Co-administration Of Quercetin Research Articles

Coadministration of Quercetin and Indocyanine Green via PEGylated Phospholipid Micelles for Augmented Chem-Photothermal Combination Tumor Therapy.

A significant impediment persists in developing multicomponent nanomedicines designed to dismantle the heat shock protein (HSP)-based protective mechanism of malignant tumors during photothermal therapy. Herein, well-defined PEGylated phospholipid micelles were utilized to coencapsulate quercetin (QUE, a natural anticancer agent and potent HSP inhibitor) and indocyanine green (ICG, a photothermal agent) with the aim of achieving synchronized and synergistic drug effects. The subsequent investigations validated that the tailored micellar system effectively enhanced QUE's water solubility and augmented its cellular internalization efficiency. Intriguingly, the compositional PEGylated phospholipids induced extraordinary endoplasmic reticulum stress, thereby sensitizing the tumor cells to QUE. Furthermore, QUE played a crucial role in inhibiting the stress-induced overexpression of HSP70, thereby augmenting the photothermal efficacy of ICG. In systemic applications, the proposed nanotherapeutics exhibited preferential accumulation within tumors and exerted notable tumoricidal effects against 4T1 xenograft tumors under 808 nm near-infrared irradiation, facilitated by prominent near-infrared fluorescence imaging-guided chemo-photothermal therapy. Therefore, our strategy for fabricating multicomponent nanomedicines emerges as a coordinated platform for optimizing antitumor therapeutic efficacy and offers valuable insights for diverse therapeutic modalities.

Effect of co-administration of gallic acid and quercetin or gallic acid and rutin on impaired spermatogenesis and oxidative damage in a busulfan-treated rat model

Gallic acid (GAL), rutin (RUT), and quercetin (QUE) are common antioxidant agents in fruits and vegetables with intriguing pharmacological effects. In the present study, we compared the therapeutic outcomes of GAL + QUE in comparison with GAL + RUT co-treatment in a busulfan (BUS) model of testicular injury in Wistar rats. BUS (4 mg kg−1 body weight (b.w) was injected intraperitoneally daily for 4 days. GAL + RUT or GAL + QUE (20 mg kg−1 b. w) was delivered by oral gavage for 52 days. Examination of the testes of BUS-treated rats both biochemically and under light microscopy revealed an increased level of lipid peroxidation, DNA fragmentation, glutathione-S-transferase, lactate dehydrogenase, gamma-glutamyl transpeptidase, alkaline phosphatase and acid phosphatase with a concomitant decrease in the level of antioxidants: glutathione, ascorbic acid, superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase activities, suggesting testicular injury. Tissue sections confirmed the testicular injury-induced by BUS, including diminished spermatogenesis score index, tubular diameter, gonado-somatic index, testis weight, epithelia thickness and higher percentage of aberrant tubules. GAL + QUE co-administration had better recovery effects than GAL + RUT on the biochemical markers and protected against BUS-induced testicular damage. GAL + QUE treatment regimen has better capacity to maintain the antioxidant capacity of the testes and is more potent at reducing BUS-induced oxidative damage compared to GAL + RUT.

Improved synergistic anticancer action of quercetin and tamoxifen citrate supported by an electrospun complex nanostructure

A tri-fluid electrospinning process was successfully developed to prepare tri-chamber complex nanofibers. The core–shell and Janus structure were combined to form a delicate and complicated architecture for solving the problem of co-administration of quercetin and tamoxifen citrate, improving the oral bioavailability, and enhancing their synergistic anti-breast cancer actions. Scanning electron microscope, transmission electron microscope and confocal fluorescent microscopy images showed the complex structure of the designed nanofibers. Fourier transform infrared and X-ray diffraction analyses verified that the model drugs and the polymeric excipients had good compatibility and were presented in an amorphous state. The in vitro release study certified that the tri-chamber nanofibers facilitated the rapid release of quercetin compared with that of the crude drug (90% versus 38%) and the delayed and sustained release of tamoxifen citrate at the same time interval (decreased by 1.88 times). The in vivo pharmacokinetic and pharmacodynamic analysis verified that the tri-chamber nanofibers could result in increased oral bioavailability and enhanced synergistic anticancer action of quercetin and tamoxifen citrate. The findings proved that a new medicated drug delivery system with advanced dual-, time-, and target-specific drug release profiles was developed using the electrospun complex nanostructure.

Synchronous Dosing of Levodopa with Quercetin Enhances Therapeutic Efficacy and Mitigates Apoptotic Events in Experimental Parkinsonism

Parkinson’s disease (PD) affects millions of people annually across the globe and is primarily managed through dopamine replacement therapy employing levodopa (L-DOPA), which is still the preferred gold standard. Prolonged use of L-DOPA leads to severe adverse effects, including motor complications such as L-DOPA-induced dyskinesia, which considerably compromise treatment outcomes and patients’ quality of life. Potentiating L-DOPA with natural or synthetic compounds with less toxicity and neuroprotective activity is an area of emerging significance, and many studies in this area have gained widespread research attention. Phytochemicals, essentially compounds with antioxidant and neuroprotective activity, may be potent candidates to potentiate L-DOPA, and in this context, we explored the potential of combining quercetin with L-DOPA to mitigate rotenone-induced PD using human neuroblastoma cells. The optimal nontoxic concentrations of L-DOPA and quercetin were determined via the MTT [3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide] assay. The combination treatment notably increased cell viability to 95% at a concentration of 6.25 μg/ml, whereas the viability of the rotenone-treated group was 46.8%. Lactate dehydrogenase leakage assays further confirmed that membrane integrity was significantly preserved in the combination-treated groups compared with those treated with L-DOPA or quercetin alone. Morphological improvements were evident under microscopic observation. Compared with the individual treatments, the combination treatment also resulted in increased inhibition of acetylcholinesterase activity. Additionally, apoptosis induction was significantly reduced in the combination group, as shown by EtBr/acridine orange fluorescence staining. Cellular calcium levels, which were elevated by rotenone exposure, were effectively normalized by the combination treatment. Moreover, the combination therapy promoted neurite outgrowth more effectively than L-DOPA or quercetin alone. These findings suggest that coadministration of quercetin with L-DOPA could be a promising strategy to increase the efficacy of L-DOPA while potentially reducing its dosage, leveraging the benefits of natural phytochemicals in PD management.

Nano-quercetin mitigates triazophos-induced testicular toxicity in rats by suppressing oxidative stress and apoptosis

The present study was designed to evaluate the testicular toxicity of triazophos in rats and to check the ameliorative effect of nano-quercetin against triazophos-induced toxicity. Nano-quercetin was synthesized from quercetin and characterized. Male Wistar rats were divided into seven groups. The control group received olive oil as a vehicle orally. The high-dose triazophos group and the low-dose triazophos group received 1/10th LD50 of triazophos (7.6 mg/kg) and 1/20th LD50 of triazophos (3.8 mg/kg), respectively. Two groups of animals were dosed with quercetin and nano-quercetin, both at 50 mg/kg body weight orally. The final two groups received high-dose triazophos with co-administration of quercetin and nano-quercetin, respectively.Triazophos disrupted the male endocrine axis by reducing the levels of steroidogenic enzymes 3-β-HSD and 17-β-HSD in testicular cells, further reducing FSH and testosterone. Also, triazophos increased the reactive oxygen species, induced lipid peroxidation, decreased the mitochondrial membrane potential, and elevated the number of apoptotic cells in rat testes. Nano-quercetin ameliorated the testicular oxidative stress and apoptotic and endocrine parameters more efficiently than quercetin. Besides, nano-quercetin alleviated the histopathological and biochemical alterations of triazophos. It is concluded that nano-quercetin has higher anti-oxidant efficacy than quercetin in protecting rats against triazophos-induced testicular toxicity.

Quercetin Mitigates Oxidative Stress, Inflammation, Apoptosis, and Histopathological Alterations Induced by Chronic Titanium Dioxide Nanoparticle Exposure in the Rat Spleen.

Titanium dioxide nanoparticles (nano-TiO2) have become widespread but are accompanied by various health concerns. Quercetin (QT), a naturally occurring flavonoid in fruits and vegetables, exhibits potent antioxidant properties. This research examined the toxic impacts of nano-TiO2 on the structure and function of the spleen in adult male rats and assessed the possible protective effects of QT. A set of randomly grouped rats was established, consisting of a control group, a QT group (50 mg/kg/day), a nano-TiO2 group (300 mg/kg/day), and a QT-nano-TiO2 group. These substances were orally administered to the respective groups for 90 days. Nano-TiO2 significantly induced oxidative stress in the spleen, leading to reduced levels of serum immunoglobulins. Additionally, there was a notable increase in the expression of apoptotic markers and proinflammatory cytokines. These biochemical disturbances were accompanied by morphological changes in the spleens of rats exposed to nano-TiO2. However, coadministration of QT and nano-TiO2 effectively mitigated most nano-TiO2-induced alterations in the spleen, including apoptotic and proinflammatory responses, antioxidant imbalance, serum immunoglobulin levels, and histopathological changes. It can be concluded that QT has the potential to function as a protective agent against the detrimental impacts of nano-TiO2 on the spleen by improving the antioxidant defense mechanism and modulating the apoptotic and inflammatory responses.

Ameliorative potential of the quercetin on lead-induced testicular damage: morphohistometric and biochemical analysis

BackgroundQuercetin, a naturally occurring flavonoid known for its potent antioxidant properties, has been investigated for its potential in counteracting the harmful effects of lead (Pb) toxicity, which induces apoptosis and oxidative damage in various human tissues. This study aims to assess the reparative effects of quercetin on lead-induced testicular damage.MethodsFour groups, each comprising ten adult male albino rats, were randomly assigned as follows: Quercetin group, Pb group, Pb + Quercetin group, and control group. All treatments were administered orally via gavage daily for a duration of 30 days. Evaluation of sex hormone levels (serum testosterone, FSH, and LH), cytokines and inflammatory mediators (IL-1β, TNF-α, MCP-1), lead concentration, oxidative and antioxidant stress markers (superoxide anion [O2−], MDA, SOD, CAT, GSH), and sperm characteristics were carried out.ResultsThe results demonstrated a significant decline in sex hormones and antioxidants, accompanied by an increase in lead concentrations, cytokines, inflammatory mediators, and oxidative stress indicators (O2−, MDA), while SOD, CAT, and GSH levels were reduced. The Pb-intoxicated group exhibited a substantial increase in dead and abnormal sperm, along with significant reductions in sperm concentration and motility. Morphometrically, a marked decrease was observed in spermatogonia, primary spermatocytes, spermatids, and sertoli cells per seminiferous tubule, as well as epithelial height. Furthermore, coadministration of quercetin exhibited notable benefits. It significantly elevated testosterone levels (P < 0.001), testicular SOD, CAT, and GSH activities, while decreasing MDA levels (P < 0.001). Quercetin also mitigated the deleterious effects of lead toxicity on sperm parameters and restored morphometric variations, including epithelial height.ConclusionsQuercetin supplementation alongside lead exposure showed a potential for ameliorating degenerative changes caused by lead toxicity in the testicles. This cotreatment effectively reduced oxidative stress, cytokine levels, inflammatory mediators, and restored biochemical alterations, thereby improving morphometric parameters.

Ameliorative Effects of Alpha Lipoic Acid, Quercetin and Ascorbic Acid Against Zinc Oxide Nanoparticles Induced Hepatic Damage: In Vivo

The current study envisioned to evaluate time related protective effect of quercetin, alpha lipoic acid and ascorbic acid on liver of mice against sub-acute exposure of zinc oxide (ZnO-NP) nanoparticle. Male Swiss albino mice (n=72) were randomly divided into eight groups (n=9, each group). G1 received saline solution 0.9%; G2 received quercetin (100 mg/kg b.w); G3 received alpha lipoic acid (100 mg/kg b.w); G4 received ascorbic acid (100 mg/kg b.w); G5 received ZnO-NPs (50 mg/kg b.w); G6 received ZnO-NPs with quercetin; G7 received ZnO-NPs with Alpha lipoic acid and G8 co-treated with ZnO-NPs and ascorbic acid for 21 consecutive days. Body weight, hepatosomatic index and plasma biochemical parameters (total protein, albumin, globulin, total cholesterol, triglycerides, high density lipoproteins, low density lipoprotein, aspartate aminotransferase, alanine transaminase, alkaline phosphatase &amp; bilirubin) were estimated. ZnO showed significant increase in body weight and cause alterations in all biochemical parameters. Co-administration of quercetin (100 mg/kg b.w), alpha lipoic acid and ascorbic acid daily along with ZnO-NPs, significantly ameliorate the dramatic alteration in biochemical parameters and hepatocellular necrosis caused by ZnO nanoparticles. Brine shrimp larvae cytotoxicity assay of ZnO nanoparticles showed 0% mortality. Present study concluded that all three active ingredients showed hepatoprotective effects against nanoparticles induced time dependent toxicity.

Quercetin in combination with hyperbaric oxygen therapy synergistically attenuates damage progression in traumatic spinal cord injury in a rat model

BackgroundOxidative stress, inflammation and cell apoptosis are the most important destructive factors in the spread of damage following trauma to the spinal cord. Therefore, presently, we investigated the synergistic effects of quercetin along with hyperbaric oxygen therapy (HBOT) as strong antioxidant, anti-inflammatory and anti-apoptotic compounds in the recovery of traumatic spinal cord injury (TSCI) in a rat model. Material and methodsSeventy-five male mature Sprague-Dawley rats allocated into 5 groups, including: Sham group (SG), TSCI group, Quercetin group (underwent TSCI and received quercetin), HBOT group (underwent TSCI and received HBOT), and Quercetin+ HBOT group (underwent TSCI and received quercetin plus HBOT). Finally, the spinal cord samples at the traumatic site were harvested and various characteristics were evaluated, including the total volumes of the spinal cord and its central cavity as well as the numerical density of neuron and glial cells by stereological method, oxidant (malondialdehyde; MDA) and antioxidant (glutathione; GSH, superoxide dismutase; SOD and catalase; CAT) factors by biochemical method, molecular levels of IL-10, TNF-α and IL-1β by qRT-PCR method, and cell apoptosis by immunohistochemistry method against Caspase-3 antibody. Furthermore, Basso-Beattie-Bresnahan (BBB) and electromyography latency (EMG Latency) tests were performed to evaluate neurological functions. ResultsFindings demonstrated that the stereological characteristics, biochemical factors (except MDA), expression of IL-10 gene and behavioral functions were significantly better in Quercetin, HBOT and Quercetin+HBOT groups than TSCI group, and were greater in Quercetin+HBOT ones (P < 0.05). While MDA levels, expression of TNF-α and IL-1β genes as well as the density of apoptotic cells significantly more decreased in Quercetin+HBOT group compared to other treated groups (P < 0.05). ConclusionOverall, co-administration of quercetin with HBOT has synergistic neuroprotective effects in animals underwent TSCI.

Neuroprotective effect of quercetin through targeting key genes involved in aluminum chloride induced Alzheimer’s disease in rats

ABSTRACT Alzheimer’s disease (AD) is a neurodegenerative disorder that is clinically characterized by deteriorating cognitive function. Quercetin (Q), a bioflavonoid, has been reported to slow down AD progression. Q at a dose of 50 mg/kg-1 shows an important therapeutic effect in aluminum chloride (AlCl3)-induced Alzheimer’s disease, which has been previously published by us. Here, this study aimed to highlight the neuroprotective effect of quercetin on hallmark genes in AlCl3-induced Alzheimer’s disease in rats. Wistar male rats were subjected to a vehicle group, AlCl3 group, and co-administration with AlCl3 + Q50 for 60 sequential days. Behavioral tests and qPCR were performed to assess the efficacy of Q. The co-administration of quercetin (50 mg kg-1) has a significant effect on memory deficits. Furthermore, AlCl3 + Q50 group resulted in significantly decreased amyloid precursor protein levels (APP), β-amyloid converting enzyme 1 (BACE1), and presenilin I (PSEN1) and increased the expression of ADAM17 in the hippocampus tissue compared to AlCl3 group (p < 0.05). The current study showed that the quercetin’s neuroprotective properties may involve its ability to target the most significant Alzheimer’s disease-related genes and slow the progression of cognitive impairment.

Quercetin potentiates the hepatoprotective effect of sildenafil and/or pentoxifylline against intrahepatic cholestasis: Role of Nrf2/ARE, TLR4/NF-κB, and NLRP3/IL-1β signaling pathways

AimIntrahepatic cholestasis is a common pathological condition of several types of liver disorders. In this study, we aimed to investigate the regulatory effects of quercetin (QU) on selected phosphodiesterase inhibitors against alpha-naphthyl isothiocyanate (ANIT)-induced acute intrahepatic cholestasis. MethodsCholestasis was induced in Wistar albino rats by ANIT as a single dose (60 mg/kg; P·O.). QU (50 mg/kg, daily, P·O.), sildenafil (Sild; 10 mg/kg, twice daily, P·O.), and pentoxifylline (PTX; 50 mg/kg, daily, P.O.) were evaluated either alone or in combinations for 10 days for their antioxidant, anti-inflammatory, and anti-pyroptotic effects. ResultsANIT produced a prominent intrahepatic cholestasis as evidenced by a significant alteration in liver functions, histological structure, inflammatory response, and oxidative stress biomarkers. Furthermore, up-regulation of NF-κB-p65, TLR4, NLRP3, cleaved caspase-1, IKK-β, and IL-1β concurrently with down-regulation of Nrf-2, HO-1, and PPAR-γ expressions were observed after ANIT. QU, Sild, or PTX treatment significantly alleviated the disturbance induced by ANIT. These findings were further supported by the improvement in histopathological features. Additionally, co-administration of QU with Sild or PTX significantly improved liver defects due to ANIT as compared to the individual drugs. SignificanceCombined QU with Sild or PTX exhibited promising hepatoprotective effects and anti-cholestatic properties through modulation of Nrf2/ARE, TLR4/NF- κB, and NLRP3/IL-1β signaling pathways.

Chemoprevention of Arseniasis-Past, Present and Future (Mini Review)

Clinical management of arsenic poisoning has been a major concern especially in countries like Bangladesh., India., Taiwan., Chile, Hungary and Argentina. In recent past, therapeutic efficacy of chelating agents, vitamins, nutrients, antioxidants and hormones has been investigated in many laboratories. Whereas, arsenic can be chelated by several agents viz: British Anti Lewisite (BAL), unithiol (DMPS), succimer (DMSA), monoisoamyl dimercaptosuccinic acid (MiADMSA), monocyclohexyl dimercaptosuccinic acid (MchDMSA), coadministration of quercetin and MiADMSA and taurine and MiADMSA have been found to reduce arsenic burdeon more effectively than their individual treatments. There are convincing reports that non-enzymatic antioxidants i.e. ascorbic acid, alpha tocopherol, B carotene, N-acetyl cysteine, alpha lipoic acid, curcumin, GSH and selenium offer protection against arseniasis by reducing oxidative stress. Melatonin, a product of pineal gland being a strong free radical scavenger possesses immense therapeutic importance against arseniasis. Thyroid hormones too influence arsenic toxicity. All these studies made in experimental animals have been briefly described in this review. However, cohorts made in human population are insignificant. Suitable clinical trials using these therapeutic agents individually or in combination may lead to the discovery of a “magic bullet” against arseniasis.

Antioxidant and antiapoptotic effects of quercetin against ochratoxin A-induced nephrotoxicity in broiler chickens

The mycotoxin ochratoxin A (OTA) is produced by the fungi Aspergillus and Penicillium. The flavonoid quercetin (QUE) is distinguished by its antioxidant, anti-inflammatory, and antiapoptotic properties. This study was designed to determine whether QUE can protect broiler chickens against OTA-induced nephrotoxicity. Forty broiler chicks were randomly divided into four equal groups: control, OTA, QUE, and OTA + QUE. For 6 weeks, OTA (0.5 mg/kg) and/or QUE (0.5 g/kg) were added to the diet of chickens. The results demonstrated that OTA exposure increased serum levels of creatinine, uric acid, and blood urea nitrogen. OTA exposure also increased renal malondialdehyde content but decreased renal antioxidants. OTA-exposed chickens exhibited multiple pathological kidney lesions. Moreover, OTA exposure induced apoptosis in renal tissue, which was manifested by the up-regulation of proapoptotic genes and down-regulation of antiapoptotic genes via the suppression of the PI3K/AKT pathway. In addition, coadministration of QUE and OTA mitigated most of these nephrotoxic effects.

Potential protective effect of quercetin on the male reproductive system against exposure of Wistar rats to crude oil vapor: Genetic, biochemical, and histopathological evidence

Toxic compounds in crude oil vapor (COV), including polycyclic aromatic hydrocarbons (PAHs), are associated with adverse effects on reproduction in living organisms. Quercetin (QT) is the most plentiful flavonoid in vegetables and fruits, with antioxidant activities. This study aimed to evaluate the protective role of QT on testicular toxicity induced by COV. Twenty-four adult male Wistar rats were randomly divided into four groups (n = 6) including control, quercetin (QT) (50 mg/kg), crude oil vapors (COV), and COV + QT. The inhalation method was used to expose the rats to crude oil vapors for 5 h daily, and QT was administered orally. After 30 days, the rats were euthanized, then, the testes were removed for gonadosomatic index (GSI), sperm parameters, H&E staining, the activity of the antioxidant enzymes, and apoptotic gene expression assessments. The COV statistically significantly (P < 0.05) reduced GSI, sperm count, motility, viability, and sperm normal morphology, histological indexes, and antioxidant enzyme activities than control. Also, COV statistically significantly (P < 0.05) increased the expression of caspase-3, p-53, and Bax genes and decreased Bcl-2 gene expression. Co-administration of QT + COV caused a statistically significant (P < 0.05) decrease in Bax gene expression and increased antioxidant enzyme activities, Bcl-2 gene expression, and reproductive parameters than the COV group. Based on the results of this study, it appears that crude oil vapor causes side effects on male reproduction. Yet, quercetin has the potential to reduce the side effects of crude oil vapor on the male reproductive system.

Multidrug resistance-associated protein 2 (MRP2) is an efflux transporter of EGCG and its metabolites in the human small intestine

Green tea polyphenols have various beneficial effects on human health, such as antiobesity and anti-carcinogenesis. (-)-Epigallocatechin-gallate (EGCG) is one of the major potent green tea catechins; however, detailed mechanisms of EGCG transport and metabolism in the human small intestine remain unknown due to lack of a suitable model. We investigated metabolite profiles of EGCG in the fresh human duodenal biopsy, cryopreserved human duodenal mucosal enterocytes and Caco-2 cells, and found that EGCG was readily metabolized into methylated and sulphate conjugates, which are major metabolites in these models. Next, we examined possible efflux transporters of EGCG and its metabolites using specific inhibitors of MRP2, P-gp and BCRP in Caco-2 cell monolayers. MRP2 was thereby identified as an efflux transporter, and further analysis using MRP2-knockout Caco-2 cells and vesicular transport assays confirmed that MRP2 is a selective efflux transporter of EGCG and its metabolites. Assuming that functional inhibition of MRP2 would result in efficient uptake of EGCG, we screened for MRP2 functional blockade and identified quercetin, which led to increased intracellular accumulation and basal transport of EGCG in Caco-2 cells. This result suggested that co-administration of quercetin and EGCG would enable efficient transport of EGCG in the human intestine. Therefore, we performed co-oral administration of quercetin and EGCG in human subjects to examine whether this occurred in humans. These studies demonstrated that MRP2 is a selective transporter of EGCG and conjugates and Caco-2 is a model to examine transport mechanisms and metabolites of polyphenols in the human small intestine.

Cyclophosphamide-induced testicular oxidative-inflammatory injury is accompanied by altered immunosuppressive indoleamine 2, 3-dioxygenase in Wister rats: Influence of dietary quercetin.

This study evaluated the role of quercetin against cyclophosphamide-induced distortion of rat testicular function. Adult rats were administered cyclophosphamide (100mg/kg), quercetin (50mg/kg) and in combination for seven days. Cyclophosphamide caused a significant increase in the activities of indoleamine 2, 3-dioxygenases (IDO), tryptophan 2, 3-dioxygenase (TDO), myeloperoxidase (MPO), and elevated the concentrations of interleukin 6 (IL-6) and interferon-γ (IFN-γ). Cyclophosphamide increased testis malondialdehyde (MDA) concentrations but depleted superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) and glutathione (GSH). However, quercetin co-administration significantly (p < 0.05) prevented the increased values of IDO, TDO, MPO, IL-6, IFN-γ, MDA, SOD, CAT, GSH-Px and GSH compared with control rats. Also, quercetin co-treatment significantly increased serum testosterone, follicle-stimulating hormone (FSH), prolactin, luteinizing hormone (LH), activities of testicular 3β-hydroxysteroid dehydrogenase (3 β-HSD), 17β-hydroxysteroid dehydrogenase (17 β-HSD) as well as sperm count, motility and viability but reduced abnormal sperm morphology. Quercetin exposure alone did not alter any of the parameters evaluated relative to control. Thus, quercetin protected the testes against cyclophosphamide-induced alterations in immunosuppressive IDO/TDO activities elicited by oxidative-inflammatory mediators.

P–060 Dose- dependent mitigation of lead acetate toxicity in males on embryo development in female mice

Abstract Study question Does quercetin (75 or 100 mg/kg BW/day) co-administration with lead acetate to male mice affects embryonic development in female mice? Summary answer The low-dose quercetin (75 mg/kg BW/day) ameliorated the adverse effects of lead acetate on mouse embryogenesis. What is known already Lead causes male infertility by impacting on endocrine system and spermatogenesis, and may exert undesirable effects on the offspring. The currently approved treatment for lead poisoning is the use of chelating agents, which form an insoluble complex with lead and shield it from biological targets; thus, reducing its toxicity. One of the main mechanisms of lead-induced toxicity is oxidative stress, and it has been reported that natural antioxidants can reduce the heavy metals toxicity. The aim of the present study was to examine the protective effects of quercetin on the toxicity induced by lead acetate on the embryogenesis in mice. Study design, size, duration Sexually mature (eight-week-old) NMRI male mice (n = 24) were randomly divided into four groups (n = 6 per group) receiving (i) distilled water (control group); (ii) lead acetate (150 mg/kg BW/day) dissolved in deionized water (LA); (iii) lead acetate (150 mg/kg BW/day) + quercetin (75 mg/kg BW/day) (LQ75); (IV) lead acetate (150 mg/kg BW/day) + quercetin (100 mg/kg BW/day) (LQ100). Treatments were applied daily as oral gavages for one cycle of the seminiferous epithelium (35 days). Participants/materials, setting, methods At the end of treatment administration, the males were joined with super-ovulated females, and the retrieved zygotes were cultured for evaluation of the embryo development (at 2-cell, 4-cell, 8-cell, and blastocyst stages), and blastocyst cell number using differential staining (propidium iodide and bisbenzimide). After incubation of capacitated sperm with oocytes, an ultraviolet light microscope was used following 3 min incubation with 25 µg⁄mL bisbenzamide solution for fertilization assessment. Main results and the role of chance Lead acetate (LA) treatment of male mice decreased the 2-cell stage compared with the control group (P &amp;gt; 0.05). There was no difference between control and LQ75, and between LA and LQ100. The other stages of embryonic development were not significantly affected by the treatment. Overall, early embryonic development in the control and LQ75 mice were better than LQ100 and LA mice. The number of cells in the trophectoderm and inner-cell mass were not affected by treatments. However, the total blastocyst cell number in the control was higher than in the other groups; there was no significant difference between LQ100, LQ75 and LA groups. Fertilization rate was not affected by the treatments (P &amp;lt; 0.05). Quercetin acts as a potent antioxidant at low doses, but at high doses exerts a pro-oxidant action. According to previous reports, higher concentrations of quercetin increased apoptosis and necrosis while decreasing the activities of the antioxidant enzymes. Also, it has been suggested that quercetin might disrupt the endocrine system and interfere with Sertoli cell function and sperm motility. Limitations, reasons for caution A limitation of this study is narrow dose selection; more studies are needed to determine the effective dose of quercetin in ameliorating the lead toxicity. There are also side effects of lead-quercetin chelates such as metal redistribution, essential metal loss, accumulation and persistency in intracellular sites, and peroxidation. Wider implications of the findings: Lead administration adversely impacted on the embryogenesis; on the other hand, paternal quercetin co-administration somewhat ameliorated the adverse effects of lead on mice embryogenesis. Trial registration number Not applicable

Atypical Antipsychotic Lumateperone Effects on the Adrenal Gland With Possible Beneficial Effect of Quercetin Co-administration.

Schizophrenia remains one of the most chronic and highly disabling mental disorders. Lumateperone is a recent FDA-approved atypical antipsychotic drug for the treatment of schizophrenia. However, the internal FDA pathologist raised concerns regarding pigment deposition associated with degeneration in different tissue in animal studies with lumateperone treatment. The adrenal gland may be implicated in lumateperone side effects, and quercetin may have the ability to fulfill this treatment gap. To prove this hypothesis, 40 male guinea pigs were used and divided into four groups; control, quercetin-treated, lumateperone-treated, and quercetin/lumateperone cotreated orally for 28 consecutive days. Behavioral forced swim (FST) and open field (OF) tests were done at the end of treatment. Retro-orbital blood samples were taken to assess hormones: adrenocorticotropic hormone (ACTH), cortisol, dehydroepiandrosterone acetate (DHEA), and aldosterone, along with an assessment of oxidative stress parameters: malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD). Adrenal glands were extracted for histopathological assessment with H&E, Mallory trichome staining, immunostaining, and electron microscopy studies. Lumateperone-treated group showed a significant reduction in the activity in FST and OF with histopathological deterioration in adrenal secretory function and structure and increased expression of interleukin-6 (IL-6), CASPASE-3, collagen deposition, and decreased proliferating cell nuclear antigen (PCNA). Cytoplasmic vacuolation, pyknosis of the nuclei, increase in the lysosome, lipofuscin pigment, and cellular infiltration with diminishing in the number of secretory granules could all be observed in lumateperone-treated group. Coadministration of quercetin and lumateperone showed improvement of the previously deteriorated parameters. Quercetin had a prophylactic effect against lumateperone depressive-like effect on animal behavior and its possible adrenal damage.Graphical Conceptual framework for the proposed mechanism of action of coadministration of quercetin and lumateperone.

Inhibitory effects of quercetin and its major metabolite quercetin-3-O-β-D-glucoside on human UDP-glucuronosyltransferase 1A isoforms by liquid chromatography-tandem mass spectrometry.

Quercetin is a flavonoid that is widely present in plant-derived food. Quercetin-3-O-β-D-glucoside (Q3GA) is a predominant metabolite of quercetin in animal and human plasma. The inhibitory effects of the UDP-glucuronosyl transferases (UGTs) caused by herbal components may be a key factor for the clinical assessment of herb-drug interactions (HDIs). The present study aimed to investigate the inhibitory profile of quercetin and Q3GA on recombinant UGT1A isoforms in vitro. The metabolism of the nonspecific substrate 4-methylumbelliferone (4-MU) by the UGT1A isoforms was assessed by liquid chromatography-tandem mass spectrometry. Preliminary screening experiments indicated that quercetin exhibited stronger inhibitory effects on UGT1A1, UGT1A3, UGT1A6 and UGT1A9 enzymes than Q3GA. Kinetic experiments were performed to characterize the type of inhibition caused by quercetin and Q3GA towards these UGT isoforms. Quercetin exerted non-competitive inhibition on UGT1A1 and UGT1A6, with half maximal inhibitory concentration (IC50) values of 7.47 and 7.07 µM and inhibition kinetic parameter (Ki) values of 2.18 and 28.87 µM, respectively. Quercetin also exhibited competitive inhibition on UGT1A3 and UGT1A9, with IC50 values of 10.58 and 2.81 µM and Ki values of 1.60 and 0.51 µM, respectively. However, Q3GA displayed weak inhibition on UGT1A1, UGT1A3 and UGT1A6 enzymes with IC50 values of 45.21, 106.5 and 51.37 µM, respectively. In the present study, quercetin was a moderate inhibitor of UGT1A1 and UGT1A3, a weak inhibitor of UGT1A6, and a strong inhibitor on UGT1A9. The results of the present study suggested potential HDIs that may occur following quercetin co-administration with drugs that are mainly metabolized by UGT1A1, UGT1A3 and UGT1A9 enzymes.

Reproductive and embryological toxicity of lead acetate in male mice and their offspring and mitigation effects of quercetin

Exposure to heavy metals not only impacts on fertility in males, it may also affect the offspring. The aim of the present study was to examine the toxic effects of lead acetate on fertility in male mice and their offspring, and the potential effect of quercetin on mitigating the likely effects. Experimental mice were randomly divided into three groups and administered with (i) distilled water (control); (ii) lead acetate (150 mg/kg BW/day); (iii) lead acetate (150 mg/kg BW/day) with quercetin (75 mg/kg BW/day). Lead acetate administration in male mice adversely affected their fertility through changes in sperm motility, viability, morphology, maturity, membrane integrity, and intracellular reactive oxygen species (P < 0.05). Similar findings were observed in the offspring of the lead-treated male mice. Early embryonic development and implantation rate were also adversely influenced in both the sires and offspring when male mice were treated with lead acetate (P < 0.05). The data demonstrated that down-regulation of Cks2 (CDC28 protein kinase regulatory subunit-2) in sperm had an association with early embryonic development in lead acetate treated group. In conclusion, lead acetate administration adversely impacted on the fertility of the male mice and their male offspring fertility; on the other hand, paternal quercetin co-administration somewhat ameliorated the adverse effects of lead on male mice and their offspring.