Liver fibrosis, a chronic inflammatory healing reaction, progresses to hepatocirrhosis without effective intervention. Hesperetin derivative (HD-16), a monomer compound derived from hesperitin, ...exerts anti-inflammatory and hepatoprotective effects against a spectrum of liver diseases. However, the anti-fibrotic potential of HD-16 in liver fibrosis and its underlying mechanism have not yet been elucidated. In this study, we investigated the anti-fibrotic effect of HD-16 on mouse liver fibrosis induced by CCl
and on LX-2 cells (human immortalized HSCs) stimulated by TGF-β1, in vivo and in vitro. HD-16 exerted an anti-fibrotic effect via regulation of the AMPK/SIRT3 pathway. Pharmacodynamic results showed that HD-16 alleviated the degree of injury and inflammation in CCl
-induced mouse liver fibrosis. Consistently, HD-16 also effectively inhibited the expression of α-SMA, Col1α1, Col3α1, and TIMP-1 in TGF-β1-activated LX-2 cells. Mechanistically, HD-16 promoted SIRT3 expression and activity in fibrotic liver and activated LX-2 cells. Furthermore, SIRT3 depletion attenuated the anti-fibrotic effects of HD-16. Intriguingly, HD-16 increased AMPK phosphorylation, whereas inhibition of SIRT3 expression did not affect AMPK phosphorylation. In contrast, AMPK silencing suppressed SIRT3 expression, suggesting that SIRT3 is a downstream target of AMPK in liver fibrosis. Overall, HD-16 attenuated CCl
-induced liver inflammation and fibrosis by activating the AMPK/SIRT3 pathway, and HD-16 may be a potential anti-fibrotic compound in the treatment of liver fibrosis.
Hesperidin belongs to flavanones class of flavonoids and is known to possess broad-spectrum applicability to prevent dreadful diseases such as cardiovascular disease, neurodegeneration, and cancer. ...The reported anticancer effects of hesperidin have been found to be associated with its anti-oxidant and anti-inflammatory activities. Hesperidin interacts with numerous recognized cellular targets and inhibits cancer cell proliferation by inducing apoptosis and cell cycle arrest. In addition, evidence has suggested its promising role in inhibiting tumor cell metastasis, angiogenesis, and chemoresistance. The present mini-review highlights the ongoing development to identify hesperidin targets in cancer. Furthermore, the potential of nano technology-based hesperidin combinations and delivery systems will also be discussed. Overall, this review highlights all the possible molecular targets affected by hesperidin in tumor cells on a single platform.
Impact statement
Experimental findings from numerous studies have demonstrated the anticancer effects of hesperidin (Hesp) to be associated with anti-oxidant and anti-inflammatory activities along with its potential role in inhibiting the tumor cell metastasis and angiogenesis. Additionally, Hesp can also reverse drug resistance of cancer cells, which make it a promising candidate to be used in combination with existing anti-cancer drugs. This review will be helpful for upcoming researchers and scientific community to find out complete capsular package about cancer drug targets of Hesp and its role in modulating various important hallmarks of cancer.
Hesperidin, a secondary orange (
) metabolite, was extracted from orange bagasse. No organic solvents or additional energy consumption were used in the clean and sustainable process. Hesperidin ...purity was approximately 98% and had a yield of 1%. Hesperidin is a known supplement due to antioxidant, chelating, and anti-ageing properties. Herein, hesperidin application to eliminate dark eye circles, which are sensitive and thin skin regions, was studied. In addition, the proposed method for its aqueous extraction was especially important for human consumption. Further, the most effective methods for hesperidin nanonization were explored, after which the nanoemulsions were incorporated into a cream formulation that was formulated for a tropical climate. Silky cream formulations (oil in water) were tested in vitro on artificial 3D skin from cultured cells extracted from skin residues after plastic surgery. The proposed in vitro assay avoided tests of the different formulations in human volunteers and animals. It was shown that one of the nanonized hesperidin formulations was the most skin-friendly and might be used in cosmetics.
Melanoma, characterized as the most aggressive and metastatic form of skin cancer, currently has limited treatment options, predominantly chemotherapy and radiation therapy. However, the drawbacks ...associated with parenterally administered chemotherapy underscore the urgent need for alternative compounds to combat melanoma effectively. Hesperidin (HES), a flavonoid present in various citrus fruits, exhibits promising anticancer activity. Nevertheless, the clinical utility of HES is hindered by challenges such as poor water solubility, a short half-life, and low oral bioavailability. In response to these limitations, we introduced a novel approach by formulating HES-loaded exosomes (Exo-HES). Isolation of exosomes was achieved through the ultracentrifugation method, and HES was efficiently loaded using the sonication method. The resulting formulations displayed a desirable particle size (∼106 nm) and exhibited a spherical morphology, as confirmed by scanning electron and atomic force microscopy. In vitro studies conducted on B16F10 cell lines demonstrated higher cytotoxicity of Exo-HES compared to free HES, supported by enhanced cellular uptake validated through coumarin-6-loaded exosomes. This superior cytotoxicity was further evidenced by DNA fragmentation, increased generation of free radicals (ROS), loss of mitochondrial membrane potential, and effective inhibition of colony formation. The antimetastatic properties of Exo-HES were confirmed through wound healing and transwell migration assays. Oral pharmacokinetics studies revealed a remarkable increase of approximately 2.5 times in oral bioavailability and half-life of HES when loaded into exosomes. Subsequent in vivo experiments utilizing a B16F10-induced melanoma model in Swiss mice established that Exo-HES exhibited superior anticancer activity compared to HES after oral administration. Importantly, no biochemical, hematological, or histological toxicities were observed in tumor-bearing mice treated with Exo-HES. These findings suggest that exosomes loaded with HES represent a promising nanocarrier strategy to enhance the therapeutic effectiveness of hesperidin in melanoma treatment.
Scope
The aim of the present work is to determine new biomarkers of the biological effects of hesperidin in orange juice (OJ) applying a non‐targeted metabolomics approach validated by targeted ...metabolomics analyses of compliance biomarkers.
Methods and Results
Plasma/serum and urine targeted (HPLC‐MS/MS) and untargeted (1H‐NMR) metabolomics signatures are explored in a subsample with pre‐ and stage‐1 hypertension subjects of the CITRUS study (N = 159). Volunteers received 500 mL day−1 of control drink, OJ, or hesperidin‐enriched OJ (EOJ) for 12‐weeks. A 6‐h postprandrial study is performed at baseline. Targeted analyses reveals plasma and urine hesperetin 7‐O‐β‐d‐glucuronide as the only metabolite differing between OJ and EOJ groups after 12‐weeks consumption, and in urine is correlated with a decreased systolic blood pressure level. The non‐targeted approach shows that after single dose and 12‐weeks consumption of OJ and EOJ change several metabolites related with an anti‐inflammatory and antioxidant actions, lower blood pressure levels and uremic toxins.
Conclusions
Hesperetin 7‐O‐β‐d‐glucuronide can be a candidate marker for distinguishing between the consumption of different hesperidin doses at 12‐weeks consumption as well as a potential agent mediating blood pressure reduction. Moreover, changes in different endogenous metabolites can explain the mechanisms of action and the biological effects of hesperidin consumption.
The aim of the present work is to determine new biomarkers of the biological effects of hesperidin in orange juice. The present study demonstrates that hesperetin 7‐O‐β‐d‐glucuronide can be a candidate marker for differentiating different hesperidin doses as well as a potential metabolite related with blood pressure reduction. Moreover, changes in different endogenous metabolites can explain the mechanisms of action and the biological effects of hesperidin consumption.
Neutrophil infiltration, pro-inflammatory cytokines, and reactive oxygen species (ROS) production have been implicated in development and progression of ulcerative colitis (UC), an inflammatory bowel ...disease (IBD) characterized by ulcerating inflammation of the mucosal layer generally restricted to the colon. The side effects, safety and human intolerance are limitations of the currently approved treatments for UC. Hesperidin methyl chalcone (HMC) is a flavonoid used to treat chronic venous disease, which shows anti-inflammatory, analgesic, and antioxidant properties in pre-clinical studies, however, its effects on colitis have never been described. Therefore, we aimed to evaluate the protective effects of HMC in a mouse model of acetic acid-induced colitis. Treatment with HMC significantly reduced neutrophil infiltration, edema, colon shortening, macro and microscopic damages induced by intracolonic administration of acetic acid. The improvement of colitis after HMC treatment is related to the increase in colon antioxidant status, and the inhibition of pro-inflammatory cytokines TNF-α, IL-6, IL-1β, and IL-33 in the colon. We observed, moreover, that HMC inhibited NF-κB activation in the colon, which might explain the reduction of the cytokines we observed. Finally, these results demonstrate a novel applicability of HMC to increase antioxidant response and reduce inflammation during acetic acid-induced colitis suggesting it as a promising therapeutic approach for the treatment of ulcerative colitis.
•Methylation of hesperidin produces hesperidin methyl chalcone (HMC).•HMC inhibited neutrophil infiltration, edema and colon shortening in mouse colitis.•HMC also inhibited macroscopic and microscopic damages in colitis.•HMC reduced oxidative stress, cytokine production and NF-κB activation.•This is the first study demonstrating that HMC treats experimental ulcerative colitis.
The benefits of the Mediterranean diet for protecting against many diseases are usually attributed to high consumption of certain foods, characterized by the presence of bioactive substances such as ...polyphenols. Inflammation plays an important role in the pathogenesis of numerous diseases such as arthritis, allergies or neurodegenerative disorders. Dietary polyphenols constitute a large family of bioactive substances with potential beneficial effects against a broad group of diseases. Citrus fruits and juices are a rich source of vitamin C and flavonoids, with a potential effect on the inflammatory response.
The aim was to evidence the potential anti-inflammatory effects of the flavonoids hesperidin for its possible therapeutic application against diverse pathologies.
In the present review, available literature about the anti-inflammatory effects of hesperidin is reported and discussed. Moreover, we also discuss the chemistry, bioavailability and proposed mechanisms of action of hesperidin.
Hesperidin is a flavonoid present in high concentration in citrus species and has numerous biological properties, principally antioxidant and anti-inflammatory. Several studies have been performed in order to evaluate the effects of hesperidin as anti-inflammatory agent using cellular and animal models and few clinical trials. Hesperidin treatment decreased inflammatory mediators and exerted significant antioxidant effects. The molecular basis for its anti-inflammatory effects seems to be mediated by signalling pathways especially the nuclear factor κβ pathway.
Although hesperidin evidenced anti-inflammatory effects, the specific mechanism of action is not completely known and additional studies are required for elucidation of the molecular targets.
SARS-CoV-2 or COVID-19 is representing the major global burden that implicated more than 4.7 million infected cases and 310 thousand deaths worldwide in less than 6 months. The prevalence of this ...pandemic disease is expected to rise every day. The challenge is to control its rapid spread meanwhile looking for a specific treatment to improve patient outcomes. Hesperidin is a classical herbal medicine used worldwide for a long time with an excellent safety profile. Hesperidin is a well-known herbal medication used as an antioxidant and anti-inflammatory agent. Available shreds of evidence support the promising use of hesperidin in prophylaxis and treatment of COVID 19. Herein, we discuss the possible prophylactic and treatment mechanisms of hesperidin based on previous and recent findings. Hesperidin can block coronavirus from entering host cells through ACE2 receptors which can prevent the infection. Anti-viral activity of hesperidin might constitute a treatment option for COVID-19 through improving host cellular immunity against infection and its good anti-inflammatory activity may help in controlling cytokine storm. Hesperidin mixture with diosmin co-administrated with heparin protect against venous thromboembolism which may prevent disease progression. Based on that, hesperidin might be used as a meaningful prophylactic agent and a promising adjuvant treatment option against SARS-CoV-2 infection.
SCOPE: Hesperetin‐7‐O‐rutinoside (hesperidin) reduces blood pressure in healthy volunteers but its intestinal absorption and metabolism are not fully understood. Therefore, we aimed to determine ...sites of absorption and metabolism of dietary flavanone glycosides in humans. METHODS AND RESULTS: Using a single‐blind, randomized crossover design, we perfused equimolar amounts of hesperetin‐7‐O‐rutinoside and hesperetin‐7‐O‐glucoside directly into the proximal jejunum of healthy volunteers. We assessed the appearance of metabolites in the perfusate, blood and urine, to determine the sites of metabolism and excretion, and compared this to oral administration. The glucoside was rapidly hydrolyzed by brush border enzymes without any contribution from pancreatic, stomach, or other secreted enzymes, or from bacterial enzymes. Only ∼3% of the dose was recovered intact in the perfusate, indicating high absorption. A proportion was effluxed directly back into the perfused segment mainly in the form of hesperetin‐3′‐O‐sulfate. In contrast, very little hydrolysis or absorption of hesperetin‐7‐O‐rutinoside was observed with ∼80% recovered in the perfusate, no hesperetin metabolites were detected in blood and only traces were excreted in urine. CONCLUSION: The data elucidate the pathways of metabolism of dietary hesperidin in vivo and will facilitate better design of mechanistic studies both in vivo and in vitro.
Citrus sinensis contains glycoside hesperetin-7-rhamnoglucoside (hesperidin) which harbor an array of therapeutic potentials including antioxidant, anticancer, and anti-inflammatory. However, a ...systematic examination of safety is needed before its utilization. Hence, the present investigation is aimed to evaluate acute and sub-chronic toxicity of hesperidin isolated from the citrus fruit. Hesperidin (73%) was isolated from a methanolic extract of dried peel of the citrus fruit, characterized using FTIR, and standardized by HPLC. Its acute oral toxicity (AOT) and sub-chronic toxicity studies were carried out in Sprague-Dawley rats. Hesperidin (5000 mg/kg) showed 10% mortality in AOT. In sub-chronic toxicity study, hesperidin (250 and 500 mg/kg) did not induce any abnormalities in body weight, food consumption, clinical signs, ophthalmological and neurological observations, urine analysis, hematology, clinical chemistry, organ weights, and gross pathology. However, hesperidin (1000 mg/kg) showed significant (p < 0.05) alterations in body and organ weights, hematology, clinical chemistry, and tissue histopathology. To conclude, hesperidin has median lethal dose (LD50) of 4837.5 mg/kg, and Low Observed Adverse Effect Level (LOAEL) at 1000 mg/kg for both male and female Sprague-Dawley rats. Thus, hesperidin isolated from citrus fruit showed a good safety profile in animal study.
•Hesperetin-7-rhamnoglucoside (Hesperidin) was isolated and standardized from citrus fruit.•In acute oral toxicity (AOT), hesperidin showed median lethal dose (LD50) of 4837.5 mg/kg.•In 90 days sub-chronic toxicity, low observed adverse effect level was 1000 mg/kg.•Hesperidin showed a good safety profile in the animal toxicological evaluation.
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