Inflammation and oxidative stress are two major causes of various life-threatening diseases. Hesperidin (Hsd) and its aglycone, hesperetin (Hst), are two flavonoids from citrus species that have numerous biological properties, particularly antioxidant and anti-inflammatory. New findings showed that the antioxidant activity of Hsd/Hst was not only limited to its radical scavenging activity, but it augmented the antioxidant cellular defenses via the ERK/Nrf2 signaling pathway as well. Various in vitro and in vivo studies have been conducted to evaluate Hsd, its metabolites, or its synthetic derivatives at reducing inflammatory targets including NF-κB, iNOS, and COX-2, and the markers of chronic inflammation. In this review, new findings regarding the molecular targets of Hsd and Hst in the reduction of oxidative stress are discussed. Also, in the anti-inflammatory section, we provide a summary of significant investigations concerning the mechanisms of action based on the studied inflammation models.

Antioxidant and anti-inflammatory properties of the citrus flavonoids hesperidin and hesperetin: an updated review of their molecular mechanisms and experimental models.

Flavonoids are a family of polyphenolic compounds which are widespread in nature (vegetables) and are consumed as part of the human diet in significant amounts. There are other types of polyphenols, including, for example, tannins and resveratrol. Flavonoids and related polyphenolic compounds have significant antiinflammatory activity, among others. This short review summarizes the current knowledge on the effects of flavonoids and related polyphenolic compounds on inflammation, with a focus on structural requirements, the mechanisms involved, and pharmacokinetic considerations. Different molecular (cyclooxygenase, lipoxygenase) and cellular targets (macrophages, lymphocytes, epithelial cells, endothelium) have been identified. In addition, many flavonoids display significant antioxidant/radical scavenging properties. There is substantial structural variation in these compounds, which is bound to have an impact on their biological profile, and specifically on their effects on inflammatory conditions. However, in general terms there is substantial consistency in the effects of these compounds despite considerable structural variations. The mechanisms have been studied mainly in myeloid cells, where the predominant effect is an inhibition of NF-κB signaling and the downregulation of the expression of proinflammatory markers. At present there is a gap in knowledge of in vitro and in vivo effects, although the pharmacokinetics of flavonoids has advanced considerably in the last decade. Many flavonoids have been studied for their intestinal antiinflammatory activity which is only logical, since the gastrointestinal tract is naturally exposed to them. However, their potential therapeutic application in inflammation is not restricted to this organ and extends to other sites and conditions, including arthritis, asthma, encephalomyelitis, and atherosclerosis, among others.

Effects of Flavonoids and other Polyphenols on Inflammation

Natural bioactive compounds of Citrus limon for food and health

Chronic unpredictable mild stress for modeling depression in rodents: Meta-analysis of model reliability

Hesperidin, a member of the flavanone group of flavonoids, can be isolated in large amounts from the rinds of some citrus species Considering the wide range of pharmacological activities and widespread application of hesperidin, this paper reviews preclinical and clinical trials of hesperidin and its related compounds, including their occurrence, pharmacokinetics, and some marketed products available Preclinical studies and clinical trials demonstrated therapeutical effects of hesperidin and its aglycone hesperetin in various diseases, such as neurological disorders, psychiatric disorders, and cardiovascular diseases and others, due to its anti-inflammatory, antioxidant, lipid-lowering, and insulin-sensitizing properties

Health-promoting effects of the citrus flavanone hesperidin

Antidepressant-like effect of geniposide on chronic unpredictable mild stress-induced depressive rats by regulating the hypothalamus–pituitary–adrenal axis

The citrus flavonoid hesperidin has been reported to possess a wide range of pharmacological properties. We have investigated the preventive and therapeutic effects of hesperidin on the development of adjuvant arthritis (AA), a rat model of rheumatoid arthritis (RA). Freund's complete adjuvant was used to induce AA in rats. Secondary paw swelling, polyarthritis index and histopathological assessment of ankle joints were used to evaluate the effects of hesperidin on AA rats. Concanavalin-A-induced T-lymphocyte proliferation and interleukin (IL)-2 production by splenocytes were measured using the MTT assay. Levels of IL-1, IL-6 and tumour necrosis factor (TNF)-alpha secreted by peritoneal macrophages (PM) were measured by RIA. Intragastric administration of hesperidin significantly attenuated secondary paw swelling and reduced the polyarthritis index of AA rats in a dose-dependent manner. In addition, hesperidin clearly ameliorated the pathological changes in AA rats. Hesperidin also restored the suppression of T-lymphocyte proliferation and IL-2 production, and downregulated production of IL-1, IL-6 and TNF-alpha by PM in AA rats. Our results suggest that hesperidin improves AA by downregulating the function of over-active macrophages and by up-regulating the activities of dysfunctional T lymphocytes. Hesperidin may therefore have therapeutic value for the clinical treatment of RA. Further research is required to clarify the detailed mechanisms of the protective effects of hesperidin on AA.

Suppression of adjuvant arthritis by hesperidin in rats and its mechanisms

The present study was designed to investigate the effect of hesperidin on rat adjuvant arthritis (AA) and to elucidate the involvement of synoviocytes in this process. Freund's complete adjuvant was used to induce AA in rats. Secondary paw swelling and the index of immune organs of AA rats were measured. Macrophage-like synoviocytes were separated by the method of collagenase and trypsin digestion. Synoviocyte proliferation was assayed by MTT assay. TNF-alpha, IL-1beta and IL-10 production of synoviocytes were examined with ELISA. The levels of TNF-alpha, IL-1beta, IL-10 mRNA were determined using RT-PCR. It was found that intragastric hesperidin administration (80, 160 mg/kg) significantly inhibited secondary paw swelling and restored the index of immune organs of AA rats. Furthermore, synoviocyte proliferation in AA rats was apparently suppressed after hesperidin treatment, which was accompanied by decreased transcription as well as production of TNF-alpha and IL-1beta from synoviocytes. Hesperidin also markedly increased IL-10 at both protein and transcription levels in AA rats. In aggregate, the above results demonstrate that hesperidin has a therapeutic effect on AA and the mechanisms are partly related to inhibiting synoviocyte activity and modulating inflammatory cytokine production of synoviocytes which play a crucial role in the pathogenesis of AA.

Hesperidin suppresses adjuvant arthritis in rats by inhibiting synoviocyte activity.

Objectives

We investigated whether inhibition of hedgehog (Hh) signal by cyclopamine attenuated inflammation and cartilage damage in adjuvant-induced arthritis (AIA) rats.



Methods

Cyclopamine (2.5, 5, 10 mg/kg) was given by intraperitoneal injection once daily from day 12 to 21 after AIA induction. Paw swelling (volume changes), serum pro-inflammatory cytokines levels (ELISA), histological analysis of joint damage (H&E staining), proteoglycans expression (Alcian blue staining), mRNA levels of sonic Hh (Shh), glioma-associated oncogene homologue 1 (Gli1), type II collagen (COII) and aggrecan in cartilage (real-time PCR) and articular chondrocyte apoptosis (terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling) were measured respectively.



Key findings

Cyclopamine effectively attenuated inflammation and cartilage damage of AIA rats, as evidenced by reduced paw swelling, serum levels of tumor necrosis factors (TNF)-α, IL-1β, IL-6 and histological scores of joint damage, increased proteoglycans expression and mRNA levels of COII and aggrecan in articular cartilage. Shh or Gli1 mRNA level was correlated negatively with COII and aggrecan mRNA levels, suggesting Hh signal inhibition was associated with promotion of cartilage extracellular matrix production. Furthermore, cyclopamine decreased the number of apoptotic articular chondrocytes of AIA rats, which might be partly related to its mechanisms on relieving cartilage damage.



Conclusions

Our findings present some experimental evidence that Hh signal inhibition might be of potential clinical interest in rheumatoid arthritis treatment.

Inhibition of hedgehog signal pathway by cyclopamine attenuates inflammation and articular cartilage damage in rats with adjuvant-induced arthritis.

Approaches inducing fibroblast-like synoviocytes (FLS) apoptosis in rheumatoid arthritis (RA) patients have been considered as a promising strategy for treating RA. Here, adjuvant arthritis (AA) in rat was induced by complete Freund's adjuvant and FLS were separated and cultured using a tissue explant cultivation method. The apoptotic effect of 7,3'-dimethoxy hesperetin (DMHP, a highly antirheumatic active derivative of hesperidin) on AA FLS was evaluated with MTT assay, Hoechst staining and flow cytometry analysis. Bcl-2, Bax, caspase 3 gene expressions and caspase 3 activity were assayed to identify whether caspase 3 was involved in the apoptosis induced by DMHP. It was found that DMHP significantly decreased AA FLS proliferation in vitro by MTT assay. The AA FLS treated with DMHP displayed typical apoptotic characteristics including irregularity in shape, nuclear shrinkage and chromatin condensation. Flow cytometry analysis indicated that DMHP could obviously increase the AA FLS apoptosis rate. Compared with the AA-FLS control group, DMHP markedly decreased the mRNA expression of Bcl-2, whereas those of Bax and caspase 3 were increased. Moreover, DMHP significantly increased caspase 3 activity in a dose-dependent manner. In aggregate, the results demonstrate that DMHP effectively induces AA FLS apoptosis through caspase 3 activation and can be considered as a possible antirheumatic agent.

Li Cai

Papers

Antidepressant-like effect of geniposide on chronic unpredictable mild stress-induced depressive rats by regulating the hypothalamus–pituitary–adrenal axis

Suppression of adjuvant arthritis by hesperidin in rats and its mechanisms

Hesperidin suppresses adjuvant arthritis in rats by inhibiting synoviocyte activity.

Inhibition of hedgehog signal pathway by cyclopamine attenuates inflammation and articular cartilage damage in rats with adjuvant-induced arthritis.

7,3'-dimethoxy hesperetin induces apoptosis of fibroblast-like synoviocytes in rats with adjuvant arthritis through caspase 3 activation.