Quercetin decreases fructose drinking in model of fructose-induced insulin resistance. Unexpected uric acid and TBARS lowering effect of methyl cellulose vehicle and fructose combination.

The aim of this study was to improve insulin sensitivity in fructose-treated animals by ingestion of flavonoid quercetin. Several signs of insulin resistance have been developed in rats by drinking 10% fructose solution for 9 weeks. The effect of 6-week-gavage-administrated quercetin (20 mg/kg/day in 1% methyl cellulose solution) was monitored. Rats of the control groups received methyl cellulose vehicle as well. The most striking result of the quercetin treatment was the normalization of the fructose solution drinking to the level of drinking water intake. In addition, quercetin supplementation considerably decreased the plasma glucose and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) index in rats consuming fructose. Surprisingly, fructose ingestion did not elevate plasma uric acid, thiobarbituric acid reactive substances, nitrotyrosine, or advanced glycation end products fluorescence. Instead, a reduction of the above parameters was observed. In summary, these results indicate that quercetin supplementation reduces fructose drinking and decreases plasma glucose and the HOMA-IR index. Furthermore, methyl cellulose, in combination with fructose, causes uric acid - lowering, antioxidant and anti-glycation effects. Thus, methyl cellulose possibly shifts fructose metabolism in favor of the utilization of antioxidant features of fructose. Our results call for using methyl cellulose in sweetened beverages and other sweetened food.

Polydopamine Synergizes with Quercetin Nanosystem to Reshape the Perifollicular Microenvironment for Accelerating Hair Regrowth in Androgenetic Alopecia.

Accumulated reactive oxygen species (ROS) and their resultant vascular dysfunction in androgenic alopecia (AGA) hinder hair follicle survival and cause permanent hair loss. However, safe and effective strategies to rescue hair follicle viability to enhance AGA therapeutic efficiency remain challenging. Herein, we fabricated a quercetin-encapsulated (Que) and polydopamine-integrated (PDA@QLipo) nanosystem that can reshape the perifollicular microenvironment to initial hair follicle regeneration for AGA treatment. Both the ROS scavenging and angiogenesis promotion abilities of PDA@QLipo were demonstrated. In vivo assays revealed that PDA@QLipo administrated with roller-microneedles successfully rejuvenated the "poor" perifollicular microenvironment, thereby promoting cell proliferation, accelerating hair follicle renewal, and facilitating hair follicle recovery. Moreover, PDA@QLipo achieved a higher hair regeneration coverage of 92.5% in the AGA mouse model than minoxidil (87.8%), even when dosed less frequently. The nanosystem creates a regenerative microenvironment by scavenging ROS and augmenting neovascularity for hair regrowth, presenting a promising approach for AGA clinical treatment.

Exploring the potential of quercetin in Alzheimer's Disease: Pharmacodynamics, Pharmacokinetics, and Nanodelivery systems.

Alzheimer's disease (AD) is a primary cause of dementia that affects millions of people worldwide and its prevalence is likely to increase largely in the coming decades. Multiple complex pathways, such as oxidative stress, tau and amyloid-beta (Aß) pathology, and cholinergic dysfunction, are involved in the pathogenesis of Alzheimer's disease. The conventional treatments provide only symptomatic relief and not a complete cure for the disease. On the other hand, recent studies have looked into the possibility of flavonoids as an effective therapeutic strategy for treating AD. Quercetin, a well-known flavonol, has been extensively studied for AD treatment. Therefore, this review mainly focuses on the pharmacokinetics properties of quercetin and its modes of action, such as antioxidant, anti-inflammatory, anti-amyloidogenic, and neuroprotective properties, which are beneficial in treating AD. It also highlights the nano delivery systems of quercetin, including liposomes, nanostructures lipid carriers, solid lipid nanoparticles, nanoemulsions, microemulsions, self-emulsifying drug delivery systems, and nanoparticles reported for AD treatment. The remarkable potential of quercetin nanocarriers has been reflected in enhancing its bioavailability and therapeutic efficacy. Therefore, clinical studies must be conducted to explore it as a therapeutic strategy for Alzheimer's disease.

The combined analysis of transcriptomics and metabolomics reveals the mechanisms by which dietary quercetin regulates growth and immunity in Penaeus vannamei.

As a potent antioxidant, the flavonoid compound quercetin (QUE) has been widely used in the farming of aquatic animals. However, there are fewer reports of the beneficial effects, especially in improving immunity of Penaeus vannamei by QUE. The aim of this study was to investigate the effects of dietary QUE on growth, apoptosis, antioxidant and immunity of P. vannamei. It also explored the potential mechanisms of QUE in improving the growth and immunity of P. vannamei. P. vannamei were fed diets with QUE for 60 days. The results revealed that QUE (0.5 or 1.0 g/kg) ameliorated the growth, and the expressions of genes related to apoptosis, antioxidant, and immunity. The differentially expressed genes (DEGs) and differential metabolites (DMs) obtained through transcriptomics and metabolomics, respectively, enriched in pathways related to nutritional metabolism such as lipid metabolism, amino acid metabolism, and carbohydrate metabolism. After QUE addition, especially at 0.5 g/kg, DEGs were enriched into the functions of response to stimulus and antioxidant activity, and the pathways of HIF-1 signaling pathway, C-type lectin receptor signaling pathway, Toll-like receptor signaling pathway, and FoxO signaling pathway. In conclusion, dietary QUE can ameliorate growth, apoptosis, antioxidant and immunity of P. vannamei, the appropriate addition amount was 0.5 g/kg rather than 1.0 g/kg. Regulations of QUE on nutrient metabolism and immune-related pathways, and bioactive metabolites, were important factors for improving the aforementioned abilities in P. vannamei.

Intranasal Delivery of Carvedilol- and Quercetin-Encapsulated Cationic Nanoliposomes for Cardiovascular Targeting: Formulation and In Vitro and Ex Vivo Studies.

Carvedilol (CVD), an adrenoreceptor blocker, is a hydrophobic Biopharmaceutics Classification System class II drug with poor oral bioavailability due to which frequent dosing is essential to attain pharmacological effects. Quercetin (QC), a polyphenolic compound, is a potent natural antioxidant, but its oral dosing is restricted due to poor aqueous solubility and low oral bioavailability. To overcome the common limitations of both drugs and to attain synergistic cardioprotective effects, we formulated CVD- and QC-encapsulated cationic nanoliposomes (NLPs) in situ gel (CVD/QC-L.O.F.) for intranasal administration. We designed CVD- and QC-loaded cationic nanoliposomal (NLPs) in situ gel (CVD/QC-L.O.F.) for intranasal administration. In vitro drug release studies of CVD/QC-L.O.F. (16.25%) exhibited 18.78 ± 0.57% of QC release and 91.38 ± 0.93% of CVD release for 120 h. Ex vivo nasal permeation studies of CVD/QC-L.O.F. demonstrated better permeation of QC (within 96 h), i.e., 75.09% compared to in vitro drug release, whereas CVD permeates within 48 h, indicating the better interaction between cationic NLPs and the negatively charged biological membrane. The developed nasal gel showed a sufficient mucoadhesive property, good spreadability, higher firmness, consistency, and cohesiveness, indicating suitability for membrane application and intranasal administration. CVD-NLPs, QC-NLPs, and CVD/QC-NLPs were evaluated for in vitro cytotoxicity, in vitro ROS-induced cell viability assessment, and a cellular uptake study using H9c2 rat cardiomyocytes. The highest in vitro cellular uptake of CVD/QC-cationic NLPs by H9c2 cells implies the benefit of QC loading within the CVD nanoliposomal carrier system and gives evidence for better interaction of NLPs carrying positive charges with the negatively charged biological cells. The in vitro H2O2-induced oxidative stress cell viability assessment of H9c2 cells established the intracellular antioxidant activity and cardioprotective effect of CVD/QC-cationic NLPs with low cytotoxicity. These findings suggest the potential of cationic NLPs as a suitable drug delivery carrier for CVD and QC combination for the intranasal route in the treatment of various cardiovascular diseases like hypertension, angina pectoris, etc. and for treating neurodegenerative disorders.

[The use of antioxidants in combination therapy of chronic prostatitis].

Currently, the significance of the chronic prostatitis (CP) is undoubted. Oxidative stress is considered as one of the standard mechanisms of cellular damage that is associated with inflammatory diseases such as CP. When choosing the combination therapy for this group of patients, a correction of oxidative stress is pathogenetically justified. Literature data about the pathogenetic feasibility and prospects of using a biologically active complex containing flavonoids and carotenoids quercetin, lycopene and naringin as part of the combination treatment of patients with CP are presented in the article. Considering the various effects of the biologically active complex Querceprost, containing quercetin, lycopene and naringin, among which antioxidant, anti-inflammatory, antimicrobial and immunomodulatory are of greatest importance, as well as taking into account the synergistic effect of flavonoids and carotenoids, we suggest that Querceprost is promising component of combination treatment of patients with CP.

Neurotherapeutic effects of quercetin-loaded nanoparticles and Biochanin-A extracted from Trifolium alexandrinum on PI3K/Akt/GSK-3ß signaling in the cerebral cortex of male diabetic rats.

Diabetes mellitus (DM) is a severe metabolic disease that can have significant consequences for cognitive health. Bioflavonoids such as Trifolium alexandrinum (TA), quercetin (Q), and Biochanin-A (BCA) are known to exert a wide range of pharmacological functions including antihyperglycemic activity. This study aimed to investigate the neurotherapeutic effects of quercetin-loaded nanoparticles (Q-LNP) and BCA extracted from TA against diabetes-induced cerebral cortical damage through modulation of PI3K/Akt/GSK-3ß and AMPK signaling pathways. Adult male Wistar albino rats (N = 25) were randomly assigned to one of five groups: control, diabetics fed a high-fat diet (HFD) for 2 weeks and intraperitoneally (i.p.) injected with STZ (40 mg/kg), and diabetics treated with Q-LNP (50 mg/kg BW/day), BCA (10 mg/kg BW/day), or TA extract (200 mg/kg BW/day). Treatments were applied by oral gavage once daily for 35 days. Diabetic rats treated with Q-LNP, BCA, and TA extract showed improvement in cognitive performance, cortical oxidative metabolism, antioxidant parameters, and levels of glucose, insulin, triglyceride, and total cholesterol. In addition, these treatments improved neurochemical levels, including acetylcholine, dopamine, and serotonin levels as well acetylcholinesterase and monoamine oxidase activities. Furthermore, these treatments lowered proinflammatory cytokine production for TNF-α and NF-κB; downregulated the levels of IL-1ß, iNOS, APP, and PPAR-γ; and attenuated the expressions of PSEN2, BACE, IR, PI3K, FOXO 1, AKT, AMPK, GSK-3ß, and GFAP. The histopathological examinations of the cerebral cortical tissues confirmed the biochemical results. Overall, the present findings suggest the potential therapeutic effects of TA bioflavonoids in modulating diabetes-induced cerebral cortical damage.

Curcumin and quercetin co-encapsulated in nanoemulsions for nasal administration: A promising therapeutic and prophylactic treatment for viral respiratory infections.

One of the most frequent causes of respiratory infections are viruses. Viruses reaching the airways can be absorbed by the human body through the respiratory mucosa and mainly infect lung cells. Several viral infections are not yet curable, such as coronavirus-2 (SARS-CoV-2). Furthermore, the side effect of synthetic antiviral drugs and reduced efficacy against resistant variants have reinforced the search for alternative and effective treatment options, such as plant-derived antiviral molecules. Curcumin (CUR) and quercetin (QUE) are two natural compounds that have been widely studied for their health benefits, such as antiviral and anti-inflammatory activity. However, poor oral bioavailability limits the clinical applications of these natural compounds. In this work, nanoemulsions (NE) co-encapsulating CUR and QUE designed for nasal administration were developed as promising prophylactic and therapeutic treatments for viral respiratory infections. The NEs were prepared by high-pressure homogenization combined with the phase inversion temperature technique and evaluated for their physical and chemical characteristics. In vitro assays were performed to evaluate the nanoemulsion retention into the porcine nasal mucosa. In addition, the CUR and QUE-loaded NE antiviral activity was tested against a murine ß-COV, namely MHV-3. The results evidenced that CUR and QUE loaded NE had a particle size of 400 nm and retention in the porcine nasal mucosa. The antiviral activity of the NEs showed a percentage of inhibition of around 99 %, indicating that the developed NEs has interesting properties as a therapeutic and prophylactic treatment against viral respiratory infections.

Senolytic drugs dasatinib and quercetin combined with Carboplatin or Olaparib reduced the peritoneal and adipose tissue metastasis of ovarian cancer.

Chemotherapy and targeted drugs-induced senescent ovarian cancer cells that accumulate in peritoneal adipose tissue contribute significantly to chronic inflammation, disrupt homeostasis, and may fuel various aspects of cancer progression. However, the pro-senescence effects of chemotherapy and targeted drugs on adipose derived stem cells (ADSCs) within peritoneal adipose tissue remain poorly understood. In this study, we show that the first-line chemotherapy and targeted drugs can induce the cellular senescence of ADSCs in vitro and increase the aging of peritoneal adipose tissue in vivo. These treatments significantly promoted the dysregulation of glucose and lipid metabolism, including insulin resistance and liver lipid accumulation. Our study shows that dasatinib and quercetin, as senolytics, effectively restore glucose homeostasis in mice with ovarian cancer and significantly reduce adipose tissue aging. Importantly, combining these drugs with Carboplatin or Olaparib results in a marked decrease in both peritoneal and adipose tissue metastasis of ovarian cancer cells. Mechanistically, we revealed that there is crosstalk between ovarian cancer cells and senescent ADSCs. The crosstalk increases inflammatory cytokines and chemokines production in ADSCs and notably upregulates chemokine receptors on cancer cells. Collectively, these data indicate that senescent ADSCs induced by chemotherapy and targeted therapy drugs impair adipose tissue function. However, the senolytic drugs dasatinib and quercetin, can significantly ameliorate organ aging and damage induced by these treatments. Notably, dasatinib and quercetin combined with Carboplatin or Olaparib reduced the peritoneal and adipose tissue metastasis of ovarian cancer, ultimately benefiting the mice undergoing chemotherapy and targeted therapy.

Beneficial effects of quercetin on vincristine-induced liver injury in rats: Modulating the levels of Nrf2/HO-1, NF-kB/STAT3, and SIRT1/PGC-1α.

Our experimental objective was to investigate the hepatotoxic effect of vincristine (VCR) administration in rats and determined whether combined therapy with Quercetin (Quer) ensured protection. Five groups with seven rats each were used for this purpose, and experimental groups were formulated as follows: Control group; Quer group; VCR group; VCR plus Quer 25 group; VCR plus Quer 50 group. The results showed that VCR significantly increased the activity of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) enzymes. Besides, VCR caused considerable increases in the malondialdehyde (MDA) contents, along with significant decreases in reduced glutathione levels, superoxide dismutase, catalase, and glutathione peroxidase enzyme activities in the rat livers. Quer treatment in VCR toxicity markedly decreased the activity of ALT, AST, ALP enzymes, and MDA contents and enhanced the activities of antioxidant enzymes. The results also showed that VCR significantly increased the levels of NF-kB, STAT3, and the expression of caspase 3, Bax, and MAP LC3 and decreased the expression of Bcl2 and levels of Nrf2, HO-1, SIRT1, and PGC-1α. Compared to the VCR group, Quer treatment exhibited significantly lower levels of NF-kB, STAT3, and the expression of caspase 3, Bax, and MAP LC3, and higher levels of Nrf2, HO-1, SIRT1, and PGC-1α. In conclusion, our study demonstrated that Quer could alleviate the harmful effects of VCR via activation of NRf2/HO-1 and SIRT1/PGC-1α pathways, and via attenuation of oxidative stress, apoptosis, autophagy, and NF-kB/STAT3 pathways.

Quercetin and resveratrol are associated with the downregulation of TNFalpha/NF-kB/inos axis-mediated acute liver injury in rats induced by paracetamol poisoning / La quercetina y el resveratrol están asociados con la regulación decreciente de la lesión hepática aguda mediada por el eje TNF-alfa/NF-kB/inos en ratas inducida por envenenamiento con paracetamol

SUMMARY: Paracetamol (known as acetaminophen, or APAP) poisoning causes acute liver damage that can lead to organ failure and death. We sought to determine that APAP overdose can augment tumor necrosis factor-alpha (TNF-α)/ nuclear factor kappa B (NF-kB)/induced nitic oxide synthase (iNOS) axis-mediated hepatotoxicity in rats, and the anti-inflammatory polyphenolic compounds, quercetin (QUR) plus resveratrol (RES) can ameliorate these parameters. Therefore, we induced acute hepatotoxicity in rats using APAP overdose (2 g/kg, orally) and the protective group of rats were treated with 50 mg/kg QUR plus 30 mg/kg RES for one week before APAP ingestion. Animals were killed at day 8. APAP poisoning caused the induction of hepatic tissue levels of TNF-α, NF-kB, and iNOS, which were significantly (p<0.05) decreased by QUR+RES. QUR+RES, also inhibited liver injury biomarkers, alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Additionally, a link between liver injury and TNF-α /NF-kB / iNOS axis mediated hepatotoxicity was observed. Thus, the presented data backing the conclusion that intoxication by paracetamol increases TNF-α / NF-kB / iNOS axis -mediated hepatotoxicity, and is protected by a combination of quercetin and resveratrol.

El envenenamiento por paracetamol (conocido como acetaminofeno o APAP) causa daño hepático agudo que puede provocar una insuficiencia orgánica y la muerte. El objetivo de este trabajo fue determinar si la sobredosis de APAP puede aumentar la hepatotoxicidad mediada por el eje del factor de necrosis tumoral alfa (TNF-α)/factor nuclear kappa B (NF-kB)/óxido nítico sintasa inducida (iNOS) en ratas, y si el polifenólico antiinflamatorio compuesto por quercetina (QUR) más resveratrol (RES) pueden mejorar estos parámetros. Por lo tanto, inducimos hepatotoxicidad aguda en ratas usando una sobredosis de APAP (2 g/kg, por vía oral). El grupo protector de ratas se trató con 50 mg/ kg de QUR más 30 mg/kg de RES durante una semana antes de la ingestión de APAP. Los animales se sacrificaron el día 8. El envenenamiento con APAP en el tejido hepático provocó la inducción de niveles de TNF-α, NF-kB e iNOS, que se redujeron significativamente (p<0,05) con QUR+RES. QUR+RES, también inhibió los biomarcadores de daño hepático, la alanina aminotransferasa (ALT) y el aspartato aminotransferasa (AST). Además, se observó una relación entre la lesión hepática y la hepatotoxicidad mediada por el eje TNF-α /NF-kB/iNOS. Por lo tanto, los datos presentados respaldan la conclusión de que la intoxicación por paracetamol aumenta la hepatotoxicidad mediada por el eje TNF-α /NF-kB / iNOS, y está protegida por una combinación de quercetina y resveratrol.

Enhancement of Annexin V in response to combination of epigallocatechin gallate and quercetin as a potent arrest the cell cycle of colorectal cancer / Aumento da anexina V em resposta à combinação de galato de epigalocatequina e quercetina como uma potente parada do ciclo celular do câncer colorretal

Colorectal cancer (CRC) is one of the most common cancers leading to comorbidities and mortalities globally. The rational of current study was to evaluate the combined epigallocatechin gallate and quercetin as a potent antitumor agent as commentary agent for therapeutic protocol. The present study investigated the effect of epigallocatechin Gallate (EGCG) (150mg) and quercetin (200mg) at different proportions on proliferation and induction of apoptosis in human colon cancer cells (HCT-116). Cell growth, colonogenic, Annexin V in addition cell cycle were detected in response to phytomolecules. Data obtained showed that, the colony formation was inhibited significantly in CRC starting from the lowest concentration tested of 10 µg/mL resulting in no colonies as visualized by a phase-contrast microscope. Data showed a significant elevation in the annexin V at 100 µg/mL EGCG(25.85%) and 150 µg/mL quercetin (48.35%). Moreover, cell cycle analysis showed that this combination caused cell cycle arrest at the G1 phase at concentration of 100 µg/mL (72.7%) and 150 µg/mL (75.25%). The combined effect of epigallocatechin Gallate and quercetin exert antiproliferative activity against CRC, it is promising in alternative conventional chemotherapeutic agent.

O câncer colorretal (CCR) é um dos cânceres mais comuns, levando a comorbidades e mortalidade em todo o mundo. O racional do presente estudo foi avaliar a combinação de galato de epigalocatequina e quercetina como um agente antitumoral potente como agente de comentário para protocolo terapêutico. O presente estudo investigou o efeito de galato de epigalocatequina (EGCG) (150 mg) e quercetina (200 mg) em diferentes proporções na proliferação e indução de apoptose em células de câncer de cólon humano (HCT-116). O crescimento celular, colonogênico, anexina V, além do ciclo celular foram detectados em resposta a fitomoléculas. Os dados obtidos mostraram que a formação de colônias foi inibida significativamente no CRC a partir da concentração mais baixa testada de 10 µg/mL, resultando em nenhuma colônia conforme visualizado por um microscópio de contraste de fase. Os dados mostraram uma elevação significativa na anexina V a 100 µg/mL de EGCG (25,85%) e 150 µg/mL de quercetina (48,35%). Além disso, a análise do ciclo celular mostrou que essa combinação causou parada do ciclo celular na fase G1 na concentração de 100 µg/mL (72,7%) e 150 µg/mL (75,25%). O efeito combinado da epigalocatequina galato e quercetina exerce atividade antiproliferativa contra o CCR, é promissor como agente quimioterápico alternativo convencional.

Evaluation of the inhibitory effect of quercetin on the pharmacokinetics of tucatinib in rats by a novel UPLC-MS/MS assay.

CONTEXT: Tucatinib (CYP2C8 substrate) and quercetin (CYP2C8 inhibitor) are two common drugs for the treatment of cancer. However, the effect of quercetin on the metabolism of tucatinib remains unknown. OBJECTIVE: We validated a sensitive method to quantify tucatinib levels in rat plasma based on ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), which was successfully employed to explore the effect of quercetin on tucatinib pharmacokinetics in rats. MATERIALS AND METHODS: An Acquity UPLC BEH C18 column was applied to achieve the separation of tucatinib and internal standard (IS) talazoparib after protein precipitation with acetonitrile. Then, we used this assay to investigate the effect of different doses of quercetin (25, 50 and 100 mg/kg) on the exposure of orally administered tucatinib (30 mg/kg) in 24 Sprague-Dawley (SD) rats, which were randomly divided into three quercetin pre-treated groups and one control group (n = 6). RESULTS: Our developed assay was verified in all aspects of bioanalytical method validation, involving lower limit of quantification (LLOQ), selectivity, accuracy and precision, calibration curve, extraction recovery, matrix effect and stability. After pre-treatment with 100 mg/kg quercetin, AUC0→t, AUC0→∞ and Cmax of tucatinib were remarkably increased by 75.4%, 75.8% and 59.1% (p < 0.05), respectively, while CLz/F was decreased significantly by 47.3% (p < 0.05) when compared with oral administration of 30 mg/kg tucatinib alone. This change is dose-dependent. CONCLUSIONS: This study will help better understand the pharmacokinetic properties of tucatinib with concurrent use with quercetin, and more clinical verifications were inspired to confirm whether this interaction has clinical significance in humans.

Dasatinib plus quercetin attenuates some frailty characteristics in SAMP10 mice.

Senolytics are a class of drugs that selectively remove senescent cells. Dasatinib and quercetin have been discovered, and their combination has shown various anti-ageing effects. The SAMP10 mouse strain is a model of brain ageing. Here, we investigated the effect of combination on frailty characteristics in SAMP10. By comparing SAMP10 with SAMR1 mice as normal ageing controls, we investigated some frailty characteristics. Frailty was assessed at 18-38 weeks of age with a clinical frailty index. Motor and cognitive function of these mice were evaluated using behavioral experiments. SAMP10 mice were divided into vehicle and combination, and these functions and histological changes in the brain hippocampus were investigated. Finally, the in vitro effects of combination on oxidative stress-induced senescent muscle and neuronal cells were investigated. As a result, we found that frailty index was higher in SAMP10 than SAMR1. Motor and cognitive function were worse in SAMP10 than SAMR1. Furthermore, combination therapy improved frailty, motor and cognitive function, and the senescent phenotype of the hippocampus compared with vehicle in SAMP10. In summary, SAMP10 showed more marked frailty characteristics than SAMR1, and dasatinib and quercetin attenuated them in SAMP10. From our results, senolytic therapy might contribute protective effects against frailty.

Combined and targeted drugs delivery system for colorectal cancer treatment: Conatumumab decorated, reactive oxygen species sensitive irinotecan prodrug and quercetin co-loaded nanostructured lipid carriers.

PURPOSE: Colorectal cancer (CRC) is the third most frequently diagnosed cancer and this study aimed to develop a conatumumab decorated, irinotecan prodrug and quercetin co-loaded delivery system for combined and targeted colorectal cancer treatment. METHODS: A conatumumab (C) decorated, irinotecan prodrug (I-p) and quercetin (Q) co-encapsulated NLC (C I-p/Q NLC) was developed. In vitro and in vivo antitumor efficiency of NLC was evaluated on CRC cells and mice xenograft. RESULTS: The results showed that the HT-29 cells uptake of C I-p/Q NLC was over 70%. Reactive oxygen species (ROS) sensitive irinotecan prodrug formulation showed improved drug release ability in hypoxic conditions. C I-p/Q NLC showed significantly higher cytotoxicity than non-decorated NLC, single drug-loaded NLC and free drugs. In vivo studies in a CRC-bearing model corroborated the capability of nanoparticles for the inhibition of cancer, leading to a reduction of tumor growth without systemic toxicity. CONCLUSION: The conatumumab decorated, ROS sensitive prodrug contained combination nano-system is a promising platform for CRC therapy.

Study on the molecular mechanism of nightshade in the treatment of colon cancer.

The present study attempts to explore the effective components, action targets, and potential mechanism of nightshade for colon cancer treatment. The relationship network diagram of 'traditional Chinese medicine - component - target - disease' was firstly constructed by employing network pharmacology. Experiments were conducted in vivo and in vitro to verify the influence of quercetin, the core effective component of nightshade, on colon cancer. Meanwhile, the regulatory effects of quercetin on core targets and main signaling pathways were determined. Based on the network diagram of 'traditional Chinese medicine - component - target - disease' and KEGG analysis, quercetin might exhibit certain effects on colon cancer treatment by regulating the biological behavior of core targets related to cell apoptosis in tumors including PIK3R1, PIK3CA, Akt1, and Akt2. Furthermore, quercetin has been demonstrated in vitro experiments to suppress the proliferation and migration of colon cancer cells whereas promote their apoptosis in a dose-dependent fashion. In vivo experiments indicate that quercetin had an antitumor effect on human colon cancer SW480 cells in nude mice bearing tumors. Furthermore, PIK3CA could bind to quercetin directly, which is validated by immunocoprecipitation. Therefore, the activation of PI3K/AKT phosphorylation was inhibited by quercetin and moreover the expressions of apoptotic proteins caspase-3 and Bcl2-Associated X protein (BAX) were up-regulated. In conclusion, the potential mechanism of nightshade lies in the activation of the PI3K/AKT signaling pathway inhibited by quercetin, thus promoting apoptosis of colon cancer cells for colon cancer treatment.

Anti-proliferative effects of the combination of Sulfamethoxazole and Quercetin via caspase3 and NFkB gene regulation: an in vitro and in vivo study.

Combination therapy comprising natural polyphenols and anticancer drugs has been used to decrease the adverse effects and increase the effectiveness and antioxidant activities of the drugs. The antioxidant and anticancer effects of quercetin (Q), a nutritive polyphenol, have been observed both in vitro and in vivo. Likewise, the anticancer activity of sulfamethoxazole (S) has been demonstrated in vitro and in vivo. This study aimed to investigate the in vitro and in vivo anticancer effects of Q alone and in combination with S. The in vitro effects of S, Q, and S + Q on HCT-116, HepG2, MCF-7, and PC3 cell lines were examined. Additionally, the in vivo effects of these drugs were evaluated using Ehrlich ascites carcinoma (EAC) tumor-bearing mice. The in vitro data revealed the potent anticancer activity of S + Q through the induction of apoptosis and cell cycle arrest. The EAC-inoculated mice treated with S + Q presented with elevated SOD, GSH, CAT, and TAC levels and decreased malondialdehyde levels compared with the untreated EAC group, thus revealing the antioxidant and protective actions of S + Q against EAC cell invasion. Furthermore, the downregulation of NFkB and upregulation of the caspase3 gene in the EAC-inoculated mice treated with the S + Q indicated the induction of the apoptotic pathway and decrease in both cell proliferation and metastasis. In conclusion, the combination of S and Q might exert anticancer effects by inducing apoptosis and exhibiting selective toxicity against the cancer cells and thereby protecting the vital organs.

Heteroconjugates of quercetin with 4'-O-sulfate selectively accumulate in rat plasma due to limited urinary excretion.

Quercetin and methylquercetin are present in a variety of sulfate and glucuronide conjugates in the plasma of quercetin-fed rats and humans. Quercetin conjugates exhibit various physiological activities, depending on the type and position of conjugation. However, little is known regarding the type and position of isomers of quercetin conjugates in the plasma, their accumulation in the liver and kidneys, and their excretion via urine. Using authentic standards of quercetin conjugates and liquid chromatography-tandem mass spectrometry (LC/MS/MS) analysis, we identified and quantified various quercetin conjugates in blood plasma, urine, liver, and kidney tissues 1, 4, and 10 h after orally administering 33.1 µmol kg-1 quercetin glucosides to rats. The profiles of quercetin conjugates were largely different among plasma, urine, liver, and kidneys. Very limited heteroconjugates (7-O-glucuronide-4'-O-sulfate) of quercetin and methylquercetin dominated in the plasma, but these heteroconjugates were much less excreted via urine and did not largely accumulate in the liver and kidneys. Heteroconjugates constituting sulfates other than 4' position sulfate, 7-O-glucuronide-3'-O-sulfate, 4'-O-glucuronide-7-O-sulfate, and 3'-O-glucuronide-7-O-sulfate were major metabolites in urine, but were minimally detected in the plasma. We also found that mono-sulfate conjugates were abundant in the liver and renal tissues. These results suggest that excretion of quercetin conjugates, especially heteroconjugates, into urine is highly selective. The heteroconjugates with 4'-O-sulfate may be scarcely excreted via urine, and thus accumulate in the blood plasma. Further research is necessary to evaluate the physiological effects of heteroconjugates accumulated in the plasma.

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.

Screening of bioactive ingredients of Tsantan Sumtang in ameliorating H9c2 cells injury.

ETHNOPHARMACOLOGICAL RELEVANCE: Tsantan Sumtang (TS), a traditional Tibetan medicine, has been used in the clinic for the treatment of myocardial ischemia (MI) for ages, however, the bioactive ingredients that are responsible for improving MI remain unknown. AIM OF THE STUDY: This study investigated the chemical components of TS and their medicinal efficacies at cell levels, in order to expound the bioactive ingredients in TS. MATERIALS AND METHODS: First, a response-surface methodology was employed to determine the optimum ethanol reflux extraction process of polyphenols in TS (PTS) due to their close correlation with MI improvement. Second, a serum pharmacochemistry technique was used to analyze the compounds of PTS absorbed into the blood of rats. Third, hypoxia-, H2O2-, and adriamycin (ADM)-induced H9c2 cell injury models were used to investigate the cardioprotective effects of these compounds in vitro. Fourth, protective effects of isovitexin, quercitrin, and isoeugenol on mitochondrial function were further tested. RESULTS: The optimum extraction conditions for obtaining PTS were an ethanol concentration of 78.22%, an extraction time of 67.4 min, and a material-liquid ratio of 1:72.60 mL/g. Serum pharmacochemistry analysis detected 21 compounds, of which 11 compounds were always present in the blood within 5 h. Cytotoxicity and the protective effect of 11 compounds in hypoxia-, H2O2-, and ADM-induced H9c2 cell injury models shown that isovitexin, quercitrin, and isoeugenol had almost no cytotoxicity, and they could elevate the survival rate in injured H9c2 cells. Furthermore, isovitexin, quercitrin, and isoeugenol could decrease mitochondrial reactive oxygen species (ROS) releasion, inhibite mitochondrial permeability transition pore (mPTP) opening, ameliorate the change of mitochondrial membrane potential (MMP) to exert mitochondrial protection effect. CONCLUSION: Isovitexin, quercitrin, and isoeugenol exhibited cardioprotective effect at cell levles, these three compounds might be the bioactive ingredients in TS. These findings elucidate the pharmacodynamic substances and mechanisms of TS, guiding its clinical use.