 2 (CCL2), and vascular cell adhesion molecule 1 (VCAM1). The CPL active components included ursolic acid, quercetin, and hesperidin. The expression of VEGFA was significantly increased after CPL treatment. Quercetin and ursolic acid acted on VEGFA. Quercetin and Hesperidin acted on VCAM1. Quercetin acted on IL-10, CCL2, VCAM1, and VEGFA. Cell experiments revealed that CPL could promote the proliferation and migration of bone marrow cells. CONCLUSIONS: CPL has the synergistic efficacy of treating anemia through multiple components, targets, and pathways.

Preparation and physicochemical properties characterization of hesperetin-grafted pectin conjugate.

Different ratios of hesperetin (HT) were successfully grafted onto pectin from basic water (PB) molecules via free radical-induced reaction. The structure of PB-HT conjugates was characterized by ultraviolet spectroscopy, infrared spectroscopy, X-ray diffraction and scanning electron microscopy. Results indicated that HT was successfully grafted onto pectin molecules, and PB-HT-0.5 showed the highest HT content (103.18 ± 2.76 mg/g). Thermogravimetric analysis indicated that HT crystals showed good thermal resistance and could improve the thermal stability of PB-HT conjugates. Additionally, PB-HT conjugates showed good cytocompatibility and blood compatibility. This study provides a novel and efficient method to synthesize hesperetin-grafted pectin conjugate, which showed potential application in the fields of functional foods in the future.

Improving Solubility and Permeability of Hesperidin through Electrospun Orange-Peel-Extract-Loaded Nanofibers.

Orange peel, which is a rich source of polyphenolic compounds, including hesperidin, is produced as waste in production. Therefore, optimization of the extraction of hesperidin was performed to obtain its highest content. The influence of process parameters such as the kind of extraction mixture, its temperature and the number of repetitions of the cycles on hesperidin content, the total content of phenolic compounds and antioxidant (DPPH scavenging assay) as well as anti-inflammation activities (inhibition of hyaluronidase activity) was checked. Methanol and temperature were key parameters determining the efficiency of extraction in terms of the possibility of extracting compounds with the highest biological activity. The optimal parameters of the orange peel extraction process were 70% of methanol in the extraction mixture, a temperature of 70 °C and 4 cycles per 20 min. The second part of the work focuses on developing electrospinning technology to synthesize nanofibers of polyvinylpyrrolidone (PVP) and hydroxypropyl-ß-cyclodextrin (HPßCD) loaded with hesperidin-rich orange peel extract. This is a response to the circumvention of restrictions in the use of hesperidin due to its poor bioavailability resulting from low solubility and permeability. Dissolution studies showed improved hesperidin solubility (over eight-fold), while the PAMPA-GIT assay confirmed significantly better transmucosal penetration (over nine-fold). A DPPH scavenging assay of antioxidant activity as well as inhibition of hyaluronidase to express anti-inflammation activity was established for hesperidin in prepared electrospun nanofibers, especially those based on HPßCD and PVP. Thus, hesperidin-rich orange peel nanofibers may have potential buccal applications to induce improved systemic effects with pro-health biological activity.

Efficacy and safety of dietary polyphenols in rheumatoid arthritis: A systematic review and meta-analysis of 47 randomized controlled trials.

Objective: To evaluate safety and efficacy of dietary polyphenols in the treatment of rheumatoid arthritis (RA). Methods: CNKI, Pubmed, Cochrane library, Embase were searched to collect randomized controlled trials (RCTs) of dietary polyphenols in the treatment of RA. The databases were searched from the time of their establishment to November 8nd, 2022. After 2 reviewers independently screened the literature, extracted data, and assessed the risk of bias of the included studies, Meta-analysis was performed using RevMan5.4 software. Results: A total of 49 records (47 RCTs) were finally included, involving 3852 participants and 15 types of dietary polyphenols (Cinnamon extract, Cranberry extract, Crocus sativus L. extract, Curcumin, Garlic extract, Ginger extract, Hesperidin, Olive oil, Pomegranate extract, Puerarin, Quercetin, Resveratrol, Sesamin, Tea polyphenols, Total glucosides of paeony). Pomegranate extract, Resveratrol, Garlic extract, Puerarin, Hesperidin, Ginger extract, Cinnamon extract, Sesamin only involve in 1 RCT. Cranberry extract, Crocus sativus L. extract, Olive oil, Quercetin, Tea polyphenols involve in 2 RCTs. Total glucosides of paeony and Curcumin involve in more than 3 RCTs. These RCTs showed that these dietary polyphenols could improve disease activity score for 28 joints (DAS28), inflammation levels or oxidative stress levels in RA. The addition of dietary polyphenols did not increase adverse events. Conclusion: Dietary polyphenols may improve DAS28, reduce C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), and improve oxidative stress, etc. However, more RCTs are needed to verify or modify the efficacy and safety of dietary polyphenols. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42022315645.

Metabolomic Analysis of Phytochemical Compounds from Ethanolic Extract of Lime (Citrus aurantifolia) Peel and Its Anti-Cancer Effects against Human Hepatocellular Carcinoma Cells.

Lime peels are food waste from lime product manufacturing. We previously developed and optimized a green extraction method for hesperidin-limonin-rich lime peel extract. This study aimed to identify the metabolomics profile of phytochemicals and the anti-cancer effects of ethanolic extract of lime (Citrus aurantifolia) peel against liver cancer cells PLC/PRF/5. The extract's metabolomics profile was analyzed by using LC-qTOF/MS and GC-HRMS. The anti-cancer effects were studied by using MTT assay, Annexin-PI assay, and Transwell-invasion assay. Results show that the average IC50(s) of hesperidin, limonin, and the extract on cancer cells' viability were 165.615, 188.073, and 503.004 µg/mL, respectively. At the IC50 levels, the extract induced more apoptosis than those of pure compounds when incubating for 24 and 48 h (p < 0.0001). A combination of limonin and hesperidin showed a synergistic effect on apoptosis induction (p < 0.001), but the effect of the combination was still less than that of the extract at 48 h. Furthermore, the extract significantly inhibited cancer cell invasion better than limonin but equal to hesperidin. At the IC50 level, the extract contains many folds lower amounts of hesperidin and limonin than the IC50 doses of the pure compounds. Besides limonin and hesperidin, there were another 60 and 22 compounds detected from the LCMS and GCMS analyses, respectively. Taken altogether, the superior effect of the ethanolic extract against liver cancer cells compared to pure compound likely results from the combinatorial effects of limonin, hesperidin, and other phytochemical components in the extract.

Comparison of the effects of methylprednisolone, hyperbaric oxygen and hesperidin + diosmin on the facial nerve injury: an experimental animal model.

BACKGROUND: Necessity of new and alternative treatments in traumatic facial nerve injury. AIMS/OBJECTIVE: In this experimental study, we aimed to evaluate the histopathologic and functional effects of methylprednisolone, hyperbaric oxygen and hesperidin + diosmin treatments on traumatic facial nerve regeneration in rats. METHODS: After facial nerve injury, five groups were formed with eight rats in each group: Group 1 (negative control), 2 (operation), 3 (corticosteroid), 4 (hyperbaric oxygen), 5 (hesperidin + diosmin). Blink reflex of rats evaluated a day after the operation and at the first, second and third weeks. Facial nerve samples from sacrificed animals were examined under a light microscope. RESULTS: According to our results, in group 4; axonal degeneration and vascular congestion were significantly lower than group 2 and 3, and myelin sheath thickness was significantly higher than group 3. In group 5; axonal degeneration was significantly lower than group 2 and vascular congestion was significantly lower than group 2 and 3. In terms of functional recovery; there was no statistically significant difference between the groups. CONCLUSIONS AND SIGNIFICANCE: It has been shown that both hyperbaric oxygen and hesperidin + diosmin treatments have positive effects on facial nerve regeneration. Both treatments may be good alternatives for ameliorating traumatic nerve injury, but these treatment modalities need to be further explored.