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Hesperetin, an aglycone metabolite of hesperidin with high bioavailability, recently gained attention due to its anti-COVID-19 and anti-cancer properties. Multiple studies revealed that cancer patients are prone to experience a severe form of COVID-19 and higher mortality risk. In addition, studies suggested that COVID-19 can potentially lead to cancer progression through multiple mechanisms. This study proposes that hesperetin not only can be used as an anti-COVID-19 agent but also can reduce the risk of multiple cancer progression by suppressing several intracellular signaling pathways in cancer patients with COVID-19. Therefore, in this review, we attempted to provide evidence demonstrating anti-COVID-19/cancer properties of hesperetin with several mechanisms. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) represents the most alarming hematological disease for adults. Several genetic modifications are known to be pivotal in AML; however, SIRT2 over-expression has attracted the scientific community's attention as an unfavorable prognostic marker. The plant kingdom is a treasure trove of bioactive principles, with flavonoids standing out among the others. On this line, the aim of this study was to investigate the anti-leukemic properties of the main flavanones of Citrus spp., exploring the potential implication of SIRT2. Naringenin (NAR), hesperetin (HSP), naringin (NRG), and neohesperidin (NHP) inhibited SIRT2 activity in the isolated recombinant enzyme, and more, the combination between NAR and HSP. In monocytic leukemic THP-1 cells, only NAR and HSP induced antiproliferative effects, altering the cell cycle. These effects may be ascribed to SIRT2 inhibition since these flavonoids reduced its gene expression and hampered the deacetylation of p53, known sirtuin substrate, and contextually modulated the expression of the downstream cell cycle regulators p21 and cyclin E1. Additionally, these two flavanones proved to interact with the SIRT2 inhibitory site, as shown by docking simulations. Our results suggest that both NAR and HSP may act as anti-leukemic agents, alone and in combination, via targeting the SIRT2/p53/p21/cyclin E1 pathway, thus encouraging deeper investigations. [ABSTRACT FROM AUTHOR]

Objectives: The aim of the current study was to assess the effects of hesperetin on damage to kidneys as remote organs following skeletal muscle ischemia-reperfusion (IR) in rats. Materials and Methods: In general, 30 male Wistar rats were randomized and placed into sham, IR, hesperetin, dimethyl sulfoxide (DMSO), and IR+hesperetin groups. The rats in the hesperetin and IR+hesperetin groups received a 50 mg/kg dose of hesperetin dissolved in DMSO intraperitoneally. In the IR+hesperetin group, hesperetin was injected exactly prior to reperfusion. To induce skeletal muscle ischemia, the femoral artery was clamped for two hours. Following a 24-hour period of reperfusion, the samples of blood were collected for renal function tests and oxidative stress measurements. Next, the rats were euthanized, and histological analyses were conducted on their removed kidneys. Results: Based on the results, urea and creatinine serum levels were significantly higher in the IR group (P

[Display omitted] • Hesperidin and hesperetin, natural flavonoids found abundantly in citrus fruits, exhibit promising therapeutic potential in combating various aspects of cardiovascular diseases. • Hesperidin and hesperetin mitigate responses related to inflammation and improve antioxidant levels following acute myocardial infarction, possibly through downregulation of Bcl‑2 and PPAR‑γ expression, and NF-κB signaling cascade. • These flavonoids protect against drug-induced cardiotoxicity, including arsenic trioxide, cisplatin, and doxorubicin. • Hesperidin and hesperetin possess antihypertensive properties by modulating the renin-angiotensin system (RAS), reducing oxidative stress while improving vascular function. • Clinical trials also support the potential benefits of hesperidin and hesperetin supplementation in improving blood pressure, endothelial function, and inflammatory markers. This investigation aims to determine how hesperidin and hesperetin, natural flavonoids found abundantly in citrus fruits, affect cardiovascular diseases. From inception until January 2024, relevant literature was reviewed using a systematic review methodology and databases such as Scopus, PubMed, and Web of Science. Hesperidin and hesperetin counteract atherosclerosis, a key contributor to heart disease, by ameliorating lipid profiles, inhibiting plaque formation, and reducing inflammation. These flavonoids protect against drug-induced cardiotoxicity, safeguarding the heart from injury developed by arsenic trioxide, cisplatin, and doxorubicin. They enhance endothelial function, regulate blood pressure, and counteract oxidative stress. Furthermore, clinical trials also support the potential benefits of hesperidin supplementation in improving blood pressure, endothelial function, and inflammatory markers. This thorough review presents significant evidence advocating the inclusion of hesperidin and hesperetin as supplementary, innovative, and cost-efficient remedies for cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Orange pomace is a byproduct of the orange juicing industry that contains several polyphenols that can exert health benefits. However, incorporating orange pomace polyphenols into functional foods is challenging because of their poor water solubility and low bioaccessibility. This problem can be overcome by incorporating the polyphenols into protein nanoparticle-based delivery systems. The objective of this research was therefore to encapsulate hesperetin in core-shell biopolymer nanoparticles assembled from zein and high-methoxy pectin using an antisolvent precipitation/electrostatic deposition method. Hesperetin is a bioactive polyphenol derived from hesperidin, which can be isolated from orange pomace. Fluorescence spectroscopy indicated a strong interaction between hesperetin and zein. Fourier transform infrared spectroscopy suggested that this interaction was primarily due to hydrogen bonding and hydrophobic interactions, while the interaction between pectin and zein was mainly due to electrostatic attraction. Hesperetin-loaded zein nanoparticles had a mean diameter, zeta-potential, and encapsulation efficiency of 179 nm, 23.2 mV, and 93% before coating with pectin, and 357 nm, −22.6 mV, and 94% after coating with pectin, respectively. The pectin coating improved the stability of the nanoparticles to aggregation and sedimentation under different environmental conditions: pH 2.0–8.0; temperatures up to 90 °C; salt levels up to 50 mM NaCl; and storage for up to one month. The antioxidant activity and in vitro bioaccessibility of the encapsulated hesperetin were significantly higher than hesperetin dispersed in water. These results show that core-shell biopolymer nanoparticles may be a promising approach to incorporate hesperetin (and possibly other polyphenols) into foods and beverages. [Display omitted] • Hesperetin was encapsulated in zein particles by antisolvent precipitation. • Hesperetin and zein showed hydrophobic attractions and hydrogen bonding. • Radical scavenging of hesperetin improved when encapsulated in nanoparticles. • Hesperetin-loaded zein/pectin nanoparticles showed excellent colloidal stability. • In vitro bioaccessibility of hesperetin increased with zein/pectin encapsulation. [ABSTRACT FROM AUTHOR]

Necrotizing enterocolitis (NEC) is one of the most common and serious intestinal illnesses in newborns and seriously affects their long-term prognosis and survival. Butyrate is a short-chain fatty acid that can relieve intestinal inflammation, but its mechanism of action is unclear. Results from an in vivo neonatal rat model has shown that butyrate caused an improved recovery from NEC. These protective effects were associated with the metabolite of hesperetin, as determined by metabolomics and molecular biological analysis. Furthermore, transcriptomics combined with inhibitor assays were used to investigate the mechanism of action of hesperetin in an in vitro NEC model (IEC-6 cells exposed to LPS) to further investigate the mechanism by which butyrate attenuates NEC. The transcriptomics analysis showed that the PI3K-Akt signaling pathway was involved in the anti-NEC effect of hesperitin. Subsequently, the results using an inhibitor of PI3K (LY294002) indicated that the suppression could be explained by the hesperetin-induced expression of tight junction (TJ) proteins by potentially blocking the PI3K-Akt signaling pathway. In summary, the present study demonstrated that butyrate could improve recovery from NEC with a hesperetin metabolite, causing potential inhibition of the phosphorylation of the PI3K-Akt signaling pathway, resulting in the increased expression of TJ proteins. These findings reveal a potential new therapeutic pathway for the treatment of NEC. • Butyrate performed the protective effect in NEC model in vivo and in vitro. • The positive effect of butyrate was related with the intestinal metabolite of hesperetin. • Hesperetin alleviated NEC by inhibiting PI3K-Akt pathway phosphorylation. • Butyrate alleviates experimental necrotizing enterocolitis through metabolite hesperetin via inhibiting the PI3K-Akt pathway. [ABSTRACT FROM AUTHOR]

The encapsulation of insoluble compounds can help improve their solubility and activity. The effects of cyclodextrin encapsulation on hesperetin’s derivatives (HHSB, HIN, and HTSC) and the physicochemical properties of the formed complexes were determined using various analytical techniques. The antioxidant (DPPH•, ABTS•+ scavenging, and Fe2+-chelating ability), cytotoxic, and antibacterial activities were also investigated. The inclusion systems were prepared using mechanical and co-evaporation methods using a molar ratio compound: HP-β-CD = 1:1. The identification of solid systems confirmed the formation of two inclusion complexes at hesperetin (CV) and HHSB (mech). The identification of systems of hesperetin and its derivatives with HP-β-CD in solutions at pHs 3.6, 6.5, and 8.5 and at various temperatures (25, 37 and 60 °C) confirmed the effect of cyclodextrin on their solubility. In the DPPH• and ABTS•+ assay, pure compounds were characterized by higher antioxidant activity than the complexes. In the FRAP study, all hesperetin and HHSB complexes and HTSC-HP-β-CD (mech) were characterized by higher values of antioxidant activity than pure compounds. The results obtained from cytotoxic activity tests show that for most of the systems tested, cytotoxicity increased with the concentration of the chemical, with the exception of HP-β-CD. All systems inhibited Escherichia coli and Staphylococcus aureus.

The aim of this research was to investigate the antimicrobial characteristics and mechanism of hesperetin against Alicyclobacillus acidoterrestris vegetative cells. The results presented show that hesperetin had effective antimicrobial activity on Alicyclobacillus acidoterrestris vegetative cells, minimum inhibition concentration (MIC) of 0.0625 g/L, and minimum bacterial concentration (MBC) greater than 2 g/L. Moreover, treatment of hesperetin caused significant damage to cell integrity, preventing the growth of Alicyclobacillus acidoterrestris vegetative cells, enhancing the leakage of nucleic acid and proteins, and destroying the vegetative cell morphology. To further investigate the mechanism, transcriptomic analysis was carried out, and 3056 differentially expressed genes (DEGs) were detected. Gene ontology (GO) enrichment analysis revealed that hesperetin inhibits Alicyclobacillus acidoterrestris by affecting the intracellular nitrogen metabolism and amino acid metabolism. The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis explained that hesperetin was also able to prevent the growth of Alicyclobacillus acidoterrestris by affecting the processes of nutrient transport, energy metabolism, and flagella motility. These results provide new insights into the antimicrobial effects and mechanism of hesperetin against Alicyclobacillus acidoterrestris, which provides a new method for inactive Alicyclobacillus acidoterrestris in the juice industry.

Hesperetin, a citrus flavonoid, exerts vasodilation and is expected to improve endothelial function and alleviate cold sensation by activating nervous system thermal transduction pathways. In this randomized, double-blind, crossover, and placebo-controlled study, the purpose was to assess the effect of an orally administered highly bioavailable soluble inclusion complex of hesperetine-7-O-glucoside with β-cyclodextrin (HEPT7G/βCD; SunActive® HES/HCD) on cold sensation response during localized cold-stimulated stress in healthy humans. A significant (p ≤ 0.05) dose-dependent increase in skin cutaneous blood flow following relatively small doses of HEPT7G/βCD inclusion complex ingestion was confirmed, which led to a relatively effective recovery of peripheral skin temperature. The time delay of an increase in blood flow during rewarming varied significantly between low- and high-dose HEPT7G/βCD inclusion complex consumption (e.g., 150 mg and 300 mg contain 19.5 mg and 39 mg of HEPT7G, respectively). In conclusion, the substantial alteration in peripheral skin blood flow observed during local cooling stress compared to placebo suggested that deconjugated hesperetin metabolites may have a distinct capacity for thermoregulatory control of human skin blood flow to maintain a constant body temperature during cold stress exposure via cutaneous vasodilation and vasoconstriction systems.

Alzheimer’s disease is a progressive neurodegenerative disorder leading to cognitive decline and memory loss. The incidence of this disease continues to increase due to the limited number of novel therapeutics that prevent or slow down its progression. Flavonoids have been investigated for their potential effects on cellular damage triggered by excessive reactive oxygen species (ROS) and neuroinflammatory conditions. This study investigated the effect of the flavonoid hesperetin on LPS-activated murine BV-2 microglial cells. Results show that hesperetin reduced nitric oxide levels and increased catalase, glutathione, and superoxide dismutase levels, suggesting its potential to reduce neuroinflammation and oxidative stress. Moreover, RT-PCR arrays showed that hesperetin modulated multiple genes that regulate oxidative stress. Hesperetin downregulated the mRNA expression of ERCC6, NOS2, and NCF1 and upregulated HMOX1 and GCLC. RT-PCR results showed that hesperetin-induced Nrf2 mRNA and protein expression in LPS-activated BV-2 microglial cells is involved in the transcription of several antioxidant genes, suggesting that hesperetin’s antioxidant effects may be exerted via the Keap1/Nrf2 signaling pathway. Furthermore, the data demonstrated that hesperetin reduced the gene expression of PD-L1, which is upregulated as an individual ages and during chronic inflammatory processes, and inhibited the expression of genes associated with NF-kB signaling activation, which is overactivated during chronic inflammation. It was concluded from this investigation that hesperetin may have therapeutic potential to prevent or slow down the progression of neurodegenerative diseases, such as Alzheimer’s disease, by reducing chronic oxidative stress and modulating neuroinflammation.

Breast cancer (BC) has high incidence and mortality rates, making it a major global health issue. BC treatment has been challenging due to the presence of drug resistance and the limited availability of therapeutic options for triple-negative and metastatic BC, thereby urging the exploration of more effective anti-cancer agents. Hesperidin and its aglycone hesperetin, two flavonoids from citrus species, have been extensively evaluated for their anti-cancer potentials. In this review, available literatures on the chemotherapeutic and chemosensitising activities of hesperidin and hesperetin in preclinical BC models are reported. The safety and bioavailability of hesperidin and hesperetin as well as the strategies to enhance their bioavailability are also discussed. Overall, hesperidin and hesperetin can inhibit cell proliferation, migration and BC stem cells as well as induce apoptosis and cell cycle arrest in vitro. They can also inhibit tumour growth, metastasis and neoplastic changes in tissue architecture in vivo. Moreover, the co-administration of hesperidin or hesperetin with doxorubicin, letrozole or tamoxifen can enhance the efficacies of these clinically available agents. These chemotherapeutic and chemosensitising activities of hesperidin and hesperetin have been linked to several mechanisms, including the modulation of signalling pathways, glucose uptake, enzymes, miRNA expression, oxidative status, cell cycle regulatory proteins, tumour suppressor p53, plasma and liver lipid profiles as well as DNA repair mechanisms. However, poor water solubility, extensive phase II metabolism and apical efflux have posed limitations to the bioavailability of hesperidin and hesperetin. Various strategies for bioavailability enhancement have been studied, including the utilisation of nano-based drug delivery systems and the co-administration of hesperetin with other flavonoids. In particular, nanoformulated hesperidin and hesperetin possess greater chemotherapeutic and chemosensitising activities than free compounds. Despite promising preclinical results, further safety and efficacy evaluation of hesperidin and hesperetin as well as their nanoformulations in clinical trials is required to ascertain their potentials to be developed as clinically useful agents for BC treatment.

Prostate cancer is the most prevalent cancer in males, and usually, death occurs due to bone metastasis. TGFβ has been shown to play an essential role in the metastasis of prostate cancer cells by promoting epithelial-to-mesenchymal transition (EMT). Hesperetin is known to possess anti-microbial, anti-fungal, antioxidant, and anti-cancer properties and good bioavailability. Therefore, this study investigated the effect of hesperetin on TGFβ-induced cell proliferation and EMT in prostate cancer cells (PC3). Interestingly, we found that hesperetin can significantly inhibit the cell proliferation of PC3 cells and arrest the cells in the S and G2M phases of the cell cycle. The invasion and migration assay results decipher the inhibitory effect of hesperetin on TGFβ-induced invasion and migration of prostate cancer cells. Our results confirmed that hesperetin also acts through the canonical signaling pathway, as we observed a significant decrease in the expression of pSmad3. Hesperetin can inhibit the TGFβ induced EMT by increasing E-cadherin expression and decreasing N-cadherin expression. Hesperetin could modulate the TGFβ induced histone methylation marks. Further investigation is required to understand the role of hesperetin in modulating these marks and thus inhibiting TGFβ-induced EMT. Hence, the results of our study identified the potential of hesperetin to modulate TGFβ-induced cell proliferation and invasion and migration of prostate cancer cells which may help inhibit the metastatic growth of prostate cancer cells.

Inhibition of inflammatory responses from the spike glycoprotein of SARS-CoV-2 (Spike) by targeting NLRP3 inflammasome has recently been developed as an alternative form of supportive therapy besides the traditional anti-viral approaches. Clerodendrum petasites S. Moore (C. petasites) is a Thai traditional medicinal plant possessing antipyretic and anti-inflammatory activities. In this study, C. petasites ethanolic root extract (CpEE) underwent solvent-partitioned extraction to obtain the ethyl acetate fraction of C. petasites (CpEA). Subsequently, C. petasites extracts were determined for the flavonoid contents and anti-inflammatory properties against spike induction in the A549 lung cells. According to the HPLC results, CpEA significantly contained higher amounts of hesperidin and hesperetin flavonoids than CpEE (p < 0.05). A549 cells were then pre-treated with either C. petasites extracts or its active flavonoids and were primed with 100 ng/mL of spike S1 subunit (Spike S1) and determined for the anti-inflammatory properties. The results indicate that CpEA (compared with CpEE) and hesperetin (compared with hesperidin) exhibited greater anti-inflammatory properties upon Spike S1 induction through a significant reduction in IL-6, IL-1β, and IL-18 cytokine releases in A549 cells culture supernatant (p < 0.05). Additionally, CpEA and hesperetin significantly inhibited the Spike S1-induced inflammatory gene expressions (NLRP3, IL-1β, and IL-18, p < 0.05). Mechanistically, CpEA and hesperetin attenuated inflammasome machinery protein expressions (NLRP3, ASC, and Caspase-1), as well as inactivated the Akt/MAPK/AP-1 pathway. Overall, our findings could provide scientific-based evidence to support the use of C. petasites and hesperetin in the development of supportive therapies for the prevention of COVID-19-related chronic inflammation. [ABSTRACT FROM AUTHOR]

Cadmium (Cd) is a major environmental contaminant that has been linked to oocyte quality reduction and early embryo mortality in various in vivo studies. In this study, we investigated the mechanism of Cd-induced mitochondrial toxicity in bovine in vitro matured oocytes, primary cultured bovine cumulus cells, and in vitro developed bovine embryos. Cd significantly reduced PPARGC1A (PGC-1α) and nuclear respiratory factors, which leads to mitochondrial damage and hence reduction in oocyte maturation and embryo development. NAD-dependent deacetylase sirtuin-1 (SIRT1) is the upstream marker of PGC-1α and nuclear respiratory factors, and its activation significantly mitigated Cd-induced mitochondrial damage. For SIRT1 activation, we used Hesperetin (Hsp), a citrus flavonoid and a potent activator of SIRT1. The molecular docking approach was used to investigate the binding of hesperetin to bovine SIRT1, which revealed that hesperetin creates polar and non-polar interactions with residues that are reported essential for the activation of SIRT1. Furthermore, the SIRT1 enzymatic activity was measured in primary cultured bovine granulosa cells after hesperetin treatment. To further confirm the SIRT1-dependent effects of hesperetin we used a specific inhibitor of SIRT1 (EX527), which significantly (p < 0.05) reduced the effects of hesperetin on embryo mitochondria. Next, we treated hesperetin and Cd to early bovine embryos and discovered a significant (p 0.05) increase in PGC-1, NRF1, and NFE2L2 protein expression as well as embryo development recovery. Thus, we came to the conclusion that hesperetin can activate PGC-1 and nuclear respiratory factors via SIRT1, which can greatly reduce Cd-induced mitochondrial toxicity and promote mitochondrial biogenesis in early bovine embryos. • Cadmium (Cd) altered PGC-1α expression and localization in early bovine embryos. • Bovine SIRT1 was generated via homology modeling. • Bovine SIRT1 was used to perform molecular docking for Hesperetin. • Activated SIRT1 improve PGC-1α expression and nuclear localization of NRF1/2. • SIRT1 inhibition reduced the embryo development and also have significant effects on embryo mitochondrial biogenesis. [ABSTRACT FROM AUTHOR]

Flavonoids are common in the plant kingdom and many of them have shown a wide spectrum of bioactive properties. Hesperetin (Hst), the aglycone form of hesperidin, is a great example, and is the most abundant flavonoid found in Citrus plants. This review aims to provide an overview on the in vitro, in vivo and clinical studies reporting the Hst pharmacological effects and to discuss the bioavailability-related issues. Preclinical studies have shown promising effects on cancer, cardiovascular diseases, carbohydrate dysregulation, bone health, and other pathologies. Clinical studies have supported the Hst promissory effects as cardioprotective and neuroprotective agent. However, further well-designed clinical trials are needed to address the other Hst effects observed in preclinical trials, as well as to a more in-depth understanding of its safety profile. [ABSTRACT FROM AUTHOR]

Oxaliplatin (OXP) is the typical treatment for colorectal cancer. Combining chemotherapeutic drugs can reduce drug resistance and side effects. In the present study, the co-delivery of OXP with Hesperetin (HSP), a natural anti-cancer flavonoid, by nanoliposomes was studied against HT-29 colon cancer cells. Cationic Okra gum (COG) was synthesized to coat nanoliposomes. The successful synthesis of COG was confirmed by NMR spectroscopy. Liposomes were prepared by thin film hydration technique. Formulations containing 0.5, 1, and 2 mg·ml−1 COG, had particle sizes ranging from 145 to 175 nm and zeta potentials for uncoated and coated formulations changed between −29 and −0.403 mV. Coated liposomes released 98 and 66% of HSP and OXP, respectively during 24 h pH-dependently. Cationic Okra gum enhanced the physical stability of the liposomes for about 30 days. The composite liposomes containing OXP and HSP at final concentrations of 1.125 and 125 µM, respectively could generate significant cytotoxicity at 48 h in comparison to each drug alone. Extracted drug-target interactions from the STITCH database, showed that Catalase (CAT) is the common target between OXP and HSP drugs. Measurement of the CAT activity may be used as an indicator to investigate the mechanism of action of these drugs in subsequent experiments. [ABSTRACT FROM AUTHOR]

1,2‐Dimethylhydrazine (DMH), a colon‐specific environmental toxicant is one among the carcinogen responsible for the cause of colon cancer. The present study was designed to evaluate the protective effect of Hesperetin (HST) against colon toxicity induced by DMH in Wistar rats. HST, a flavonoid widely found in citrus fruits possesses several biological activities including anti‐microbial, anti‐oxidant properties among others. A single dose of DMH (40 mg/kg body weight) was administered subcutaneously on 1st day for induction of colon toxicity followed by oral treatment with HST at a dose of 20 mg/kg bodyweight for 14 consecutive days. DMH administration leads to excessive ROS generation, resulting in an imbalance in redox homeostasis and causing membrane lipid peroxidation, which is also partly due to the decrease in the level of tissue antioxidant machinery. Our result showed HST significantly ameliorates DMH‐induced lipid peroxidation and also substantially increases the activity/level of various anti‐oxidant proteins (GR, GPx, GST, GSH, and SOD). HST was also found to reduce the expression of inflammatory proteins (TNF‐α, IL‐6, i‐NOS, COX‐2, NF‐kB‐p65), goblet cell disintegration as well as mucin depletion (sulfo and sialomucin) in the colon that was found to be elevated upon administration of DMH. Our histological results further provide confirmation of the protective role of HST against DMH‐induced pathological alterations. The results of the present study demonstrate supplementation of HST is beneficial in ameliorating DMH‐induced toxicity by suppressing oxidative stress, inflammation, goblet cell disintegration as well mucin depletion in the colon of Wistar rats. [ABSTRACT FROM AUTHOR]

A method for the synthesis of esters of natural flavonoids—naringenin, quercetin and hesperetin—in the presence of regioselective Novozyme 435 lipase was developed. Benzoic, salicylic, nicotinic, and cinnamic acids were used as acids participating in the esterification reaction. 12 new esters of naringenin, quercetin, hesperetin were obtained. [ABSTRACT FROM AUTHOR]

Nicosulfuron is a post-emergence herbicide used to control weeds while hesperetin found in citrus fruits has been reported to have anti-inflammatory, anti-cancer, and antioxidant properties. This study was designed to investigate the ameliorative properties of Hesperetin on Nicosulfuron-induced reproductive oxidative stress in male Wistar rats. Twenty-four male wistar rats weighing 200 ± 20g were assigned to different groups, each with six animals. Group A serves as the control group and were administered distilled water only. Group B received 25 mg/kg body weight (B.W.) Nicosulfuron. Group C were co-administered with 25 mg/kg B.W. Nicosulfuron and 100 mg/kg Hesperetin while animals in group D received 100 mg/kg B. W. Hesperetin. All treatment lasted for 14 days. An increase in the percentage of sperm with abnormal morphology (23.07%) in the group exposed to Nicosulfuron was observed. Sperm motility, testicular Ascorbic acid, reduced glutathione (GSH) levels were reduced significantly in the Nicosulfuron-treated group by 20.33%, 48.11%, and 41.10% respectively. Also, GST, Catalase, and SOD activities were significantly down-regulated in the Nicosulfuron-treated group. Furthermore, as compared to the control group, the Nicosulfuron-treated group had significantly higher activity of testicular acid phosphatase (ACP), alkaline phosphatase (ALP), MDA, and NO levels. However, co-treatment of Nicosulfuron and Hesperetin significantly ameliorated the Nicosulfuron-induced changes in sperm morphology, motility; testicular ascorbic acid, GSH, NO levels; SOD, CAT, GST, ALP, and ACP activities. The result from this study indicates that Hesperetin, due to its antioxidant properties, protects against testicular oxidative stress induced by Nicosulfuron exposure. [ABSTRACT FROM AUTHOR]

Hesperetin showed a higher effect than hesperidin and hesperidin glucoside, and hesperidin and hesperidin glucoside did not show a significant difference. Abbreviation, HD; hesperidin, HG1; hesperidin mono-glucoside, HG2; hesperidin di-glucoside, HG3; hesperidin tri-glucoside, HG4; hesperidin tetra-glucoside, HG5; hesperidin penta-glucoside. Keywords: hesperetin; hesperidin; hesperidin glucoside; solubility; antioxidant; anti-inflammatory; antibacterial; in vitro EN hesperetin hesperidin hesperidin glucoside solubility antioxidant anti-inflammatory antibacterial in vitro N.PAG N.PAG 18 08/29/22 20220801 NES 220801 1. The solubility of glucosylated hesperidin, whether hesperidin mono-glucoside or hesperidin poly-glucoside, increased drastically compared to hesperidin. FT-IT Spectra of Hesperetin, Hesperidin and Hesperidin Glucoside In the FT-IR spectra of hesperetin (Figure 3), hesperidin and hesperidin glucoside, the characteristic absorption bands were present, and then identified, respectively, using OMNIC software library (Thermo Fisher Scientific, Waltham, MA, USA). [Extracted from the article]

UV radiation can cause damages, such as erythema, skin photoaging, and carcinogenesis. The adoption of protective measures against sun exposure is essential to prevent these damages, and the interest in using natural substances as an alternative for photoprotection is growing. Thus, hesperetin with antioxidant, anti-inflammatory, and anticancer properties is a promising substance to be used with photochemopreventive action and to protect the skin from damage induced by UV radiation. Therefore, the present study aimed to develop a topical formulation based on AAMVPC gel containing hesperetin and evaluate its photoprotective effect on the skin of rats exposed to UVA-UVB radiation. The animals were submitted to the irradiation protocol UVA-UVB, and at the end, erythema, lipid peroxidation, and activity of the antioxidant enzyme catalase and superoxide dismutase were evaluated. Additionally, it evaluated the activity of myeloperoxidase and histological changes. The formulation presented a rheological and spreadability profile suitable for cutaneous application. In vivo results demonstrated that the topical formulation of AAMVPC gel containing hesperetin at a concentration of 10% protected the skin from damage induced by UVA-UVB radiation, with the absence of erythema, lipid lipoperoxidation, and inflammation (low myeloperoxidase activity), and increased catalase and superoxide dismutase activities. The morphology and architecture of the dermo-epidermal tissue of these animals were like those observed under normal conditions (non-irradiated animals). Thus, the results showed that hesperetin was able to protect the animals' skin against UV radiation–induced skin damage and the protection mechanisms may be related to the antioxidant and anti-inflammatory properties of this natural product. [ABSTRACT FROM AUTHOR]

Summary: Our previous studies have already revealed that β-cryptoxanthin (BCX), hesperetin (HES), and icariin (ICA) antioxidants are effective for in vitro maturation (IVM) of porcine oocytes. In this study, we investigated which of BCX, HES, or ICA was more effective for IVM of porcine oocytes. The antioxidant properties were assessed with aged porcine oocytes and embryos by comparing 2,2-diphenyl-1-(2,4,6-trinitrophenyl)hydrazyl (DPPH), reducing power, and H2O2 scavenging activity assays. The chemical assay results demonstrated that BCX had a greater DPPH scavenging activity and reducing power than HES and ICA, compared with controls. However, the H2O2 scavenging activity of the antioxidants was similar when tested at the optimal concentrations of 1 μM BCX (BCX-1), 100 μM HES (HES-100), and 5 μM ICA (ICA-5). The biological assay results showed that BCX-1 treatment was more effective in inducing a significant reduction in reactive oxygen species (ROS), improving glutathione levels, and increasing the expression of antioxidant genes. In addition, BCX-1 inhibited apoptosis by increasing the expression of anti-apoptotic genes and decreasing pro-apoptotic genes in porcine parthenogenetic blastocysts. BCX-1 also significantly increased the blastocyst formation rate compared with the ageing control group, HES-100 and ICA-5. This study demonstrates that damage from ROS produced during oocyte ageing can be prevented by supplementing antioxidants into the IVM medium, and BCX may be a potential candidate to improve assisted reproductive technologies. [ABSTRACT FROM AUTHOR]

Air particulate matter exposure has been linked to cardiovascular and atherosclerosis as a result of increase oxidative stress and inflammatory response. This study aims to determine the effect of the use of hesperetin (HESP) as a therapeutic agent to mitigate the cardiovascular oxidative and pro-inflammatory effects of diesel exhaust particles in Wistar rats. DEP was collected from an Iveco cargo engine truck, and n-hexane fraction (hDEP) was obtained. Forty Wistar strains of male albino rats (6 weeks) were divided into 8 groups: control group received DMSO and CMC-Na; other groups received either n-hexane extract of DEP (0.064 or 0.640 mg/kg hDEP) or Standard Reference Material 2975 (0.064 mg/kg hSRM) in the presence or absence of 200 mg/kg HESP. Extracts were administered orally. Serum lipids, lipid peroxidation (LPO), conjugated dienes (CDs), and GSH levels were determined. Also, inflammatory cytokines, PCSK-9, LDL-receptor, and antioxidant genes expression were assessed by RT-PCR in both the heart and aorta. The molecular interaction of targeted proteins with HESP was assessed by the in silico approach. Extracts of DEP caused a significant (p < 0.001) increase in serum lipids but significantly decreased HDL-CHOL. It also increased CDs and MDA levels but decreased GSH levels. In addition, the particulate extracts caused a significant (p < 0.001) increase in pro-inflammatory genes expression in the heart and aorta but significantly decreased IL-10 and LDL-R gene expressions. Pre-treatment with hesperetin significantly reversed all these effects. This study shows that hesperetin has the ability to protect against DEP-induced oxidative stress and inflammation in the cardiovascular system. [ABSTRACT FROM AUTHOR]

In this study, cross‐linked poly(cyclotriphosphazene‐co‐hesperetin) (PCTPHP) microspheres were synthesized by the reaction of hexachlorocyclotriphosphazene (HCCP) with hesperetin (HSP). Fourier transform infrared (FT‐IR) spectroscopy was used to confirm the successful preparation of the PCTPHP microspheres. The cross‐linking density of the prepared PCTPHP microspheres was examined by electron paramagnetic resonance (EPR) spectroscopy. The results showed that the increased HSP mole might be more suitable to cross‐link with HCCP in high density. The thermal properties, particle size distribution, morphology and crystalline nature of PCTPHP microspheres were investigated by thermogravimetric analysis (TGA), dynamic light scattering (DLS), scanning electron microscope (SEM) and X‐ray diffraction (XRD). The prepared PCTPHP‐3 microspheres were used as drug carriers. The 5‐fluorouracil (5‐FU) was loaded on the microspheres and their in vitro release behavior was observed at two different pH values. The results showed a controlled release of 5‐FU from the PCTPHP‐3/5‐FU in both basic and acidic mediums up to 216 h. The results showed that the PCTPHP microspheres might play a vital role as drug carriers in cancer therapy. [ABSTRACT FROM AUTHOR]

Background: The human CISD2 gene is located within a longevity region mapped on chromosome 4q. In mice, Cisd2 levels decrease during natural aging and genetic studies have shown that a high level of Cisd2 prolongs mouse lifespan and healthspan. Here, we evaluate the feasibility of using a Cisd2 activator as an effective way of delaying aging. Methods: Hesperetin was identified as a promising Cisd2 activator by herb compound library screening. Hesperetin has no detectable toxicity based on in vitro and in vivo models. Naturally aged mice fed dietary hesperetin were used to investigate the effect of this Cisd2 activator on lifespan prolongation and the amelioration of age-related structural defects and functional decline. Tissue-specific Cisd2 knockout mice were used to study the Cisd2-dependent anti-aging effects of hesperetin. RNA sequencing was used to explore the biological effects of hesperetin on aging. Results: Three discoveries are pinpointed. Firstly, hesperetin, a promising Cisd2 activator, when orally administered late in life, enhances Cisd2 expression and prolongs healthspan in old mice. Secondly, hesperetin functions mainly in a Cisd2-dependent manner to ameliorate age-related metabolic decline, body composition changes, glucose dysregulation, and organ senescence. Finally, a youthful transcriptome pattern is regained after hesperetin treatment during old age. Conclusions: Our findings indicate that a Cisd2 activator, hesperetin, represents a promising and broadly effective translational approach to slowing down aging and promoting longevity via the activation of Cisd2. [ABSTRACT FROM AUTHOR]

Hesperidin and hesperetin are polyphenols that can be found predominantly in citrus fruits. They possess a variety of pharmacological properties such as neuroprotective and antidiabetic activity. However, the bioavailability of these compounds is limited due to low solubility and restricts their use as pro-healthy agents. This paper described the limitations resulting from the low bioavailability of the presented compounds and gathered the methods aiming at its improvement. Moreover, this work reviewed studies providing pieces of evidence for neuroprotective and antidiabetic properties of hesperidin and hesperetin as well as providing a detailed look into the significance of reported modes of action in chronic diseases. On account of a well-documented pro-healthy activity, it is important to look for ways to overcome the problem of poor bioavailability. [ABSTRACT FROM AUTHOR]

Hesperetin is a flavonoid compound naturally occurring in the peel of Citrus fruits from the Rutaceae family. Previous studies have demonstrated that hesperetin exhibits various pharmacological effects, such as anti-inflammatory, anti-tumor, antioxidative, anti-aging, and neuroprotective properties. In recent years, with the increasing prevalence of diseases and the rising awareness of traditional Chinese medicine, hesperetin has garnered growing attention for its wide-ranging pharmacological effects. To substantiate its health benefits and elucidate potential mechanisms, knowledge of pharmacokinetics is crucial. However, the limited solubility of hesperetin restricts its bioavailability, thereby diminishing its efficacy as a beneficial health agent. To enhance the bioavailability of hesperetin, various novel formulations have been developed, including nanoparticles, liposomes, and cyclodextrin inclusion complexes. This article reviews recent advances in the pharmacokinetics of hesperetin and methods to improve its bioavailability, as well as its pharmacological effects and mechanisms, aiming to provide a theoretical basis for clinical applications., Competing Interests: Declaration of competing interest No potential conflict of interest was reported by the authors., (Copyright © 2024. Published by Elsevier B.V.)

One of the ways Aflatoxin B1 damages the liver is through ferroptosis. Ferroptosis is characterized by the build-up of lipid peroxides and reactive oxygen species (ROS) due to an excess of iron. Dietary supplements have emerged as a promising strategy for treating ferroptosis in the liver. The flavonoid component hesperetin, which is mostly present in citrus fruits, has a number of pharmacological actions, such as those against liver fibrosis, cancer, and hyperglycemia. However, hesperetin's effects and mechanisms against hepatic ferroptosis are still unknown. In this study, 24 male C57BL/6 J mice were randomly assigned to CON, AFB1 (0.45 mg/kg/day), and AFB1+ hesperetin treatment groups (40 mg/kg/day). The results showed that hesperetin improved the structural damage of the mouse liver, down-regulated inflammatory factors (Cxcl1, Cxcl2, CD80, and F4/80), and alleviated liver fibrosis induced by aflatoxin B1. Hesperetin reduced hepatic lipid peroxidation induced by iron accumulation by up-regulating the levels of antioxidant enzymes (GPX4, GSH-Px, CAT, and T-AOC). It is worth noting that hesperetin not only improved lipid peroxidation but also maintained the dynamic balance of iron ions by reducing ferritin autophagy. Mechanistically, hesperetin's ability to regulate ferritin autophagy mostly depends on the PI3K/AKT/mTOR/ULK1 pathway. In AFB1-induced HepG2 cells, the addition of PI3K inhibitor (LY294002) and AKT inhibitor (Miransertib) confirmed that hesperetin regulated the PI3K/AKT/mTOR/ULK1 pathway to inhibit ferritin autophagy and reduced the degradation of ferritin in lysosomes. In summary, our results suggest that hesperetin not only regulates the antioxidant system but also inhibits AFB1-induced ferritin hyperautophagy, thereby reducing the accumulation of iron ions to mitigate lipid peroxidation. This work provides a fresh perspective on the mechanism behind hesperetin and AFB1-induced liver damage in mice., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Transmembrane protein 106B (TMEM106B), which is a type II transmembrane protein, is believed to be involved in intracellular dynamics and morphogenesis in the lysosome. TMEM106B is known to be a risk factor for frontotemporal lobar degeneration and has been recently identified as the receptor needed for the entry of SARS-CoV-2, independently of angiotensin-converting enzyme 2 (ACE2). A missense mutation, p.Asp252Asn, of TMEM106B is associated with hypomyelinating leukodystrophy 16 (HLD16), which is an oligodendroglial cell-related white matter disorder causing thin myelin sheaths or myelin deficiency in the central nervous system (CNS). However, it remains to be elucidated how the mutated TMEM106B affects oligodendroglial cells. Here, we show that the TMEM106B mutant protein fails to exhibit lysosome distribution in the FBD-102b cell line, an oligodendroglial precursor cell line undergoing differentiation. In contrast, wild-type TMEM106B was indeed localized in the lysosome. Cells harboring wild-type TMEM106B differentiated into ones with widespread membranes, whereas cells harboring mutated TMEM106B failed to differentiate. It is of note that the output of signaling through the lysosome-resident mechanistic target of rapamycin (mTOR) was greatly decreased in cells harboring mutated TMEM106B. Furthermore, treatment with hesperetin, a citrus flavonoid known as an activator of mTOR signaling, restored the molecular and cellular phenotypes induced by the TMEM106B mutant protein. These findings suggest the potential pathological mechanisms underlying HLD16 and their amelioration.

Nicosulfuron is a post-emergence herbicide used to control weeds while hesperetin found in citrus fruits has been reported to have anti-inflammatory, anti-cancer, and antioxidant properties. This study was designed to investigate the ameliorative properties of Hesperetin on Nicosulfuron-induced reproductive oxidative stress in male Wistar rats. Twenty-four male wistar rats weighing 200 ± 20g were assigned to different groups, each with six animals. Group A serves as the control group and were administered distilled water only. Group B received 25 mg/kg body weight (B.W.) Nicosulfuron. Group C were co-administered with 25 mg/kg B.W. Nicosulfuron and 100 mg/kg Hesperetin while animals in group D received 100 mg/kg B.W. Hesperetin. All treatment lasted for 14 days. An increase in the percentage of sperm with abnormal morphology (23.07%) in the group exposed to Nicosulfuron was observed. Sperm motility, testicular Ascorbic acid, reduced glutathione (GSH) levels were reduced significantly in the Nicosulfuron-treated group by 20.33%, 48.11%, and 41.10% respectively. Also, GST, Catalase, and SOD activities were significantly down-regulated in the Nicosulfuron-treated group. Furthermore, as compared to the control group, the Nicosulfuron-treated group had significantly higher activity of testicular acid phosphatase (ACP), alkaline phosphatase (ALP), MDA, and NO levels. However, co-treatment of Nicosulfuron and Hesperetin significantly ameliorated the Nicosulfuron-induced changes in sperm morphology, motility; testicular ascorbic acid, GSH, NO levels; SOD, CAT, GST, ALP, and ACP activities. The result from this study indicates that Hesperetin, due to its antioxidant properties, protects against testicular oxidative stress induced by Nicosulfuron exposure.

Hesperetin (HT) is a polyphenolic compound with anti-carcinogenic, tumor necrosis, and anti-oxidant properties. The present study reports the fabrication, optimization, and evaluation of HT-loaded nanosponges (HTN)- based gel (HTNG) for sustained anti-inflammatory effect. HTN formulation was prepared by quasi emulsion solvent diffusion method using a 42 factorial design. HTN was subjected to different solid and liquid state characterizations and subsequently loaded in carbopol gel. The effects of pro-inflammatory cytokines (IL- 1β and IL-6) were evaluated using RAW 264.7 macrophage cells, and the anti-inflammatory potential was tested in rats. Tiny, porous, and spherical HTN retarded the drug release (39.98%) up to 8 h compared to the pure drug (70.74%) and physical mixture (73.72%) and followed the Higuchi-matrix model. HTNG had a strong downregulating effect on cytokines. It showed no skin irritation and 18.52% skin permeation at 8 h. Further, HTNG-treated rats exhibited 33.16% inflammation inhibition compared to the control group. In conclusion, nanosponges significantly retarded the topical delivery and could circumvent the bioavailability issues associated with HT.

Alzheimer’s disease (AD) is characterized by excessive formation of beta-amyloid peptides (Aβ), mitochondrial dysfunction, enhanced production of reactive oxygen species (ROS), and altered glycolysis. Since the disease is currently not curable, preventive and supportive approaches are in the focus of science. Based on studies of promising single substances, the present study used a mixture (cocktail, SC) of compounds consisting of hesperetin (HstP), magnesium-orotate (MgOr), and folic acid (Fol), as well as the combination (KCC) of caffeine (Cof), kahweol (KW) and cafestol (CF). For all compounds, we showed positive results in SH-SY5Y-APP695 cells—a model of early AD. Thus, SH-SY5Y-APP695 cells were incubated with SC and the activity of the mitochondrial respiration chain complexes were measured, as well as levels of ATP, Aβ, ROS, lactate and pyruvate. Incubation of SH-SY5Y-APP695 cells with SC significantly increased the endogenous respiration of mitochondria and ATP levels, while Aβ1–40 levels were significantly decreased. Incubation with SC showed no significant effects on oxidative stress and glycolysis. In summary, this combination of compounds with proven effects on mitochondrial parameters has the potential to improve mitochondrial dysfunction in a cellular model of AD.

Type 1 diabetes mellitus (T1DM) was established to be ameliorated by islet transplantation, but the shortage of the transplanted human islet tissue and the use of immunosuppressive drugs to inhibit the rejection of allogeneic grafts make this type of therapy is limited. Nowadays, therapy with stem cells is one of the most promising future treatments. This kind of therapy could have a profound impact on both replacement, as well as regenerative therapies, to improve or even cure various disorders, including diabetes mellitus. Flavonoids have also been shown to possess anti-diabetic effects. Thus, this study aims to evaluate the effectiveness of the bone marrow-derived mesenchymal stem cells (BM-MSCs) and hesperetin in the treatment of a T1DM rat model. T1DM was induced in male Wistar rats that had been starved for 16 h via intraperitoneal injection of STZ at a dose of 40 mg/kg body weight (b.wt.). After 10 days of STZ injection, the diabetic rats were allocated into four groups. The first diabetic animal group was considered a diabetic control, while the other three diabetic animal groups were treated for six weeks, respectively, with hesperetin (given orally at a dose of 20 mg/kg b.wt.), BM-MSCs (injected intravenously at a dose of 1 × 106 cells/rat/week), and their combination (hesperetin and BM-MSCs). The use of hesperetin and BM-MSCs in the treatment of STZ-induced diabetic animals significantly improved the glycemic state, serum fructosamine, insulin and C-peptide levels, liver glycogen content, glycogen phosphorylase, glucose-6-phosphatase activities, hepatic oxidative stress, and mRNA expressions of NF-κB, IL-1β, IL-10, P53, and Bcl-2 in pancreatic tissue. The study suggested the therapy with both hesperetin and BM-MSCs produced marked antihyperglycemic effects, which may be mediated via their potencies to ameliorate pancreatic islet architecture and insulin secretory response, as well as to decrease hepatic glucose output in diabetic animals. The improvement effects of hesperetin and BM-MSCs on the pancreatic islets of diabetic rats may be mediated via their antioxidant, anti-inflammatory, and antiapoptotic actions.

Colon cancer is a major cause of cancer-related death, with significantly increasing rates of incidence worldwide. The current study was designed to evaluate the anti-carcinogenic effects of hesperetin (HES) alone and in combination with capecitabine (CAP) on 1,2 dimethylhydrazine (DMH)-induced colon carcinogenesis in Wistar rats. The rats were given DMH at 20 mg/kg body weight (b.w.)/week for 12 weeks and were orally treated with HES (25 mg/kg b.w.) and/or CAP (200 mg/kg b.w.) every other day for 8 weeks. The DMH-administered rats exhibited colon-mucosal hyperplastic polyps, the formation of new glandular units and cancerous epithelial cells. These histological changes were associated with the significant upregulation of colon Ki67 expression and the elevation of the tumor marker, carcinoembryonic antigen (CEA), in the sera. The treatment of the DMH-administered rats with HES and/or CAP prevented these histological cancerous changes concomitantly with the decrease in colon-Ki67 expression and serum-CEA levels. The results also indicated that the treatments with HES and/or CAP showed a significant reduction in the serum levels of lipid peroxides, an elevation in the serum levels of reduced glutathione, and the enhancement of the activities of colon-tissue superoxide dismutase, glutathione reductase and glutathione-S-transferase. Additionally, the results showed an increase in the mRNA expressions of the anti-inflammatory cytokine, IL-4, as well as the proapoptotic protein, p53, in the colon tissues of the DMH-administered rats treated with HES and/or CAP. The TGF-β1 decreased significantly in the DMH-administered rats and this effect was counteracted by the treatments with HES and/or CAP. Based on these findings, it can be suggested that both HES and CAP, singly or in combination, have the potential to exert chemopreventive effects against DMH-induced colon carcinogenesis via the suppression of oxidative stress, the stimulation of the antioxidant defense system, the attenuation of inflammatory effects, the reduction in cell proliferation and the enhancement of apoptosis.

Hesperidin is a flavanone abundantly found in citrus fruits for which health beneficial effects have been reported. However, hesperidin shows a low bioavailability among individuals. The aim of this study was to evaluate the effects of the micronization process and 2R- and 2S-hesperidin diastereoisomers ratio on hesperidin bioavailability. In a first phase, thirty healthy individuals consumed 500 mL of orange juice with 345 mg of hesperidin, and the levels of hesperidin metabolites excreted in urine were determined. In the second phase, fifteen individuals with intermediate hesperidin metabolite levels excreted in urine were randomized in a crossover, postprandial and double-blind intervention study. Participants consumed 500 mg of the hesperidin-supplemented Hesperidin epimeric mixture (HEM), the micronized Hesperidin epimeric mixture (MHEM) and micronized 2S-Hesperidin (M2SH) in each study visit with 1 week of washout. Hesperidin metabolites and catabolites were determined in blood and urine obtained at different timepoints over a 24 h period. The bioavailability—relative urinary hesperidin excretion (% of hesperidin ingested)—of M2SH (70 ± 14%) formed mainly by 2S-diastereoisomer was significantly higher than the bioavailability of the MHEM (55 ± 15%) and HEM (43 ± 8.0%), which consisted of a mixture of both hesperidin diastereoisomers. Relative urinary excretion of hesperidin metabolites for MHEM (9.2 ± 1.6%) was significantly higher compared to the HEM (5.2 ± 0.81%) and M2SH (3.6 ± 1.0%). In conclusion, the bioavailability of 2S-hesperidin extract was higher compared to the standard mixture of 2S-/2R-hesperidin extract due to a greater formation of hesperidin catabolites. Furthermore, the micronization process increased hesperidin bioavailability. [ABSTRACT FROM AUTHOR]

Objective: In this study, it was aimed to investigate the effects of hesperetin on renal transforming growth factor-beta 1 (TGF-β1) expression and apoptosis in rat lipopolysaccharide (LPS)-induced acute renal injury model. Methods: In the study, 18 adult male Wistar albino rats were used. Rats divided into three groups, respectively (n=6); control, LPS and LPS + hesperetin. Sepsis model was created with a singledose of LPS (Escherichia coli, O26: B6 serotype, Sigma-aldrich). LPS + hesperetin group was administered intragastrically with the aid of hesperetin oral gavage at a dose of 100 mg/kg, after LPS-induction. Twenty four hours after LPS administration, the rats were opened from the midline under ketamine-xylazine anesthesia and kidney tissue and cardiac blood were collected. Kidney tissue was examined with hematoxylin-eosin staining. TGF-β1 expression was determined by indirect immunohistochemical method. TUNEL method was used to determine renal apoptosis. Blood urea nitrogen (BUN) and creatinine levels in blood serum were determined using spectrophotometric methods. Results: Decreased histopathological changes, TGF-β1 expression and apoptosis were determined in the LPS + hesperetin group compared to the LPS group (p<0.05). In addition, a significant decrease in BUN and creatinine levels was observed in the LPS + hesperetin group compared to the LPS group (p<0.05). Conclusion: The data obtained show that in the LPS-induced rat sepsis model, hesperetin suppresses the expression of TGF-β1 in kidney tissue and provides a protective effect. [ABSTRACT FROM AUTHOR]

Oligodendrocytes (oligodendroglial cells) are glial cells that wrap neuronal axons with their differentiated plasma membranes called myelin membranes. In the pathogenesis of inflammatory cytokine-related oligodendroglial cell and myelin diseases such as multiple sclerosis (MS), typical inflammatory cytokines tumor necrosis factor α (TNFα) and interleukin-6 (IL-6) are thought to contribute to the degeneration and/or progression of the degeneration of oligodendroglial cells and, in turn, the degeneration of naked neuronal cells in the central nervous system (CNS) tissues. Despite the known involvement of these inflammatory cytokines in disease progression, it has remained unclear whether and how TNFα or IL-6 affects the oligodendroglial cells themselves or indirectly. Here we show that TNFα or IL-6 directly inhibits morphological differentiation in FBD-102b cells, which are differentiation models of oligodendroglial cells. Their phenotype changes were supported by the decreased expression levels of oligodendroglial cell differentiation and myelin marker proteins. In addition, TNFα or IL-6 decreased phosphorylation levels of Akt kinase, whose upregulation has been associated with promoting oligodendroglial cell differentiation. Hesperetin, a flavonoid mainly contained in citrus fruit, is known to have neuroprotective effects. Hesperetin might also be able to resolve pre-illness conditions, including the irregulated secretion of cytokines, through diet. Notably, the addition of hesperetin into cells recovered TNFα- or IL-6-induced inhibition of differentiation, as supported by increased levels of marker protein expression and phosphorylation of Akt kinase. These results suggest that TNFα or IL-6 itself contributes to the inhibitory effects on the morphological differentiation of oligodendroglial cells, possibly providing information not only on their underlying pathological effects but also on flavonoids with potential therapeutic effects at the molecular and cellular levels. [ABSTRACT FROM AUTHOR]

This study examined the effects of phase II metabolism and efflux transportation on the bioavailability of naringin, hesperidin, and their aglycones (naringenin and hesperetin) in rats. Results indicated naringin and hesperidin have a lower oral bioavailability than their aglycones. Of all the phase II enzymes tested, UDP-glucuronosyltransferase (UGT) 1A1, UGT1A2, UGT1A3, UGT1A7 and SULT sulfotransferase (SULT) 1B1 were of minor importance regarding the phase II metabolism of naringenin and hesperetin in the small intestine. Naringin, hesperidin, and their aglycones were all extensively metabolised in the liver. Naringin and hesperidin were more extensively transported by efflux transporters compared to their aglycones. Significant correlations between phase II enzymes and efflux transporters were detected. In conclusion, more extensive metabolism of naringin and hesperidin than their aglycones in the small intestine, and the interplay of phase II enzymes and efflux transporters in the small intestine explain the lower relative oral bioavailability of naringin and hesperidin than their aglycones. [ABSTRACT FROM AUTHOR]

Neurodegenerative disorders affect more than fifty million Americans each year and represent serious health threats as the population ages. Neuroinflammation and oxidative stress are critical in the onset, progression, and pathogenesis of neurodegenerative diseases such as Alzheimer's (AD), Parkinson's (PD), and amyotrophic lateral sclerosis (ALS). A wide range of natural compounds has been investigated because of their antioxidant, anti-inflammatory, and neuroprotective properties. The citrus flavonoid hesperetin (HPT), an aglycone of hesperidin found in oranges, mandarins, and lemons, has been extensively reported to exert neuroprotective effects in experimental models of neurogenerative diseases. This review has compiled multiple studies on HPT in both in vivo and in vitro models to study neurodegeneration. We focused on the modulatory effects of hesperetin on the release of cellular anti-inflammatory and antioxidative stress mediators. Additionally, this review discusses the hesperetin effect in maintaining the levels of microRNA (miRNA) and modulating autophagy as it relates to hesperetin's protective mechanisms against neurodegeneration. Moreover, this review is focused on providing experimental data for hesperetin's potential as a neuroprotective compound and discusses reported evidence that HPT crosses the blood–brain barrier. In summary, this review shows the evidence available in the literature to indicate the efficacy of hesperetin in delaying the onset of neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Flavonoids are natural phytochemicals that have therapeutic effects and act in the prevention of several pathologies. These phytochemicals can be found in seeds, grains, tea, coffee, wine, chocolate, cocoa, vegetables and, mainly, in citrus fruits. Neohesperidin, hesperidin and hesperetin are citrus flavonoids from the flavanones subclass that have anti-inflammatory and antioxidant potential. Neohesperidin, in the form of neohesperidin dihydrochalcone (NHDC), also has dietary properties as a sweetener. In general, these flavanones have been investigated as a strategy to control bone diseases, such as osteoporosis and osteoarthritis. In this literature review, we compiled studies that investigated the effects of neohesperidin, hesperidin and its aglycone, hesperetin, on bone health. In vitro studies showed that these flavanones exerted an antiosteoclastic and anti- inflammatory effects, inhibiting the expression of osteoclastic markers and reducing the levels of reactive oxygen species, proinflammatory cytokines and matrix metalloproteinase levels. Similarly, such studies favored the osteogenic potential of preosteoblastic cells and induced the overexpression of osteogenic markers. In vivo, these flavanones favored the regeneration of bone defects and minimized inflammation in arthritis- and periodontitis-induced models. Additionally, they exerted a significant anticatabolic effect in ovariectomy models, reducing trabecular bone loss and increasing bone mineral density. Although research should advance to the clinical field, these flavanones may have therapeutic potential for controlling the progression of metabolic, autoimmune or inflammatory bone diseases. [ABSTRACT FROM AUTHOR]

Nitrite and amine reactions can occur rapidly and produce nitrosamines, in-vivo. Diethylnitrosamine (DEN) and phenobarbital (PB) are readily inducing liver injury and hesperetin (HES), as a flavonoid found in citrus fruits, have the potential to compensate for their harmful effects. In this study, the therapeutic effects of HES were evaluated in DEN and PB mediated liver defect. Adult male Sprague-Dawley rats were split into 5 groups (n=10): Control, DEN, DEN+PB, HES, and DEN+PB+HES. 150 mg/kg DEN was applied intraperitoneally to DEN groups. Fifteen days after the DEN application 500ppm of PB was given in drinking water. HES were administered at 50 mg/kg dose orally for 8 weeks. Blood and liver malondialdehyde (MDA), glutathione (GSH) levels, and catalase (CAT), superoxide dismutase (SOD) activities were measured spectrophotometrically. Moreover, histologic examination of liver sections and apoptosis were determined with hematoxylin-eosin and TUNEL methods, respectively. DEN-PB application was found to increase blood and liver MDA levels and liver CAT activity, oppositely, decreased blood and liver SOD activity, GSH levels, and blood CAT activity. HES was found to have a positive impact on oxidative stress parameters by decreasing liver and blood MDA activity, increasing blood CAT and SOD activity together with liver GSH levels and SOD activity. Whereas DEN and PB application increased all histopathological findings and TUNEL positive cells, HES administration decreased these findings which might be important for the protection of liver cell structure from cell damage. These results suggest that HES administration could be an alternative therapeutic approach to liver damage. [ABSTRACT FROM AUTHOR]

Intracellular reactive oxygen species (ROS) play an important role in cancer stem cell (CSC) function. Hesperetin (Hst) is a flavonoid that has been shown to affect cellular ROS level. The goal of this study was to investigate the effect of Hst on the level of ROS in gastric CSCs (GCSCs). MTT assay was used to evaluate cell survival. Cellular ROS level was measured using 2′,7′-dichlorofluorescin diacetate by flow cytometry. A significant decrease in the survival of GCSCs treated with Hst was observed. Hst decreased ROS level to about 47% and 40% at concentrations of 200 and 400 mM, respectively. It can be concluded that Hst reduces the survival and ROS level of GCSCs and may be influences the function of these cells such as proliferation and differentiation as well as response to chemotherapy by affecting cellular ROS level. [ABSTRACT FROM AUTHOR]

This study aimed at obtaining hesperidin (Hed) and hesperetin (Het) systems with HP-β-CD by means of the solvent evaporation method. The produced systems were identified using infrared spectroscopy (FT-IR), X-ray powder diffraction (XRPD), and differential scanning calorimetry (DSC). Moreover, in silico docking and molecular dynamics studies were performed to assess the most preferable site of interactions between tested compounds and HP-β-CD. The changes of physicochemical properties (solubility, dissolution rate, and permeability) were determined chromatographically. The impact of modification on biological activity was tested in an antioxidant study as well as with regards to inhibition of enzymes important in pathogenesis of neurodegenerative diseases. The results indicated improvement in solubility over 1000 and 2000 times for Hed and Het, respectively. Permeability studies revealed that Hed has difficulties in crossing biological membranes, in contrast with Het, which can be considered to be well absorbed. The improved physicochemical properties influenced the biological activity in a positive manner by the increase in inhibitory activity on the DPPH radical and cholinoesterases. To conclude the use of HP-β-CD as a carrier in the formation of an amorphous inclusion complex seems to be a promising approach to improve the biological activity and bioavailability of Hed and Het. [ABSTRACT FROM AUTHOR]

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Background: Chronic obstructive pulmonary disease (COPD) is an important risk factor for developing lung cancer. Aged citrus peel (chenpi) has been used as a dietary supplement for respiratory diseases in China. Objective: To explore the mechanism and candidate compounds of chenpi preventing COPD and its progression to lung cancer. Methods: The active components and potential targets of chenpi were retrieved from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database. Disease-associated targets of COPD and lung cancer were collected in the Gene Cards and TTD database. The component-target network and PPI network were constructed using the Cytoscape 3.8.0 software. David database was used for GO and KEGG enrichment analysis. The main active components were verified by using the autodock Vina 1.1.2 software. Mouse lung cancer with COPD was induced by cigarette smoking (CS) combined with urethane injection to confirm preventing the effect of hesperetin (the candidate compound of chenpi) on COPD progression to lung cancer and its underlying mechanisms. Results: The network analysis revealed that the key active components of chenpi (nobiletin, naringenin, hesperetin) regulate five core targets (AKT1, TP53, IL6, VEGFA, MMP9). In addition, 103 potential pathways of chenpi were identified. Chenpi can prevent COPD and its progression to lung cancer by getting involved in the PI3K-Akt signaling pathway and MAPK signaling pathway. Molecular docking indicated that hesperetin had better binding activity for core targets. In mouse lung cancer with COPD, treatment with hesperetin dose-dependently improved not only lung tissue injury in COPD but also carcinoma lesions in lung cancer. Meanwhile, hesperetin could suppress the protein expression of AKT1, IL6, VEGFA, MMP9 and up-regulate the protein expression of TP53, and thus reduced the risk of COPD progression to lung cancer. Conclusion: Hesperetin is a candidate compound of chenpi that helps in preventing COPD and its progression to lung cancer by regulating AKT1, IL6, VEGFA, MMP9 and TP53.

Antiviral and non-toxic effects of silver nanoparticles onto in vitro cells infected with coronavirus were evaluated in this study using High-Resolution Magic-Angle Spinning Nuclear Magnetic Resonance (HR-MAS NMR) spectroscopy. Silver nanoparticles were designed and synthesized using an orange flavonoid—hesperetin (HST)—for reduction of silver(I) and stabilization of as obtained nanoparticles. The bio-inspired process is a simple, clean, and sustainable way to synthesize biogenic silver nanoparticles (AgNP@HST) with diameters of ∼20 nm and low zeta potential (−40 mV), with great colloidal stability monitored for 2 years. The nanoparticles were used for the fabrication of two types of antiviral materials: colloids (AgNP@HST spray) and 3D flexible nanostructured composites. The composites, decorated with AgNP@HST (0.05 mmol L−1), were made using cellulose nanofibers (CNF) obtained from orange peel and graphene oxide (GO), being denominated CNF@GO@AgNP@HST. Both materials showed high virucidal activity against coronaviruses in cell infection in vitro models and successfully inhibited the viral activity in cells. HR-MAS 1H-NMR technique was used for determining nanomaterials’ effects on living cells and their influences on metabolic pathways, as well as to study viral effects on cells. It was proven that none of the manufactured materials showed toxicity towards the intact cells used. Furthermore, viral infection was reverted when cells, infected with the coronavirus, were treated using the as-fabricated nanomaterials. These significant results open possibilities for antiviral application of 3D flexible nanostructured composite such as packaging papers and filters for facial masks, while the colloidal AgNP@HST spray can be used for disinfecting surfaces, as well as a nasal, mouth, and eye spray.

Diabetes is a metabolic disease that is mainly characterized by hyperglycemia. The present work investigated the efficacy of the flavanones hesperetin (HES) and quercetin (Q) extracted from Trifolium alexandrinum (TA) to treat type 2 diabetic rats. Wistar albino rats were supplemented with a high fat diet (HFD) for 2 weeks and then administered streptozotocin to induce diabetes. Diabetic rats were orally treated with Q, HES, and TA extract at concentrations of 40, 50, and 200 mg/kg BW, respectively, for 4 weeks. Various biochemical, molecular, and histological analysis were performed to evaluate the antidiabetic effects of these treatments. Q, HES, and TA extract treatments all significantly improved diabetic rats’ levels of serum glucose, insulin, glucagon, liver function enzymes, hepatic glycogen, α-amylase, lipase enzymes, lipid profiles, oxidative stress indicators, and antioxidant enzymes as compared with control diabetic untreated rats. In addition, supplementation with Q, HES, and TA extract attenuated the activities of glucose-6-phosphate; fructose-1,6-bisphospahate; 6-phosphogluconate dehydrogenase; glucose-6-phosphate dehydrogenase; glucokinase; and hexokinase in pancreatic tissue, and they improved the levels of glucose transporter 2 and glucose transporter 4. Furthermore, these treatments modulated the expressions levels of insulin receptor (IR), phosphoinositide 3-kinase (PI3K), AMP-activated protein kinase (AMPK), caspase-3, and interleukin-1β (IL-1β). Enhancement of the histological alterations in pancreatic tissues provided further evidence of the ability of Q, HES, and TA extract to exert antidiabetic effects. Q, HES, and TA extract remedied insulin resistance by altering the IR/PI3K and AMPK signaling pathways, and they attenuated type 2 diabetes by improving the antioxidant defense system.