The effectiveness of hesperidin on bisphenol A-induced spinal cord toxicity in a diabetic rat model.

The potential health risks of bisphenol A (BS) and diabetes (DI) has sparked public concern due to be ubiquitous worldwide. The purpose of this study was to investigate the detrimental impact of BS (200 mg/kg) on the spinal cord tissue in a rat diabetic model. We also evaluated the antioxidant capacity of hesperidin (HS) (100 mg/kg) on spinal cord in BS-treated diabetic rat. Seventy male Wistar albino rats, weighing 180-230 g and 8 weeks old, were randomly chosen, and assigned into seven groups of 10 rats: Control (KON), BS, DI, BS + DI, HS + BS, HS + DI, HS + BS + DI. At the end of the 14-day experimental period, all samples were examined using stereological, biochemical, and histopathological techniques. Our biochemical findings revealed that the SOD level was significantly lower in the BS, DI, and BS + DI groups compared to the KON group (p < 0.05). Compared to the KON group, there was a significant decrease in the number of motor neurons and an increase in the mean volume of central canals in the BS, DI, and BS + DI groups (p < 0.05). In the HS + BC group than the BS group and in the HS + DI group than the DI group, SOD activity and the number of motor neurons were significantly higher; also, the mean volume of spinal central canal was significantly lower (p < 0.05). The novel findings gathered from the histopathological assessment supported our quantitative results. Our speculation was that the exposure to BS and DI was the main cause of neurological alteration in the spinal cord tissues. The administration of HS had the therapeutic potential to mitigate spinal cord abnormalities resulting from BS and DI. However, HS supplementation did not alleviate spinal cord complications in BS-treated diabetic rats.

Cyclosporine-induced kidney damage was halted by sitagliptin and hesperidin via increasing Nrf2 and suppressing TNF-α, NF-κB, and Bax.

Cyclosporine A (CsA) is employed for organ transplantation and autoimmune disorders. Nephrotoxicity is a serious side effect that hampers the therapeutic use of CsA. Hesperidin and sitagliptin were investigated for their antioxidant, anti-inflammatory, and tissue-protective properties. We aimed to investigate and compare the possible nephroprotective effects of hesperidin and sitagliptin. Male Wistar rats were utilized for induction of CsA nephrotoxicity (20 mg/kg/day, intraperitoneally for 7 days). Animals were treated with sitagliptin (10 mg/kg/day, orally for 14 days) or hesperidin (200 mg/kg/day, orally for 14 days). Blood urea, serum creatinine, albumin, cystatin-C (CYS-C), myeloperoxidase (MPO), and glucose were measured. The renal malondialdehyde (MDA), glutathione (GSH), catalase, and SOD were estimated. Renal TNF-α protein expression was evaluated. Histopathological examination and immunostaining study of Bax, Nrf-2, and NF-κB were performed. Sitagliptin or hesperidin attenuated CsA-mediated elevations of blood urea, serum creatinine, CYS-C, glucose, renal MDA, and MPO, and preserved the serum albumin, renal catalase, SOD, and GSH. They reduced the expressions of TNF-α, Bax, NF-κB, and pathological kidney damage. Nrf2 expression in the kidney was raised. Hesperidin or sitagliptin could protect the kidney against CsA through the mitigation of oxidative stress, apoptosis, and inflammation. Sitagliptin proved to be more beneficial than hesperidin.

Iron overload induced submandibular glands toxicity in gamma irradiated rats with possible mitigation by hesperidin and rutin.

BACKGROUND: Radiation triggers salivary gland damage and excess iron accumulates in tissues induces cell injury. Flavonoids are found in some fruits and are utilized as potent antioxidants and radioprotective agents. This study aimed to evaluate the antioxidant and anti-inflammatory effects of hesperidin and rutin on gamma radiation and iron overload induced submandibular gland (SMG) damage and to evaluate their possible impact on mitigating the alteration in mTOR signaling pathway and angiogenesis. METHODS: Forty-eight adult male Wistar albino rats were randomly assigned to six groups: group C received a standard diet and distilled water; group H received hesperidin at a dose of 100 mg/kg; four times a week for four weeks; group U received rutin at a dose of 50 mg/kg; three times a week for three weeks; group RF received a single dose (5 Gy) of gamma radiation followed by iron at a dose of 100 mg/kg; five times a week for four weeks; group RFH received radiation and iron as group RF and hesperidin as group H; group RFU received radiation and iron as group RF and rutin as group U. SMG specimens from all groups were removed at the end of the experiment; and some were used for biochemical analysis, while others were fixed for histological and immunohistochemical examination. RESULTS: In the RF group, several genes related to antioxidants (Nrf-2 and SOD) and DNA damage (BRCA1) were significantly downregulated, while several genes related to inflammation and angiogenesis (TNFα, IL-1ß and VEGF) and the mTOR signaling pathway (PIK3ca, AKT and mTOR) were significantly upregulated. Acinar cytoplasmic vacuolation, nuclear pyknosis, and interacinar hemorrhage with distinct interacinar spaces were observed as histopathological changes in SMGs. The duct system suffered significant damage, eventually degenerating entirely as the cells were shed into the lumina. VEGF and NF-κB were also significantly overexpressed. Hesperidin and rutin cotreatment generated partial recovery as indicated by significant upregulation of Nrf-2, SOD and BRCA1 and considerable downregulation of TNF-α, IL-1ß, VEGF, PIK3ca, AKT, and mTOR. Although some acini and ducts continued to deteriorate, most of them had a normal appearance. There was a notable decrease in the expression of VEGF and NF-κB. CONCLUSIONS: In γ-irradiated rats with iron overload, the administration of hesperidin and rutin may mitigate salivary gland damage.

Preventive effects of hesperidin in an experimental model ofs acute lung inflammation.

In this study, we hypothesized that long-term administration of hesperidin can modulate the inflammatory response and oxidative stress in animals submitted to mechanical ventilation (MV). Twenty-five C57BL/6 male mice were divided into 5 groups: control, MV, animals receiving hesperidin in three doses 10, 25 and 50 mg/kg. The animals received the doses of hesperidin for 30 days via orogastric gavage, and at the end of the period the animals were submitted to MV. In animals submitted to MV, increased lymphocyte, neutrophil and monocyte/macrophage cell counts were observed in the blood and airways. Associated to this, MV promoted an increase in inflammatory cytokine levels such as CCL2, IL-12 and TNFα. The daily administration of hesperidin in the three doses prevented the effects caused by MV, which was observed by a lower influx of inflammatory cells into the airways, a reduction in inflammatory markers and less oxidative damage.

Synergistic effects of bee venom, hesperidin, and piperine with tamoxifen on apoptotic and angiogenesis biomarker molecules against xerographic MCF-7 injected rats.

Breast cancer ranks as the second leading most significant of mortality for women. Studies have demonstrated the potential benefits of natural compounds in cancer treatment and prevention, either in isolation or in conjunction with chemotherapy. In order to improve Tamoxifen's therapeutic efficacy in in-vivo studies, our research sought to determine the effects of hesperidin, piperine, and bee venom as natural compounds, as well as their combination effect with or without Tamoxifen. First, 132 female albino rats were equally divided into six groups and five subgroups, and breast cancer was induced in the selected groups by xenografting of MCF7 cells. Second, the effect of single and best ratio combinations treatment from previous in vitro studies were selected. Next, tumorous mammary glands were collected for apoptotic and antiapoptotic biomarkers and cell cycle analysis. Single or combined natural products with or without Tamoxifen revealed a significant up-regulation in apoptotic genes Bax and Casp3 and a downregulation of antiapoptotic and angiogenesis genes Bcl-2 and VEGF genes. We found that cell cycle arrest in the G0/G1 phase was exclusively caused by Tamoxifen and/ or hesperidin. However, the cell cycle arrest in the G2/M phase is a result of the combination of piperine and bee venom, with or without Tamoxifen by using the flow cytometric technique. Our research concludes that bee venom, hesperidin, and piperine can synergistically enhance to increase Tamoxifen's efficiency in the management of breast cancer.

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

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

Hesperidin improves physiological outcomes in an arginine vasopressin rat model of pre-eclampsia.

BACKGROUND: Hesperidin, a flavanone commonly found in citrus fruits and herbal formulations, has emerged as a potential new therapeutic agent for modulating several diseases. Since pre-eclampsia is a growing public health threat, it may negatively impact the economy and increase the disease burden of South Africa. Phytocompounds are easily accessible, demonstrate minimal side effects, and may confer novel medicinal options as a treatment and preventive preference. OBJECTIVE: To investigate the physiological, biochemical, and hematological outcomes of hesperidin in an arginine vasopressin (AVP)-induced rodent model of pre-eclampsia. METHODS: Female Sprague-Dawley rats were surgically implanted with mini-osmotic pumps to deliver AVP (200 ng/h) subcutaneously. Animals were treated with hesperidin at 200 mg/kg.b.w via oral gavage for 14 days. Systolic and diastolic blood pressures were measured on GD 7, 14, and 18 using a non-invasive tail-cuff method and were euthanized on GD 21. RESULTS: The findings showed that hesperidin administration significantly decreased blood pressure (P < 0.05) and urinary protein levels in pregnant rats (P < 0.001). Placental and individual pup weight also increased significantly in the pregnant hesperidin-treated groups compared to AVP untreated groups (P < 0.001). Biochemical and hematological markers such as white blood cell count and lymphocyte levels differed significantly (P < 0.05) in AVP groups treated with and without hesperidin. CONCLUSION: Our results suggest that hesperidin is an antihypertensive agent with modes of action associated with its diuretic and blood pressure lowering effects and reduction of proteinuria in AVP-induced pre-eclamptic rats.

Protective role of hesperetin in sorafenib-induced hepato- and neurotoxicity in mice via modulating apoptotic pathways and mitochondrial reprogramming.

INTRODUCTION: Sorafenib, an FDA-approved standard chemotherapy for advanced hepatocellular carcinoma, is associated with numerous adverse effects that significantly impact patients' physiological well-being. Consequently, identifying agents that mitigate these side effects while enhancing efficacy is crucial. Hesperetin, a flavone present in fruits and vegetables, possesses antioxidant, anti-inflammatory, and anti-cancer properties. This study aimed to investigate the hepatotoxic and neurotoxic effects of sorafenib and the potential protective role of hesperetin. MATERIALS AND METHODS: Swiss albino mice were orally administered sorafenib (100 mg/kg) alone or in combination with hesperetin (50 mg/kg) over 21 days. Behavioral assessments for anxiety and depressive-like behaviors were conducted. Additionally, evaluations encompassed apoptotic activity, mitochondrial integrity, liver enzyme levels, proliferation rates, and histopathological changes. RESULTS: Combining hesperetin with sorafenib showed improvements in behavioral alterations, liver damage, brain mitochondrial dysfunction, and liver apoptosis compared to the sorafenib-only group in mice. CONCLUSION: Hesperetin exhibits potential as an adjunct to sorafenib, mitigating its side effects by attenuating its toxicity, enhancing efficacy, and potentially reducing the occurrence of sorafenib-induced resistance through the downregulation of hepatocyte growth factor levels.

Hesperidin counteracts chlorpyrifos-induced neurotoxicity by regulating oxidative stress, inflammation, and apoptosis in rats.

Chlorpyrifos (CPF), considered one of the most potent organophosphates, causes a variety of human disorders including neurotoxicity. The current study was designed to evaluate the efficacy of hesperidin (HSP) in ameliorating CPF-induced neurotoxicity in rats. In the study, rats were treated with HSP (orally, 50 and 100 mg/kg) 30 min after giving CPF (orally, 6.75 mg/kg) for 28 consecutive days. Molecular, biochemical, and histological methods were used to investigate cholinergic enzymes, oxidative stress, inflammation, and apoptosis in the brain tissue. CPF intoxication resulted in inhibition of acetylcholinesterase (AChE) and butrylcholinesterase (BChE) enzymes, reduced antioxidant status [superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione (GSH)], and elevation of malondialdehyde (MDA) levels and carbonic anhydrase (CA) activities. CPF increased histopathological changes and immunohistochemical expressions of 8-OHdG in brain tissue. CPF also increased levels of glial fibrillary acidic protein (GFAP) and nuclear factor kappa B (NF-κB) while decreased levels of nuclear factor erythroid 2-related factor 2 (Nrf-2), heme oxygenase-1 (HO-1) and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α). Furthermore, CPF increased mRNA transcript levels of caspase-3, Bax, PARP-1, and VEGF, which are associated with apoptosis and endothelial damage in rat brain tissues. HSP treatment was found to protect brain tissue by reducing CPF-induced neurotoxicity. Overall, this study supports that HSP can be used to reduce CPF-induced neurotoxicity.

Naringenin, Hesperidin and Quercetin Ameliorate Radiation-Induced Damage In Rats: In Vivo And In Silico Evaluations.

In this study, we sought to determine how well naringenin, hesperidin, and quercetin prevented damage brought on by radiotherapy. During the investigation, 48 adult female Sprague Dawley rats were used. Eight groups of eight rats each were formed by randomly assigning the rats to the groups. The normal control group was represented by Group 1. Group 2 rats were those that received a dose of 15 Gray (Gy) of radiotherapy. The rats assigned to Group 3 received only Naringenin, whereas those assigned to Group 4 received only quercetine, and those assigned to Group 5 received only hesperidin. Rats in Group 6, 7 and 8 were received naringenin, quarcetin and hesperidin at a dose of 50 mg/kg daily for one week prior to radiotheraphy exposition. After radiotheraphy and phenolic compounds rats were sacrificed and some metabolic enzyme (aldose reductase (AR), sorbitol dehydrogenase (SDH), paraoxonase-1 (PON1), butyrylcholinesterase (BChE) and glutathione S-transferase (GST)) activity was determined in eye and brain tissues. It was found that phenolic compounds have protective effect against radiation-induced damage because of their anti-diabetic antioxidant and anti-inflammatory properties. In addition, hesperidin was found to be superior to quercetin and naringenin in terms of enzyme activity efficacy. Furthermore, hesperidin exhibited favorable binding affinity for BChE in silico compared to other enzymes.

Oral phytochemicals as photoprotectants in UVR exposed hairless mice: A study of hesperidin methyl chalcone, phloroglucinol, and syringic acid.

Ultraviolet radiation is the primary risk factor for keratinocyte carcinoma. Because of increasing incidence rates, new methods of photoprotection must be explored. Oral supplementation with photoprotective compounds presents a promising alternative. Phytochemical compounds like hesperidin methyl chalcone, phloroglucinol, and syringic acid are particularly of interest because of their antioxidant properties. Our primary outcome was to evaluate the effects of oral phytochemicals on photocarcinogenesis with time until tumour onset as the primary endpoint. A total of 125 hairless C3.Cg-Hrhr/TifBom Tac mice were randomised to receive tap water supplemented with either 100 mg/kg hesperidin methyl chalcone, phloroglucinol, or syringic acid, 600 mg/kg nicotinamide as a positive control, or no supplementation. The mice were irradiated with 3.5 standard erythema doses thrice weekly to induce photocarcinogenesis. Supplementation with the phytochemicals phloroglucinol and syringic acid and nicotinamide delayed tumour onset from a median of 140 days to 151 (p = 0.036), 157 days (p = 0.02), and 178 (p = 2.7·10-5), respectively. Phloroglucinol and nicotinamide supplementation reduced tumour number. Nicotinamide increased UV-induced pigmentation and reduced oedema formation, while phloroglucinol supplementation reduced epidermal thickness. These results indicate that oral supplementation with phloroglucinol and syringic acid protects against photocarcinogenesis in hairless mice, but not to the same extent as nicotinamide.

Hesperidin suppressed metastasis, angiogenesis and tumour growth in Balb/c mice model of breast cancer.

Considering the unfavourable response of breast cancer (BC) to treatment, we assessed the therapeutic potential hesperidin in mice bearing 4T1 BC tumours. Anti-tumour effects were assessed by measuring pathologic complete response (pCR), survival analysis, immunohistochemistry for E-cadherin, VEGF, MMP9, MMP2 and Ki-67, serum measurement of IFNγ and IL-4, and gene expression analysis of CD105, VEGFa, VEGFR2 and COX2. Survival of tumour-bearing mice was the highest in mice receiving a combination of hesperidin and doxorubicin (Dox) (80%) compared to the normal saline (43%), hesperidin 5 (54%), 10 (55.5%), 10 (60.5%) and 40 (66%) mg/kg, and 10 mg/kg Dox-treated (73%) groups (p < 0.0001 for all). Compared to the normal saline group, there was a significant elevation in IFNγ level in the animals receiving 20 (p = 0.0026) and 40 (p < 0.001) mg/kg hesperidin, 10 mg/kg Dox (p < 0.001), and combined hesperidin (20 mg/kg) and Dox (10 mg/kg) (p < 0.001). A significant reduction in the gene expression of CD 105 (p = 0.0106), VEGFa (p < 0.0001), VEGFR2 (p < 0.0001), and Cox2 (p = 0.034) and a significant higher pCR score (p = 0.006) were noticed in mice treated with 10 mg/kg Dox + 20 mg/kg hesperidin compared to those treated with 10 mg/kg Dox alone. Immunohistochemical staining showed significant reductions in Ki-67 (p < 0.001) and VEGF (p < 0.001) and a significant elevation in E-cadherin (p = 0.005) in the 10 mg/kg Dox + 20 mg/kg treatment group than in 10 mg/kg Dox alone group. Hesperidin can be considered as a potentially suitable anti-cancer agent for BC that can synergize with other chemotherapeutics.

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

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

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

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

Effect of Hesperidin on Sciatic Nerve Damage in STZ-Induced Diabetic Neuropathy: Modulation of TRPM2 Channel.

Diabetic neuropathy (DNP) is a severe complication of diabetes mellitus. In this study, we examined the potential of hesperidin (HES) to attenuate DNP and the involvement of the TRPM2 channel in this process. The rats were given a single dose of 45 mg/kg of streptozotocin (STZ) intraperitoneally to induce diabetic neuropathic pain. On the third day, we confirmed the development of diabetes in the DNP and DNP + HES groups. The HES groups were treated with 100 mg/kg and intragastric gavage daily for 14 days. The results showed that treatment with HES in diabetic rats decreased STZ-induced hyperglycemia and thermal hyperalgesia. Furthermore, in the histopathological examination of the sciatic nerve, HES treatment reduced STZ-induced damage. The immunohistochemical analysis also determined that STZ-induced increased TRPM2 channel, type-4 collagen, and fibrinogen immunoactivity decreased with HES treatment. In addition, we investigated the TRPM2 channel activation in the sciatic nerve damage mechanism of DNP model rats created by STZ application using the ELISA method. We determined the regulatory effect of HES on increased ROS, and PARP1 and TRPM2 channel activation in the sciatic nerves of DNP model rats. These findings indicated that hesperidin treatment could attenuate diabetes-induced DNP by reducing TRPM2 channel activation.

The renoprotective effects of hesperidin on kidney injury induced by exposure to severe chronic dust storm particulate matter through inhibiting the Smads/TGF-ß1 signaling in rat.

Exposure to dust storm particulate matter (PM) is detrimental to kidney tissue. In this study, the impacts of chronic intake of dusty PM were explored as a major objective in a specified compartment to make a real-like dust storm (DS) model, and the role of hesperidin (HSP) as an antioxidant on kidney tissue was assessed in rats. Thirty-two male Wistar rats (200-220 g) were randomly allocated into 4 groups: CA+NS: (clean air and normal saline as a vehicle of HSP). Dusty PM and NS (DS+NS). HSP+ CA: rats received 200 mg/kg of HSP by gavage for 28 days, once daily in addition to exposure to clean air. HSP+DS: HSP plus DS. In DS groups, the animals were exposed to dust storms at a concentration of 5000-8000 µg/m3 in the chamber for 1 h daily, for 4 consecutive weeks, except Thursdays and Fridays. At the end of the experiment, the animals were sacrificed for biochemical, inflammatory, oxidative stress, molecular parameters, and histological evaluation. DS significantly enhanced blood urea nitrogen and creatinine, inflammatory (tumor necrosis factor-α, and interleukin-1ß), and oxidative stress indexes. Likewise, a significant increase was seen in mRNA Smads, collagen-I, and transforming growth factor-ß1 (TGF-ß1) expressions in the kidney. Histological findings showed contracted glomeruli and kidney structure disorder. In addition, Masson's trichrome staining demonstrated renal fibrosis. Nevertheless, HSP could significantly reverse these changes. Our data confirmed that DS results in kidney fibrosis through enhancing Smads/TGF-ß1 signaling. However, HSP was able to inhibit these changes as confirmed by histological findings.

Hesperidin may improve depressive symptoms by binding NLRP3 and influencing the pyroptosis pathway in a rat model.

OBJECTIVE: Major depressive disorder (MDD) is a debilitating psychiatric disorder which is common and endangers human physical and mental health. Studies have shown that hesperidin could improve the symptoms of depression with unclear mechanisms. METHOD: In this study, hesperidin was administered to chronic unpredictable mild stress (CUMS) depressed mice before behavioral test, network pharmacology analysis, RNA expression microarray analysis, pathway validation and molecular docking experiments. RESULTS: we found that hesperidin intervention could significantly improve the depressive symptoms and downregulate the expression level of pyroptosis pathway including caspase 1 (Casp1), interleukin 18 (IL18), interleukin-1ß (IL-1ß) and NOD-like receptor thermal protein domain associated protein 3 (NLRP3). In addition, we found that hesperidin could possibly bind to NLRP3. CONCLUSIONS: Our study demonstrated that hesperidin had huge potential as anti-depressive neuroprotectant, and may play a role in treating MDD by regulating NLRP3-mediated pyroptosis.

The protective effects of hesperidin pretreatment on kidney and remote organs against renal ischemia-reperfusion injury.

OBJECTIVE: As an antioxidant and anti-inflammatory agent, Hesperidin was investigated to prove whether it prevents damage to the kidney and lung tissues of rats undergoing renal ischemia-reperfusion injury. MATERIALS AND METHODS: Four groups of rats were set, including eight subjects each as Group 1 (control), Group 2-RIR (renal ischemia reperfusion), Groups 3 and 4 as pretreatment groups (50 HES, 100 HES). RESULTS: According to our results, Hesperidin pretreatment improved the biochemical and histopathological parameters in kidney and lung tissues of rats with ischemia-reperfusion injury. Besides, a 100 mg/kg dose of Hesperidin was found to be more beneficial to the rats than 50 mg/kg. CONCLUSIONS: The study suggests that Hesperidin is protective against renal and lung tissues of rats that underwent ischemia-reperfusion injury.

Therapeutic potential of hesperidin: Apoptosis induction in breast cancer cell lines.

Hesperidin is a flavonoid commonly found in citrus fruits. Studies have shown that hesperidin has anti-inflammatory, analgesic, and antimicrobial properties, as well as its effectiveness in carcinogenesis. In this paper, we aim to investigate the molecular mechanisms of hesperidin-induced apoptosis in MCF-7 and MDA-MB-231 cancer cells. The inhibitory effect of hesperidin on cellular proliferation was evaluated with the MTT assay. Cell cycle analysis of hesperidin-treated cells was then performed, as well as immunocytochemical analysis of the effect on the apoptosis pathway (TUNEL, Bax, and Bcl-2 expression). Moreover, hesperidin induced cellular apoptosis in MCF-7 breast cancer cells by inhibiting Bcl-2 and enhancing Bax expression at protein levels. On the other hand, hesperidin caused apoptosis in the MDA-MB-231 breast cancer cell line, but it did not activate the Bax/Bcl-2 pathway. Hesperidin also induced cell cycle arrest at the S phase in the MCF-7 and MDA-MB-231 cell lines. These findings showed that hesperidin is a potential therapeutic candidate for preventing the progression of breast cancer. In addition, hesperidin could significantly stimulate the death mechanisms in ER/PR (+) MCF-7 cells by changing the expression balance of Bax and Bcl-2 proteins, but lead ER/PR (-) MDA-MB-231 breast cancer cells to apoptosis in a different way.

Hesperidin mitigates oxidative stress-induced ferroptosis in nucleus pulposus cells via Nrf2/NF-κB axis to protect intervertebral disc from degeneration.

Intervertebral disc degeneration (IVDD), a widely known contributor to low back pain (LBP), has been proved to be a global health challenging conundrum. Hesperidin (hesperetin-7-O-rutinoside, HRD) is a flavanone glycoside that belongs to the subgroup of citrus flavonoids with therapeutic effect on various diseases due to its anti-inflammatory, antioxidant properties. However, the effect of HRD on IVDD remains elusive. The human nucleus pulposus tissues were harvested for isolating human nucleus pulposus (HNP) cells to verify the expression of Nrf2. The biological effect of HRD on HNP cells were assessed in vitro, and the in vivo therapeutic effects of HRD were assessed in mice. Firstly, we found that the expression of Nrf2 was decreased with the progression of degeneration in degenerated human nucleus pulposus tissue. Subsequently, we confirmed that HRD could mitigate oxidative stress-induced ferroptosis in nucleus pulposus cells via enhancing the expression of Nrf2 axis and suppressing the NF-κB pathway to protect intervertebral disc from degeneration in vitro. Finally, the therapeutic effects of HRD were confirmed in vivo. The current study proved for the first time that HRD may protect HNP cells from degeneration by suppressing ferroptosis in an oxidative stress-dependent via enhancing the expression of Nrf2 and suppressing the NF-κB pathway. The evidence will provide a possible basis for future targeted treatment for IVDD.