Quercetin Attenuates Endoplasmic Reticulum Stress and Apoptosis in TNBS-Induced Colitis by Inhibiting the Glucose Regulatory Protein 78 Activation.

Background: The inflammatory bowel diseases (IBD) are significantly influenced by apoptosis and endoplasmic reticulum (ER) stress. Aims: To investigate the effects of quercetin on ER stress-mediated apoptosis in a trinitrobenzene sulfonic acid (TNBS) induced experimental IBD model. Study Design: In vivo animal experimental study. Methods: To demonstrate the effect of quercetin in an experimental colitis model, Control, TNBS, and TNBS+quercetin groups were created with 24 Wistar Albino rats. Colitis was induced by intrarectal administration of 25 mg TNBS. In the TNBS+quercetin group, intragastrically 100 mg/kg quercetin was given for 7 days, immediately after colitis induction. In the TNBS-induced experimental IBD model, we evaluated the effects of quercetin on colonic epithelial cell apoptosis, oxidative stress, ER stress, the mitogen-activated protein kinase c-Jun N-terminal kinase, and the nuclear factor kappa B immunoreactivities, the levels of myeloperoxidase and tumor necrosis factor-α, the disease activity index with colonic histopathologic changes. Results: TNBS administration induced an elevated level of disease activity and oxidative stress indices, inflammation markers, and an increase in the immunoreactivities of nuclear factor kappa B and the mitogen-activated protein kinase c-Jun N-terminal kinase in the colon of the colitis group. Glucose regulatory protein 78, caspase-12 immunoreactivities, and epithelial cell apoptosis also were shown in the colon. However, quercetin improved TNBS-induced histopathological alterations, apoptosis, inflammation, oxidative stress, and ER stress. Conclusion: This study suggests that quercetin has a regulatory effect on ER stress-mediated apoptosis, and thus may be beneficial in treating IBD.

Assessment of the anti-inflammatory and analgesic effects of Opuntia ficus indica L. Cladodes extract.

This study aimed to evaluate the anti-inflammatory and analgesic properties of the methanolic extract of Opuntia ficus indica L. in small animal (rats and mice model). The current treatment for febrile conditions often involves the use of non-steroidal anti-inflammatory drugs (NSAIDs), which can have adverse effects, particularly gastrointestinal ulcers. Therefore, there is a growing need to explore natural alternatives with fewer side effects. The study utilized various experimental models to assess the effects of the extract. The results demonstrated a significant analgesic effect of the extract, as evidenced by a reduction in pain induced by acetic acid and hot plate tests. Additionally, the extract exhibited anti-inflammatory effects, as indicated by a decrease in carrageenan-induced paw edema and dextran-induced inflammation. To gain insights into the chemical composition of the extract, HPLC analysis was conducted. The analysis successfully identified and quantified 20 compounds, including luteolin, galangin, catechin, thymol, methylated quercetin, quercetin, rutin, acacetin, hesperidin, apigenin, kaempferol, pinocembrin, chrysin, gallic acid, caffeic acid, ascorbic acid, ferulic acid, m-coumaric acid, rosmarinic acid, and trans-cinnamic acid.The findings suggest that Opuntia ficus indica L. extract holds promise as an effective and reasonably priced natural remedy for pain and inflammation in rats and mice model. The comprehensive chemical composition analysis provided valuable insights into the presence of various bioactive compounds, which may contribute to the observed therapeutic effects. Further research and exploration of the extract's mechanisms of action are warranted to fully understand its potential in small animal healthcare.

Polyphenol-enriched Desmodium elegans DC. ameliorate scopolamine-induced amnesia in animal model of Alzheimer's disease: In Vitro, In Vivo and In Silico approaches.

The current study aims to quantify HPLC-DAD polyphenolics in the crude extracts of Desmodium elegans, evaluating its cholinesterase inhibitory, antioxidant, molecular docking and protective effects against scopolamine-induced amnesia in mice. A total of 16 compounds were identified which include gallic acid (239 mg g-1), p-hydroxybenzoic acid (11.2 mg g-1), coumaric acid (10.0 mg g-1), chlorogenic acid (10.88 mg g-1), caffeic acid (13.9 mg g-1), p-coumaroylhexose (41.2 mg g-1), 3-O-caffeoylquinic acid (22.4 mg g-1), 4-O-caffeoylquinic acid (6.16 mg g-1), (+)-catechin (71.34 mg g-1), (-)-catechin (211.79 mg g-1), quercetin-3-O-glucuronide (17.9 mg g-1), kaempferol-7-O-glucuronide (13.2 mg g-1), kaempferol-7-O-rutinoside (53.67 mg g-1), quercetin-3-rutinoside (12.4 mg g-1), isorhamnetin-7-O-glucuronide (17.6 mg g-1) and isorhamnetin-3-O-rutinoside (15.0 mg g-1). In a DPPH free radical scavenging assay, the chloroform fraction showed the highest antioxidant activity, with an IC50 value of 31.43 µg mL-1. In an AChE inhibitory assay, the methanolic and chloroform fractions showed high inhibitory activities causing 89% and 86.5% inhibitions with IC50 values of 62.34 and 47.32 µg mL-1 respectively. In a BChE inhibition assay, the chloroform fraction exhibited 84.36% inhibition with IC50 values of 45.98 µg mL-1. Furthermore, molecular docking studies revealed that quercetin-3-rutinoside and quercetin-3-O-glucuronide fit perfectly in the active sites of AChE and BChE respectively. Overall, the polyphenols identified exhibited good efficacy, which is likely as a result of the compounds' electron-donating hydroxyl groups (-OH) and electron cloud density. The administration of methanolic extract improved cognitive performance and demonstrated anxiolytic behavior among tested animals.

The therapeutic potential of quercetin for cigarette smoking-induced chronic obstructive pulmonary disease: a narrative review.

Quercetin is a flavonoid with antioxidant and anti-inflammatory properties. Quercetin has potentially beneficial therapeutic effects for several diseases, including cigarette smoking-induced chronic obstructive pulmonary disease (CS-COPD). Many studies have shown that quercetin's antioxidant and anti-inflammatory properties have positive therapeutic potential for CS-COPD. In addition, quercetin's immunomodulatory, anti-cellular senescence, mitochondrial autophagy-modulating, and gut microbiota-modulating effects may also have therapeutic value for CS-COPD. However, there appears to be no review of the possible mechanisms of quercetin for treating CS-COPD. Moreover, the combination of quercetin with common therapeutic drugs for CS-COPD needs further refinement. Therefore, in this article, after introducing the definition and metabolism of quercetin, and its safety, we comprehensively presented the pathogenesis of CS-COPD related to oxidative stress, inflammation, immunity, cellular senescence, mitochondrial autophagy, and gut microbiota. We then reviewed quercetin's anti-CS-COPD effects, performed by influencing these mechanisms. Finally, we explored the possibility of using quercetin with commonly used drugs for treating CS-COPD, providing a basis for future screening of excellent drug combinations for treating CS-COPD. This review has provided meaningful information on quercetin's mechanisms and clinical use in treating CS-COPD.

Mesenchymal stem cells transplantation combined with IronQ attenuates ICH-induced inflammation response via Mincle/syk signaling pathway.

BACKGROUND: Intracerebral hemorrhage (ICH) is a severe brain-injured disease accompanied by cerebral edema, inflammation, and subsequent neurological deficits. Mesenchymal stem cells (MSCs) transplantation has been used as a neuroprotective therapy in nervous system diseases because of its anti-inflammatory effect. Nevertheless, the biological characteristics of transplanted MSCs, including the survival rate, viability, and effectiveness, are restricted because of the severe inflammatory response after ICH. Therefore, improving the survival and viability of MSCs will provide a hopeful therapeutic efficacy for ICH. Notably, the biomedical applications of coordination chemistry-mediated metal-quercetin complex have been verified positively and studied extensively, including growth-promoting and imaging probes. Previous studies have shown that the iron-quercetin complex (IronQ) possesses extraordinary dual capabilities with a stimulating agent for cell growth and an imaging probe by magnetic resonance imaging (MRI). Therefore, we hypothesized that IronQ could improve the survival and viability of MSCs, displaying the anti-inflammation function in the treatment of ICH while also labeling MSCs for their tracking by MRI. This study aimed to explore the effects of MSCs with IronQ in regulating inflammation and further clarify their potential mechanisms. METHODS: C57BL/6 male mice were utilized in this research. A collagenase I-induced ICH mice model was established and randomly separated into the model group (Model), quercetin gavage group (Quercetin), MSCs transplantation group (MSCs), and MSCs transplantation combined with IronQ group (MSCs + IronQ) after 24 h. Then, the neurological deficits score, brain water content (BWC), and protein expression, such as TNF-α, IL-6, NeuN, MBP, as well as GFAP, were investigated. We further measured the protein expression of Mincle and its downstream targets. Furthermore, the lipopolysaccharide (LPS)-induced BV2 cells were utilized to investigate the neuroprotection of conditioned medium of MSCs co-cultured with IronQ in vitro. RESULTS: We found that the combined treatment of MSCs with IronQ improved the inflammation-induced neurological deficits and BWC in vivo by inhibiting the Mincle/syk signaling pathway. Conditioned medium derived from MSCs co-cultured with IronQ decreased inflammation, Mincle, and its downstream targets in the LPS-induced BV2 cell line. CONCLUSIONS: These data suggested that the combined treatment exerts a collaborative effect in alleviating ICH-induced inflammatory response through the downregulation of the Mincle/syk signaling pathway following ICH, further improving the neurologic deficits and brain edema.

Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is an age-related, chronic, irreversible fibrotic lung disease. IPF is associated with increased senescent cells burden, which may be alleviated with administration of senescent cell targeting drugs termed 'senolytics'. We previously conducted an open-label single-arm pilot study of the senolytic combination of dasatinib and quercetin (D + Q) in patients with IPF but lack of control group limited interpretation and next-stage trial planning. The primary objective of this confirmatory randomized placebo-controlled pilot trial (RCT; NCT02874989) was to report adverse events with D + Q and inform study feasibility for future efficacy trials. METHODS: Twelve participants with IPF aged >50 years were blinded and randomized at a 1:1 ratio to either receive three weeks of D + Q (D: 100 mg/d and Q: 1250 mg/d, three consecutive days per week) or matching placebo. FINDINGS: All participants completed the scheduled drug dosing regimen (108/108 doses) and planned assessments (60/60). While the placebo arm reported fewer overall non-serious AEs (65 vs 22), there were no serious adverse events related to D + Q. Most AEs in the D + Q arm are common in IPF patients or anticipated side effects of D. Sleep disturbances and anxiety were disproportionately represented in the D + Q arm (4/6 vs 0/6). Frailty, pulmonary, or physical function were explored before and after intermittent D + Q; though under-powered to evaluate change, these measures do not appear to differ meaningfully between groups. INTERPRETATION: Intermittently-dosed D + Q in patients with IPF is feasible and generally well-tolerated. Further prospective studies, such as a larger RCT, are needed to confirm the safety and efficacy of D + Q in patients with IPF. FUNDING: This work was supported by National Institutes of Health grants R33AG61456 (JLK, TT), Robert and Arlene Kogod (JLK, TT), the Connor Fund (JLK, TT), Robert J. and Theresa W. Ryan (JLK, TT), and the Noaber Foundation (JLK, TT) San Antonio Claude D. Pepper Older Americans Independence Center's (OAIC)Pilot/Exploratory Studies Core (PESC) Grant (AMN, NM); NIHK01 AG059837 (JNJ), P30 AG021332 (SBK, JNJ); NIHR37 AG013925 (JLK), the Connor Group (JLK), Glenn/AFAR BIG Award (JLK), Robert J. and Theresa W. Ryan (JLK), and the Noaber and Ted Nash Long Life Foundations (JLK).

Investigation of effects of quercetin and low-level laser therapy in cisplatin-induced in vitro peripheral neuropathy model.

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the dose-dependent side effects of cisplatin. The loss of sensory neurons is observed in CIPN. There are many methods to minimalize CIPN symptoms such as pharmacological agents and photobiostimulation but the mechanisms of these methods are unclear. Our study is aimed at determining the effects of quercetin and low-level laser therapy (LLLT) in undifferentiated and nerve growth factor-differentiated PC12 cells in cisplatin-induced peripheral neuropathy. PC12 cells with cisplatin were co-treated with quercetin and LLLT (diode pumped all-solid-state laser, 670 nm, output 500 mW, and the laser beam surface area was 1.96 cm2). The effects of quercetin and LLLT on GAP-43 and Synapsin I expressions were analyzed by real-time PCR, cell viability was assessed by MTT assay, Annexin and dead assay measured the induction of apoptosis, the alterations in mitopotential were assessed by mitopotential assay, and lactate dehydrogenase activity in cells was analyzed. All experiment data were analyzed by the Tukey test and applied as a post hoc test, and statistical evaluation was made. Our results indicated that cisplatin increased apoptosis (24,210 ± 2189, 46,504 ± 8246) cells, mitochondrial dysfunction (44,312 ± 0.751, 68,788 ± 1271), and LDH activity (62,821 ± 8245, 87,838 ± 8116). Furthermore, it decreased cell viability (42,447 ± 1780, 36,140 ± 3682) and inhibited GAP-43 and Synapsin I genes in undifferentiated and differentiated PC12 cells. However, apoptosis, the alterations in mitopotential, and lactate dehydrogenase activity decreased by applications of quercetin and LLLT. It has been recommended that quercetin and low-level laser therapy roles on cisplatin-induced peripheral neuropathy should be investigated in vivo, and the relationship between quercetin and low-level laser therapy should be molecular.

Different protective capability of chlorogenic acid and quercetin against indomethacin-induced gastrointestinal ulceration.

OBJECTIVES: The study compared the protective effects against indomethacin-induced GI ulceration of chlorogenic acid with quercetin in rats. METHODS: Rats were orally given chlorogenic acid or quercetin (100 mg/kg; 5 days), followed by indomethacin (40 mg/kg; single dose). After 24 h, GI tissues were assessed for histopathological damages, then analysed by ELISA and western blot methods. Cell viability was measured in vitro by MTT assay. KEY FINDINGS: Unlike quercetin, chlorogenic acid could not prevent gastric ulcers in indomethacin-treated rats. The levels of gastric prostaglandin E2 (PGE2) and Bax/Bcl-2 ratio in the chlorogenic acid-treated group were not different from those receiving indomethacin alone. Nevertheless, both compounds alleviated jejunum ulcers through suppression of PERK/eIF-2/ATF-4/CHOP-related endoplasmic reticulum (ER) stress and decrease Bax/Bcl-2 ratio. Moreover, at 100 µM, they abolished the cytotoxicity of tunicamycin (an ER stress inducer) in gastric (AGS) and intestinal (Caco-2) cells. In silico docking studies suggested that both compounds could interact with key amino acid residues in the -catalytic domain of PERK. CONCLUSION: Chlorogenic acid and quercetin exerted comparable protective effects against indomethacin-induced intestinal ulcer through suppression of ER stress-mediated apoptosis but, unlike quercetin, chlorogenic acid offered no protection against gastric ulceration due to its -inability to increase PGE2 production.

Modulatory effects of concomitant quercetin/sitagliptin administration on the ovarian histological and biochemical alterations provoked by doxorubicin in a streptozotocin-induced diabetic rat model.

Limited literature was available on the effects of sitagliptin or quercetin treatments on doxorubicin induced ovarian dysfunction in diabetic animals. The study aim was test the efficacy and suggested mechanisms of quercetin/sitagliptin combined treatment on the doxorubicin-induced ovarian toxicity in rat model with streptozotocin-induced diabetes. Forty eight female Wistar rats were divided into six groups: 1) Control; 2) Streptozotocin induced diabetes; 3) Streptozotocin-induced diabetes + doxorubicin ovarian damage; 4) Streptozotocin-induced diabetes + doxorubicin ovarian damage with; 5) Streptozotocin-induced diabetes + doxorubicin ovarian damage with sitagliptin treatment and 6) Streptozotocin-induced diabetes + doxorubicin ovarian damage with concomitant quercetin/sitagliptin treatment. Biochemical tests for serum estrogen, progesterone, insulin, blood glucose, and ovarian levels of malondialdehyde, nitric oxide, and superoxide dismutase and qRT-PCR for NOBOX, FSHr, and iNOS genes were performed. Histological evaluation was done on ovary sections with hematoxylin and eosin and immunohistochemistry for 8-OHdG and iNOS followed by morphometric analysis. The streptozotocin-induced diabetic group showed varying degrees of follicle atresia and altered biochemical parameters, both were marked in the streptozotocin-induced diabetic + doxorubicin group. The mRNA of NOBOX, FSHr, and iNOS genes were disturbed with increased immunoexpression of iNOS and 8-OHdG. Quercetin and/or sitagliptin administration improved all altered histological and biochemical parameters and was more effective as a combined treatment. The study suggested equal efficacy of both quercetin and sitagliptin in mitigating the doxorubicin-induced ovarian toxicity in the streptozotocin diabetic rat model, and the combined therapy showed anti-inflammatory, anti-antioxidant, and anti-DNA damage mechanisms.

Network pharmacology strategy to investigate the pharmacological effects of Suanzaoren Decoction on insomnia

Abstract Suanzaoren Decoction (SZRD) is an ancient prescription used in the treatment of insomnia. This study aimed to investigate the components and targets of SZRD in treating insomnia. First, the compounds of five herbs in SZRD were collected from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), and the putative targets for treating insomnia were obtained from DrugBank to construct the herb-compound-target- disease network. A protein-protein interaction (PPI) network was constructed in the STRING database, and then Gene Ontology functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed to predict the mechanism of action of intersection target. Finally, 30 mice were divided into five groups: control, model, and quercetin groups (100, 50, 25 mg/kg). The sleep latency and duration of pentobarbital-induced sleeping were measured. The production of interleukin-6 (IL-6) and γ-aminobutyric acid (γ-GABA) was detected by using an enzyme-linked immunosorbent assay kit (ELISA), and Gamma-aminobutyric acid type a receptor subunit alpha1 (GABRA1) was tested by Reverse Transcription-Polymerase Chain Reaction (RT-PCR). A total of 152 active ingredients, including 80 putative targets of SZRD, were obtained. The main active compounds included quercetin and kaempferol, and the key targets involved IL-6 and nitric oxide synthase 3 (NOS3). The results of pathway enrichment analysis indicated that the putative targets of SZRD mainly participated in Neuroactive ligand-receptor interaction. The experiment of P-chlorophenylalanine (PCPA)-induced insomnia model showed that quercetin obviously shortened the sleep latency and prolonged the sleep duration of the insomnia model. The production of IL-6, γ-GABA, and GABRA1 mRNA was significantly increased in mice treated with quercetin. This study predicted the active ingredients and potential targets of SZRD on insomnia on the basis of a systematic network pharmacology approach and illustrated that SZRD might exert hypnotic effects via regulating IL-6, γ-GABA, and GABRA1

Effect of quercetin and role of nitric oxide pathway in chloroquine-induced scratching

Abstract Nitric oxide (NO) is an abundant mediator which is demonstrated to be involved in pruritus. Assuming that the increased NO also mediates chloroquine-induced pruritus, which is a frequent complication seen in the chronic chloroquine treatment, the current study aimed to investigate the effect of quercetin and the role of NO in chloroquine-induced pruritus in C57BL/6 mice. Model was created with subcutaneous chloroquine (400µg/site) injection to the nape of the mice. Effect of quercetin and role of NO were investigated with administration of quercetin, and co-administration with L-NAME, 7-NI and L-arginine before chloroquine injection. Locomotor activity was assessed by activity cage and number of the scratching bouts after chloroquine injection was recorded for 30 minutes. Our results show that quercetin significantly reduced scratching bouts at the doses of 10, 20, 40 and 80 mg/kg. Locomotor activity was decreased at the 40 and 80 mg/kg doses of quercetin. Additionally, decrease of the number of scratching bouts by quercetin prevented by L-arginine treatment, while L-NAME and 7-NI enhanced the anti-pruritic effect of sub-effective doses of quercetin. Therefore, our study demonstrated that acute injection of quercetin significantly diminished chloroquine-induced scratching behavior, and this effect is partly mediated by inhibition of neuronal nitric oxide synthase enzyme.

Phytochemical quercetin alleviates hyperexcitability of trigeminal nociceptive neurons associated with inflammatory hyperalgesia comparable to NSAIDs.

Quercetin is a flavonoid that is widely found in fruits and vegetables. Quercetin inhibits cyclooxygenase-2 and modulates voltage-gated ion channels, however, its effect on nociceptive neuron-associated inflammatory hyperalgesia remains unknown. The present study investigated under in vivo conditions whether systemic administration of quercetin attenuates the inflammation-induced hyperexcitability of trigeminal spinal nucleus caudalis (SpVc) neurons associated with mechanical hyperalgesia and compared its effect to the non-steroidal anti-inflammatory drug, diclofenac. Complete Freund's adjuvant was injected into the whisker pads of rats to induce inflammation, and then mechanical stimulation was applied to the orofacial area to assess the threshold of escape. The mechanical threshold was significantly lower in inflamed rats compared to uninjected naïve rats, and this lowered threshold returned to control levels 2 days after administration of quercetin or diclofenac. The mean discharge frequency of SpVc wide-dynamic range (WDR) neurons to both non-noxious and noxious mechanical stimuli in inflamed rats was significantly decreased after quercetin or diclofenac administration under combination of three anesthetic agents (medetomidine, midazolam and butorphanol). In addition, the increased mean spontaneous discharge of SpVc WDR neurons in inflamed rats significantly decreased after quercetin or diclofenac administration. Similarly, quercetin or diclofenac restored the expanded mean receptive field size in inflamed rats to control levels. In this study, the combination of three anesthetic agents did not result in any obvious "noxious pinch-evoked after discharges" in CFA inflamed day 2 rat as described previously in pentobarbital-anesthetized rats. Together, these results suggest that administration of quercetin attenuates inflammatory hyperalgesia associated with hyperexcitability of nociceptive SpVc WDR neurons via inhibition of the peripheral cyclooxygenase-2 signaling cascade and voltage-gated ion channels. These findings support the proposed potential of quercetin as a therapeutic agent in complementary alternative medicine strategies for preventing trigeminal inflammatory mechanical hyperalgesia.

Effect of Exercise and Quercetin in Rats with Metabolic Syndrome Induced with Fructose.

Background: Metabolic syndrome (MetS), one of the most researched topics in recent years, is a metabolic disorder that presents with increased inactivity and has increasing prevalence in the developing world where many ready-made foods are consumed. This research aimed to investigate the protective effect of exercise and quercetin administration in a rat model of MetS induced by fructose. Methods: Forty-two male rats were divided into seven groups (n = 6): control (C), fructose (F), exercise (E), quercetin (Q), fructose+exercise (F+E), fructose+quercetin (F+Q), and fructose+quercetin+exercise (F+Q+E). Fructose was given as 20% solution in drinking water, and quercetin (15 mg/kg/day) was administered by oral gavage. Treadmill running exercises were applied 30 min a day for 5 days a week. After the experiments, biochemical assays, Lee index, and body fat mass analyses were measured. Result: Fructose administration caused a statistically significant increase in systolic blood pressures (SBP), triglycerides (TG), VLDL-cholesterol, glucose, insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) compared with the control group, and the MetS model was successfully demonstrated (P < 0.05). It was determined that SBP, serum TG, serum insulin, HOMA-IR, and Lee indexes, and body fat mass, were decreased in the F + E group (P < 0.05). In addition, it was found that the MetS-related parameters improved, except lipid profile in the F + Q group (P < 0.05). Conclusion: These results show that high fructose consumption leads to elevated SBP, TG, cholesterol, body fat mass, glucose, insulin, and HOMA-IR levels, and aerobic exercise training treatment has beneficial effects on these biochemical parameters in rats. Although quercetin has positive effects on SBP and insulin levels, it was observed to cause a significant increase especially in TG and body fat mass. Therefore, more detailed dose studies and pathways of quercetin are needed to elucidate its mechanism of action in body fat mass.

Evaluation of Therapeutic Effects of Quercetin Against Achilles Tendinopathy in Rats via Oxidative Stress, Inflammation, Apoptosis, Autophagy, and Metalloproteinases.

BACKGROUND: Achilles tendinopathy, seen in athletes and manual labor workers, is an inflammatory condition characterized by chronic tendon pain. Owing to the toxicity that develops in various organs attributed to the use of anti-inflammatory drugs, there is a need for new therapeutic agents. PURPOSE: In the present study, the effects of quercetin (Que), the one that attracted the most attention of researchers studying this group of flavonoids, were investigated against collagenase-induced tendinopathy. STUDY DESIGN: Controlled laboratory study. METHODS: A total of 35 Sprague-Dawley rats were used in the study. Tendinopathy was created by injecting a single dose of collagenase (10 µL; 10 mg/mL) into the tendons of rats. Thirty minutes after the injection, Que was administered at doses of 25 or 50 mg/kg. Que administration was carried out for 7 days. Animals underwent a motility test at the end of the study. In addition, markers of oxidative stress, inflammation, apoptosis, and autophagy, as well as the expression levels of matrix metalloproteinases (MMPs 2, 3, 9, and 13), ICAM-1, and STAT3, were measured in tendon tissues with biochemical, molecular, and Western blot techniques. RESULTS: The results showed that oxidative stress, inflammation, apoptosis, and autophagy were triggered by the injection of collagenase. In addition, MMPs, ICAM-1, and STAT3 were activated to participate in the development of tendinopathy. Que was found to reduce ICAM-1 levels in tendon tissue. Moreover, Que showed antioxidant, anti-inflammatory, antiapoptotic, and antiautophagic effects on tendons against tendinopathy. More important, Que suppressed the expression of MMPs in the tendon tissues. CONCLUSION: Que has protective properties against collagenase-induced tendon damage in rats. CLINICAL RELEVANCE: We believe that with further study, Que may be shown to be an alternative treatment option for athletes or others who experience tendon injuries.

The therapeutic efficacy of quercetin in combination with antiviral drugs in hospitalized COVID-19 patients: A randomized controlled trial.

In this study, the therapeutic efficacy of quercetin in combination with remdesivir and favipiravir, were evaluated in severe hospitalized COVID-19 patients. Our main objective was to assess the ability of quercetin for preventing the progression of the disease into critical phase, and reducing the levels of inflammatory markers related to SARS-Cov-2 pathogenesis. Through an open-label clinical trial, 60 severe cases were randomly divided into control and intervention groups. During a 7-day period, patients in the control group received antivirals, i.e., remdesivir or favipiravir, while the intervention group was treated with 1000 mg of quercetin daily in addition to the antiviral drugs. According to the results, taking quercetin was significantly associated with partial earlier discharge and reduced serum levels of ALP, q-CRP, and LDH in the intervention group. Furthermore, although the values were in normal range, the statistical outputs showed significant increase in hemoglobin level and respiratory rate in patients who were taking quercetin. Based on our observations, quercetin is safe and effective in lowering the serum levels of ALP, q-CRP, and LDH as critical markers involved in COVID-19 severity. However, according to the non-significant borderline results in comparing the mortality, the ICU-admission rate, and the duration of ICU-admission, further studies can be helpful to compensate the limitations of our study and clarify the therapeutic potential of quercetin in COVID-19 treatments.

The effects of quercetin on seizure, inflammation parameters and oxidative stress in acute on chronic tramadol intoxication.

BACKGROUND: Tramadol is a widely used synthetic opioid for moderate to severe pain. Some studies have shown that tramadol can increase oxidative stress in different tissues of the body. Quercetin is also a substance with various biological effects, including antioxidant, anti-inflammatory, hepatoprotective, nephroprotective, and cardioprotective activities. The current investigation aimed at determining the effects of quercetin, with or without naloxone, on tramadol intoxication. METHODS: This study was performed on 30 male Wistar rats divided into five groups: Group I) control group: intraperitoneal injections of normal saline 0.9% for 14 days; Group II) tramadol: 25 mg/kg for 14 days, and then a 50 mg/kg acute dose injection on the last day; Group III) acute quercetin (single dose): tramadol injection as with the second group plus 100 mg/kg of quercetin on the last day; Group IV) chronic quercetin: tramadol injection similar to the second group plus quercetin 100 mg/kg for 14 days; Group V) quercetin plus naloxone: tramadol injection similar to the second group plus injection of quercetin 100 mg/kg + intravenous naloxone 2 mg/kg on the last day, followed by a 4 mg/kg/h injection of naloxone for six hours. The rats were monitored for six hours on the last day, relating to the number and severity of seizures. Finally, the samples were prepared for biochemical investigation of the serum level of oxidative stress markers (MDA, SOD, NOx), inflammatory factors (IL-6, TNF-α), biochemical parameters (ALT, AST, creatinine, glucose) and hematological assay. The liver, heart, kidney, cortex, cerebellum, and adrenal tissues were collected to investigate the redox state. RESULTS: None of the treatments had positive effects on the number and severity of seizures. Chronic administration of quercetin led to alteration of some blood parameters, including reduced hemoglobin level and elevated platelet counts. Acute on chronic tramadol administration resulted in a significant rise in AST, where different treatments failed to reduce their levels down to the control group. CONCLUSION: chronic administration of quercetin showed decreased oxidative/nitrosative stress in the liver, kidney, adrenal, and heart tissues. Quercetin plus naloxone decreased oxidative stress in the heart and adrenal tissues, but adverse effects on the brain cortex and hepatic function. Single-dose quercetin reduced cardiac oxidative stress.

Pharmacological basis and new insights of taxifolin: A comprehensive review.

The pharmacological characteristics of phytochemicals have prompted a lot of interest in their application in disease management. Due to the high incidence of cancer related mortality and morbidity throughout the world; experiments have concentrated on identifying the anticancer potential of natural substances. Many phytochemicals such as flavonoids and their derivatives produced from food offer a variety of new anti-cancer agents which prevent the cancer progression. Taxifolin, a unique bioactive flavonoid, is a dietary component that has grabbed the interest of dietitians and medicinal chemists due to its wide range of health benefits. It is a powerful antioxidant with a well-documented effect in the prevention of several malignancies in humans. Taxifolin has shown promising inhibitory activity against inflammation, malignancies, microbial infection, oxidative stress, cardiovascular disease, and liver disease. Anti-cancer activity has been shown to be relatively significant than other activities investigated in vitro and in vivo with a little or no side effects to the normal healthy cells. In summary this review offers the synopsis of recent breakthroughs in the use of taxifolin as a cancer treatment, as well as mechanisms of action. However, to develop a medicine for human usage, more study on pharmacokinetic profile, profound molecular mechanisms, and drug safety criteria should be conducted utilizing well-designed randomized clinical trials.

Quercetin decreases the antinociceptive effect of diclofenac in an arthritic gout-pain model in rats.

OBJECTIVE: To analyse the antinociceptive interaction between quercetin (QUER) and diclofenac (DIC) in experimental arthritic gout-pain. METHODS: The antinociceptive effect of DIC and QUER alone and in combination were evaluated using an arthritic gout-pain model. Pain was induced through intra-articular administration of uric acid in the rats and the treatments were administered 2 h later. Additionally, the cyclooxygenase (COX) activity was determined in rats treated with DIC, QUER and their combination. KEY FINDINGS: DIC induced a maximal effect of 69.7 ± 2.7% with 3.1 mg/kg; whereas QUER only produced 17.6 ± 2.6% with the maximal dose (316 mg/kg). Ten of twelve DIC + QUER combinations showed a lesser antinociceptive effect than DIC alone did (P < 0.05). Moreover, DIC reduced total-COX (70.4 ± 1.3 versus 52.4 ± 1.8 and 77.4 ± 9.0 versus 56.1 ± 1.3, P < 0.05) and COX-2 (60.1 ± 1.0 versus 42.4 ± 1.8 and 58.1 ± 2.4 versus 48.7 ± 1.3, P < 0.05) activity after 1 and 3 h, respectively. Nevertheless, only the COX-2 activity induced by DIC was prevented in the presence of QUER (63.2 ± 3.0 versus 60.1 ± 1.0 and 56.6 ± 1.3 versus 58.1 ± 2.4 at 1 and 3 h, respectively). CONCLUSIONS: All these data demonstrated that the simultaneous administration of QUER + DIC produces an unfavorable interaction on the antinociceptive effect of DIC. Therefore, this combination might not be recommendable to relieve arthritic gout-pain.

Sodium R-lipoate and enzymatically-modified isoquercitrin suppressed IgE-independent anaphylactic reactions and stress-induced gastric ulceration in mice.

Anaphylaxis is a life-threatening allergic reaction, for which the worldwide prevalence is rapidly increasing. The currently used synthetic antiallergic drugs have a high tendency to cause adverse effects, like gastric ulcers, in long-term use. Therefore, a great deal of attention has been given to develop new safer and more effective antiallergic agents from natural compounds that are chemically/enzymatically-modified. Here, we evaluated/compared the efficacy of two different doses (50 and 100 mg/kg body weight "b.w", given orally) of sodium R-lipoate (NaRLA) and enzymatically-modified isoquercitrin (EMIQ) in alleviating both local/systemic non-immunological anaphylactic reactions and stress-induced gastric ulceration in mice, in comparison with sulfasalazine (SSZ) as a reference drug. The results indicated that the pre-treatment of animals with NaRLA or EMIQ (especially at 100 mg/kg b.w) completely succeeded, as SSZ, in alleviating the hind paw edema induced by either histamine or compound 48/80 (Cpd 48/80). Furthermore, NaRLA and EMIQ prevented the mast cell degranulation and anaphylactic shock caused by Cpd 48/80 (in a dose-dependent manner) and reduced significantly (P < 0.001) the histamine release from the mouse peritoneal mast cells, like SSZ. Moreover, their use was associated with alleviating both gastric histopathological and biochemical alterations in the water-restraint stress (WRS) mice model towards the control values. They also decreased the percentage of degranulated mesenteric mast cells in the WRS mice model. In conclusion, our findings provide possibility that both NaRLA and EMIQ may serve as an effective therapeutic agents for mast cells-dependent anaphylactic reactions without risks of inducing gastric ulcers.

Mild exacerbation of obesity- and age-dependent liver disease progression by senolytic cocktail dasatinib + quercetin.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent and represents a growing challenge in terms of prevention and treatment. A minority of affected patients develops inflammation, subsequently fibrosis, cirrhosis and hepatocellular carcinoma (HCC). HCC is a leading cause of cancer-related death. An increased number of senescent cells correlate with age-related tissue degeneration during NAFLD-induced HCC. Senolytics are promising agents that target selectively senescent cells. Previous studies showed that whereas a combination of the senolytic drugs dasatinib and quercetin (D + Q) reduced NAFLD in mice, D + Q lacked efficacy in removing doxorubicin-induced ß-gal-positive senescent cells in human HCC xenografted mice. Whether D + Q has an effect on the age-associated spectrum of NAFLD-inflammation-HCC remains unknown. METHODS: Here, we utilized an established model of age- and obesity-associated HCC, the low dose diethylnitrosamine (DEN)/high fat diet (HFD), a regimen promoting liver inflammation and tumorigenesis over a long period of 9 months. Four groups of mice each were created: group 1 included control untreated mice; group 2 included mice treated with D + Q; group 3 included mice undergoing the DEN/HFD protocol; group 4 included mice undergoing the DEN/HFD protocol with the administration of D + Q. At the end of the chemical/dietary regimen, we analyzed liver damage and cell senescence by histopathology, qPCR and immunoblotting approaches. RESULTS: Unexpectedly, D + Q worsened liver disease progression in the DEN/HFD mouse model, slightly increasing histological damage and tumorigenesis, while having no effect on senescent cells removal. CONCLUSIONS: In summary, using an animal model that fully recapitulates NAFLD, we demonstrate that these compounds are ineffective against age-associated NAFLD-induced HCC. Video Abstract.