ABSTRACT
BACKGROUND: Intrauterine adhesions (IUAs) jeopardise uterine function in women, which is a great challenge in the clinic. Previous studies have shown that endometrial perivascular cells (En-PSCs) can improve the healing of scarred uteri and that hydroxysafflor yellow A (HSYA) promotes angiogenesis. The purpose of this study was to observe whether the combination of En-PSCs with HSYA could improve the blood supply and fertility in the rat uterus after full-thickness injury. METHODS: En-PSCs were sorted by flow cytometry, and the effect of HSYA on the proliferation and angiogenesis of the En-PSCs was detected using CCK-8 and tube formation assays. Based on a previously reported rat IUA model, the rat uteri were sham-operated, spontaneously regenerated, or treated with collagen-loaded PBS, collagen-loaded HSYA, collagen-loaded En-PSCs, or collagen-loaded En-PSCs with HSYA, and then collected at both 30 and 90 days postsurgery. HE staining and Masson staining were used to evaluate uterine structure and collagen fibre deposition, and immunohistochemical staining for α-SMA and vWF was used to evaluate myometrial regeneration and neovascularization in each group. A fertility assay was performed to detect the recovery of pregnancy function in each group. RNA-seq was performed to determine the potential mechanism underlying En-PSCs/HSYA treatment. Immunofluorescence, tube formation assays, and Western blot were used to validate the molecular mechanism involved. RESULTS: The transplantation of Collagen/En-PSCs/HSYA markedly promoted uterine repair in rats with full-thickness injury by reducing fibrosis, increasing endometrial thickness, regenerating myometrium, promoting angiogenesis, and facilitated live births. RNA sequencing results suggested that En-PSCs/HSYA activated the NRG1/ErbB4 signaling pathway. In vitro tube formation experiments revealed that the addition of an ErbB inhibitor diminished the tube formation ability of cocultured En-PSCs and HUVECs. Western blot results further showed that elevated levels of NRG1 and ErbB4 proteins were detected in the Collagen/En-PSCs/HSYA group compared to the Collagen/En-PSCs group. These collective results suggested that the beneficial effects of the transplantation of Collagen/En-PSCs/HSYA might be attributed to the modulation of the NRG1/ErbB4 signaling pathway. CONCLUSIONS: The combination of En-PSCs/HSYA facilitated morphological and functional repair in rats with full-thickness uterine injury and may promote endometrial angiogenesis by regulating the NRG1/ErbB4 signaling pathway.
Subject(s)
Chalcone , Endometrium , Quinones , Uterus , Animals , Female , Rats , Endometrium/drug effects , Endometrium/metabolism , Humans , Uterus/drug effects , Uterus/metabolism , Chalcone/analogs & derivatives , Chalcone/pharmacology , Quinones/pharmacology , Quinones/therapeutic use , Rats, Sprague-Dawley , Neovascularization, Physiologic/drug effects , Stem Cells/metabolism , Stem Cells/drug effects , Stem Cell Transplantation/methods , Cell Proliferation/drug effects , Regeneration/drug effectsABSTRACT
BACKGROUND: Inflammatory bowel disease (IBD) represents a significant global health challenge, and there is an urgent need to explore novel therapeutic interventions. Natural products have demonstrated highly promising effectiveness in the treatment of IBD. PURPOSE: This study systematically reviews the latest research advancements in leveraging natural products for IBD treatment. METHODS: This manuscript strictly adheres to the PRISMA guidelines. Relevant literature on the effects of natural products on IBD was retrieved from the PubMed, Web of Science and Cochrane Library databases using the search terms "natural product," "inflammatory bowel disease," "colitis," "metagenomics", "target identification", "drug delivery systems", "polyphenols," "alkaloids," "terpenoids," and so on. The retrieved data were then systematically summarized and reviewed. RESULTS: This review assessed the different effects of various natural products, such as polyphenols, alkaloids, terpenoids, quinones, and others, in the treatment of IBD. While these natural products offer promising avenues for IBD management, they also face challenges in terms of clinical translation and drug discovery. The advent of metagenomics, single-cell sequencing, target identification techniques, drug delivery systems, and other cutting-edge technologies heralds a new era in overcoming these challenges. CONCLUSION: This paper provides an overview of current research progress in utilizing natural products for the treatment of IBD, exploring how contemporary technological innovations can aid in discovering and harnessing bioactive natural products for the treatment of IBD.
Subject(s)
Biological Products , Inflammatory Bowel Diseases , Humans , Biological Products/therapeutic use , Biological Products/pharmacology , Inflammatory Bowel Diseases/drug therapy , Alkaloids/therapeutic use , Alkaloids/pharmacology , Polyphenols/pharmacology , Polyphenols/therapeutic use , Drug Delivery Systems , Terpenes/therapeutic use , Animals , Phytotherapy , Drug Discovery , Quinones/therapeutic use , Quinones/pharmacologyABSTRACT
Depression is a common non-motor symptom of Parkinson's disease. Previous studies demonstrated that hydroxysafflor yellow A had properties of improving motor symptoms of Parkinson's disease. The effect of hydroxysafflor yellow A on depression in Parkinson's disease mice is investigated in this study. To induce Parkinson's disease model, male Swiss mice were exposed to rotenone (30 mg/kg) for 6 weeks. The chronic unpredictable mild stress was employed to induce depression from week 3 to week 6. Sucrose preference, tail suspension, and forced swimming tests were conducted. Golgi and Nissl staining of hippocampus were carried out. The levels of dopamine, 5-hydroxytryptamine and the expression of postsynaptic density protein 95, brain-derived neurotrophic factor in hippocampus were assayed. It showed that HSYA improved the depression-like behaviors of Parkinson's disease mice. Hydroxysafflor yellow A attenuated the injury of nerve and elevated contents of dopamine, 5-hydroxytryptamine in hippocampus. Treatment with hydroxysafflor yellow A also augmented the expression of postsynaptic density protein 95 and brain-derived neurotrophic factor. These findings suggest that hydroxysafflor yellow A ameliorates depression-like behavior in Parkinson's disease mice through regulating the contents of postsynaptic density protein 95 and brain-derived neurotrophic factor, therefore protecting neurons and neuronal dendrites of the hippocampus.
Subject(s)
Behavior, Animal , Brain-Derived Neurotrophic Factor , Chalcone , Depression , Hippocampus , Quinones , Serotonin , Animals , Quinones/pharmacology , Quinones/therapeutic use , Chalcone/analogs & derivatives , Chalcone/pharmacology , Chalcone/therapeutic use , Male , Mice , Brain-Derived Neurotrophic Factor/metabolism , Depression/drug therapy , Depression/metabolism , Hippocampus/drug effects , Hippocampus/metabolism , Hippocampus/pathology , Behavior, Animal/drug effects , Serotonin/metabolism , Dopamine/metabolism , Rotenone/pharmacology , Disease Models, Animal , Disks Large Homolog 4 Protein/metabolism , Parkinson Disease/drug therapy , Parkinson Disease/metabolism , Parkinson Disease/psychologyABSTRACT
The morbidity and mortality of malignant tumors are progressively rising on an annual basis. Traditional Chinese Medicine (TCM) holds promise as a possible therapeutic agent for the avoidance or therapy of malignant tumors. Salvia miltiorrhiza Bunge (Danshen), a traditional Asian functional food, has therapeutic characteristics in application for the treatment of malignant tumors. Dihydrotanshinone I (DHTS) is the principal lipophilic phenanthraquinone compound found in Salvia miltiorrhiza Bunge, whose anti-tumor effect has attracted widespread attention. The anti-tumor effects include inhibiting cancer cell proliferation, triggering apoptosis of tumor cells, inducing ferroptosis in tumor cells, inhibiting tumor cell invasion and metastasis, and improving drug resistance of tumor cells. In this paper, we summarized and analyzed the mechanisms and targets of anti-tumor effect of DHTS, providing new ideas and establishing a solid theoretical basis for the future advancement and clinical treatment of DHTS.
Subject(s)
Neoplasms , Phenanthrenes , Quinones , Humans , Neoplasms/drug therapy , Neoplasms/pathology , Phenanthrenes/pharmacology , Phenanthrenes/therapeutic use , Animals , Quinones/pharmacology , Quinones/therapeutic use , Apoptosis/drug effects , Antineoplastic Agents, Phytogenic/therapeutic use , Antineoplastic Agents, Phytogenic/pharmacology , Cell Proliferation/drug effects , Drugs, Chinese Herbal/therapeutic use , Drugs, Chinese Herbal/pharmacology , Salvia miltiorrhiza/chemistry , Drug Resistance, Neoplasm/drug effects , FuransABSTRACT
Numerous natural bioactive compounds extracted from Chinese medicines have been proved to be promising and potent agents in the treatment of ischemic stroke. Hydroxysafflor yellow A (HSYA), separated from Carthamus tinctorius, has increasingly attracted attention for its broad spectrum of pharmacological effects, especially of its neuroprotective action. Our previous studies revealed that HSYA plays significant beneficial roles in a dose-dependent manner in rats with focal cerebral ischemia. However, treatment with higher doses of HSYA appeared to bring about adverse reactions in the rats. In present study, we adopted tenuigenin (TEN), extracted from the Polygala tenuifolia root, in combination with HSYA to optimize the therapeutic strategy against ischemic stroke, and further explored the underlying mechanisms of action of the combination in vivo and in vitro. We firstly confirmed the pharmacological efficacies of co-treatment of HSYA and TEN in middle cerebral ischemia occlusion (MCAO) rats and observed the synergistic improvement of infarct volume, cerebral edema, and morphology of neuron cell body. Behavioral experiments indicated that combination of HSYA and TEN could synergistically improve motor and cognitive function in MCAO rats. We also observed increased viability and suppressed cell apoptosis after HSYA and TEN co-treatments in the oxygen-glucose deprivation/reperfusion (OGD/R) SH-SY5Y cells. Furthermore, JAK2/STAT3 and SOCS3 signaling interaction was demonstrated to be a critical responsor to the co-treatment of HSYA and TEN. In the subsequent experiments with silencing SOCS3 in OGD/R-exposed cells, we found that HSYA and TEN might suppress JAK2/STAT3 pathway through different regulatory mechanisms targeting SOCS3-negative feedback signaling. HSYA seemed to impose excessive activation of JAK2/STAT3 to trigger SOCS3-negative feedback signaling, while TEN appeared to provoke SOCS3 inhibitory feedback role directly to further attenuate JAK2-mediated signaling. Collectively, HSYA and TEN might modulate the crosstalk between JAK2/STAT3 and SOCS3 signaling pathways in different manners that eventually contributed to their synergistic therapeutic effects against cerebral ischemic stroke.
Subject(s)
Brain Ischemia , Chalcone , Janus Kinase 2 , Neuroprotective Agents , Quinones , Rats, Sprague-Dawley , STAT3 Transcription Factor , Signal Transduction , Suppressor of Cytokine Signaling 3 Protein , Animals , Janus Kinase 2/metabolism , Chalcone/analogs & derivatives , Chalcone/pharmacology , Chalcone/therapeutic use , Quinones/pharmacology , Quinones/therapeutic use , STAT3 Transcription Factor/metabolism , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic use , Signal Transduction/drug effects , Suppressor of Cytokine Signaling 3 Protein/metabolism , Male , Brain Ischemia/drug therapy , Brain Ischemia/metabolism , Brain Ischemia/pathology , Infarction, Middle Cerebral Artery/drug therapy , Infarction, Middle Cerebral Artery/pathology , Infarction, Middle Cerebral Artery/complications , Rats , Drugs, Chinese Herbal/pharmacology , Drugs, Chinese Herbal/therapeutic use , Apoptosis/drug effectsABSTRACT
Mesalamine, also called 5-ASA (5-aminosalicylic acid), is a largely used anti-inflammatory agent and is a main choice to treat Ulcerative Colitis. This report is aimed to investigate enzymatic processes involved in the oxidation of mesalamine to better understand some of its side-effects. Oxidation with oxygen (catalyzed by ceruloplasmin) or with hydrogen peroxide (catalyzed by peroxidase or hemoglobin) showed that these oxidases, despite their different mechanisms of oxidation, could recognize mesalamine as a substrate and trigger its oxidation to a corresponding quinone-imine. These enzymes were chosen because they may recognize hydroquinone (a p-diphenol) as substrate and oxidize it to p-benzoquinone and that mesalamine, as a p-aminophenol, presents some similarities with hydroquinone. The UV-Vis kinetics, FTIR and 1H NMR supported the hypothesis of oxidizing mesalamine. Furthermore, mass spectrometry suggested the quinone-imine as reaction product. Without enzymes, the oxidation process was very slow (days and weeks), but it was markedly accelerated with the oxidases, particularly with peroxidase. Cyclic voltammetry supported the hypothesis of the oxidative process and allowed a ranking of susceptibility to oxidizing mesalamine in comparison with other oxidizable drug molecules with related structures. The susceptibility to oxidation was higher for mesalamine, in comparison with Tylenol (acetaminophen) and with aspirin (salicylic acid).
Subject(s)
Colitis, Ulcerative , Mesalamine , Humans , Mesalamine/chemistry , Monophenol Monooxygenase , Hydroquinones , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Peroxidase , Colitis, Ulcerative/drug therapy , Oxidation-Reduction , Peroxidases , Quinones/therapeutic use , Catalysis , IminesABSTRACT
Ferroptosis is closely associated with the pathophysiology of myocardial ischemia. Hydroxysafflor yellow A (HSYA), the main active ingredient in the Chinese herbal medicine safflower, exerts significant protective effects against myocardial ischemia/reperfusion injury (MI/RI). The aim of this study was to investigate the protective effects of HSYA against MI/RI and identify the putative underlying mechanisms. An in vivo model of acute MI/RI was established in C57 mice. Subsequently, the effects of HSYA on myocardial tissue injury were evaluated by histology. Lipid peroxidation and myocardial injury marker contents in myocardial tissue and serum and iron contents in myocardial tissue were determined using biochemical assays. Mitochondrial damage was assessed using transmission electron microscopy. H9C2 cardiomyocytes were induced in vitro by oxygen-glucose deprivation/reoxygenation, and ferroptosis inducer erastin was administered to detect ferroptosis-related indicators, oxidative-stress-related indicators, and expressions of ferroptosis-related proteins and HIF-1α. In MI/RI model mice, HSYA reduced myocardial histopathological damage, ameliorated mitochondrial damage in myocardial cells, and decreased total cellular iron and ferrous ion contents in myocardial tissue. HSYA increased the protein levels of SLC7A11, HIF-1α, and GPX4 and mitigated erastin- or HIF-1α siRNA-induced damage in H9C2 cells. In summary, HSYA alleviated MI/RI by activating the HIF-1α/SLC7A11/GPX4 signaling pathway, thereby inhibiting ferroptosis.
Subject(s)
Ferroptosis , Myocardial Reperfusion Injury , Reperfusion Injury , Mice , Animals , Myocardial Reperfusion Injury/drug therapy , Myocardial Reperfusion Injury/metabolism , Signal Transduction , Quinones/pharmacology , Quinones/therapeutic use , Reperfusion Injury/pathologyABSTRACT
INTRODUCTION: Pancreatic cancer is highly fatal and its incidence is rising worldwide. Its poor prognosis is attributed to a lack of effective diagnostic and therapeutic strategies. Dihydrotanshinone I (DHT), a phenanthrene quinone liposoluble compound from Salvia miltiorrhiza Bunge (Danshen), exerts anti-tumor effects by inhibiting cell proliferation, enhancing apoptosis, and inducing cell differentiation. However, its effects on pancreatic cancer are unclear. > Methods: The role of DHT in the growth of tumor cells was explored using real-time cell analysis (RTCA), colony formation assay, and CCK-8. The effects of DHT on tumor cells invasion as well as migration were assessed by Transwell and migration assays. Expressions of pro-apoptosis and metastasis factors in tumor cells were examined using western blot. Tumor apoptosis rates were studied using flow cytometry. The anticancer effect of DHT in vivo was assessed by tumor transplantation into nude mice. RESULTS: Our analyses show that DHT has a suppressive role in epithelial-mesenchymal transition (EMT), invasiveness, proliferation, as well as migratory ability of Patu8988 and PANC-1 cells via Hedgehog/Gli signaling. Moreover, it drives apoptosis via caspases/BCL2/BAX signaling. Experiments in nude mice transplanted with tumors have shown DHT to have anticancer effects in vivo. > Conclusion: Our data show that DHT effectively suppresses pancreatic cancer cell proliferation as well as metastasis, and induces apoptosis via Hedgehog/Gli signaling. These effects have been reported to be dose- and time-dependent. Therefore, DHT can be exploited as a potential treatment for pancreatic cancer.>.
Subject(s)
Pancreatic Neoplasms , Phenanthrenes , Animals , Mice , Apoptosis , Cell Line, Tumor , Cell Movement , Cell Proliferation , Epithelial-Mesenchymal Transition , Hedgehog Proteins/metabolism , Mice, Nude , Pancreatic Neoplasms/pathology , Phenanthrenes/pharmacology , Phenanthrenes/therapeutic use , Quinones/pharmacology , Quinones/therapeutic use , Signal Transduction , Humans , Pancreatic NeoplasmsABSTRACT
Chemotherapy based on small molecule drugs, hormones, cycline kinase inhibitors, and monoclonal antibodies has been widely used for breast cancer treatment in the clinic but with limited efficacy, due to the poor specificity and tumor microenvironment (TME)-caused diffusion barrier. Although monotherapies targeting biochemical cues or physical cues in the TME have been developed, none of them can cope with the complex TME, while mechanochemical combination therapy remains largely to be explored. Herein, a combination therapy strategy based on an extracellular matrix (ECM) modulator and TME-responsive drug for the first attempt of mechanochemically synergistic treatment of breast cancer is developed. Specifically, based on overexpressed NAD(P)H quinone oxidoreductase 1 (NQO1) in breast cancer, a TME-responsive drug (NQO1-SN38) is designed and it is combined with the inhibitor (i.e., ß-Aminopropionitrile, BAPN) for Lysyl oxidases (Lox) that contributes to the tumor stiffness, for mechanochemical therapy. It is demonstrated that NQO1 can trigger the degradation of NQO1-SN38 and release SN38, showing nearly twice tumor inhibition efficiency compared with SN38 treatment in vitro. Lox inhibition with BAPN significantly reduces collagen deposition and enhances drug penetration in tumor heterospheroids in vitro. It is further demonstrated that the mechanochemical therapy showed outstanding therapeutic efficacy in vivo, providing a promising approach for breast cancer therapy.
Subject(s)
Breast Neoplasms , Humans , Female , Breast Neoplasms/pathology , Aminopropionitrile/pharmacology , Aminopropionitrile/therapeutic use , Quinones/therapeutic use , Collagen/metabolism , Extracellular Matrix/metabolism , Tumor MicroenvironmentABSTRACT
Context: KOA characterized by recurrent joint pain and progressive joint dysfunction. Is the present clinical common chronic progressive degenerative osteoarthropathy, how long the disease is difficult to cure and easy to relapse. Exploring new therapeutic approaches and mechanisms is important for the treatment of KOA. One of the main applications for sodium hyaluronate (SH) in the medical field is treatment of osteoarthritis. However, the effects of SH alone in the treatment of KOA are limited. Hydroxysafflor yellow A (HSYA) may have therapeutic effects for KOA. Objective: The study intended to investigate the therapeutic effects and possible mechanisms of action HSYA+SH for cartilage tissue of rabbits with KOA and to provide a theoretical basis for the treatment of KOA. Design: The research team performed an animal study. Setting: The study that took place at Liaoning Jijia Biotechnology, Shenyang, Liaoning, China. Animals: The animals were 30 healthy, adult, New Zealand white rabbits, weighing 2-3 kg. Intervention: The research team randomly divided the rabbits into three groups, with 10 rabbits in each group: (1) a control group, for which the research team didn't induce KOA and provided no treatment; (2) the HSYA+SH group, the intervention group, for which the research team induced KOA and injected the rabbits with the HSYA+SH treatment; and (3) the KOA group, for which the research team induced KOA and injected the rabbits with saline. Outcome Measures: The research team: (1) observed the morphological changes in the cartilage tissue using hematoxylin-eosin (HE) staining; (2) measured levels of serum inflammatory factors, including tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1ß), interferon gamma (IFN-γ), IL-6, and IL-17 using an enzyme-linked immunosorbent assay (ELISA); (3) measured cartilage-cell apoptosis using "terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling" (TUNEL); and (4) used Western Blot to detect the expression of proteins related to the "neurogenic locus notch homolog protein 1" (Notch1) signaling pathway. Results: Compared with the control group, morphological changes had occurred to the cartilage tissue in the KOA group. Compared with the control group, that group's level of apoptosis was higher, the levels of serum inflammatory factors were significantly higher (P < .05), and the protein expression related to the Notch1 signaling pathway was also significantly higher (P < .05). The morphology of the cartilage tissue in the HSYA+SH was better than that of the KOA group but not as good as that of the control group. Compared with the KOA group, the HSYA+SH group's level of apoptosis was lower, the levels of serum inflammatory factors were significantly lower (P < .05), and the protein expression related to the Notch1 signaling pathway was also significantly lower (P < .05). Conclusions: HSYA+SH can reduce the cellular apoptosis in the cartilage tissue of rabbits with KOA, downregulate the levels of inflammatory factors, and protect against KOA-induced cartilage tissue injury, and the mechanism may be related to the regulation of the Notch1 signaling pathway.
Subject(s)
Osteoarthritis, Knee , Rabbits , Animals , Osteoarthritis, Knee/drug therapy , Hyaluronic Acid/therapeutic use , Quinones/pharmacology , Quinones/therapeutic use , Inflammation/drug therapyABSTRACT
Respiratory viruses represent a world public health problem, giving rise to annual seasonal epidemics and several pandemics caused by some of these viruses, including the COVID-19 pandemic caused by the novel SARS-CoV-2, which continues to date. Some antiviral drugs have been licensed for the treatment of influenza, but they cause side effects and lead to resistant viral strains. Likewise, aerosolized ribavirin is the only drug approved for the therapy of infections by the respiratory syncytial virus, but it possesses various limitations. On the other hand, no specific drugs are licensed to treat other viral respiratory diseases. In this sense, natural products and their derivatives have appeared as promising alternatives in searching for new compounds with antiviral activity. Besides their chemical properties, quinones have demonstrated interesting biological activities, including activity against respiratory viruses. This review summarizes the activity against respiratory viruses and their molecular targets by the different types of quinones (both natural and synthetic). Thus, the present work offers a general overview of the importance of quinones as an option for the future pharmacological treatment of viral respiratory infections, subject to additional studies that support their effectiveness and safety.
Subject(s)
COVID-19 , Respiratory Tract Infections , Virus Diseases , Humans , SARS-CoV-2 , Pandemics , Quinones/therapeutic use , Antiviral Agents/pharmacology , Virus Diseases/drug therapy , Respiratory Tract Infections/drug therapyABSTRACT
INTRODUCTION: Luteolin is a plant-derived flavonoid that exhibits a broad range of pharmacological activities. Studies on luteolin have mainly focused on its use for hyperlipidaemia prevention, whereas the capacity of the flavonoid to hinder hyperglycaemia development remains underexplored. OBJECTIVES: To probe the anti-hyperglycemic mechanism of 6,8-guanidyl luteolin quinone-chromium coordination (GLQ.Cr), and to assess its regulatory effect on intestinal microbiota in type 2 diabetes mellitus (T2DM) mice. METHODS: High-sucrose/high-fat diet-induced and intraperitoneal injection of streptozotocin was used to develop a T2DM model. Glycometabolism related indicators, histopathology, and gut microbiota composition in caecum samples were evaluated, and RNA sequencing (RNA-seq) of liver samples was conducted. Faecal microbiota transplantation (FMT) was further used to verify the anti-hyperglycemic activity of intestinal microbiota. RESULTS: The administration of GLQ.Cr alleviated hyperglycaemia symptoms by improving liver and pancreatic functions and modulating gut microbe communities (Lactobacillus, Alistipes, Parabacteroides, Lachnoclostridium, and Desulfovibrio). RNA-seq analysis showed that GLQ.Cr mainly affected the peroxisome proliferative activated receptor (PPAR) signalling pathway in order to regulate abnormal glucose metabolism. FMT significantly modulated the abundance of Lactobacillus, Alloprevotella, Alistipes, Bacteroides, Ruminiclostridium, Brevundimonas and Pseudomonas in the caecum to balance blood glucose levels and counteract T2DM mice inflammation. CONCLUSION: GLQ.Cr improved the abnormal glucose metabolism in T2DM mice by regulating the PPAR signalling pathway and modulating intestinal microbial composition. FMT can improve the intestinal microecology of the recipient and in turn ameliorate the symptoms of T2DM-induced hyperglycaemia.
Subject(s)
Diabetes Mellitus, Type 2 , Gastrointestinal Microbiome , Hyperglycemia , Mice , Animals , Gastrointestinal Microbiome/physiology , Diabetes Mellitus, Type 2/drug therapy , Luteolin/pharmacology , Luteolin/therapeutic use , Peroxisome Proliferator-Activated Receptors/pharmacology , Peroxisome Proliferator-Activated Receptors/therapeutic use , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/therapeutic use , Quinones/pharmacology , Quinones/therapeutic use , Glucose/pharmacology , Glucose/therapeutic use , Hyperglycemia/drug therapyABSTRACT
Rheumatoid arthritis (RA) is a joint ailment with multi-factorial immune-mediated degenerative pathogenesis, including genetic and environmental defects. Resistance to disease-modifying anti-rheumatic drugs (DMARDs) happens due to excessive drug efflux over time, rendering the concentration insufficient to elicit a response. Thymoquinone (TQ) is a quinone-based phenolic compound with antioxidant and anti-inflammatory activities that downregulate numerous pro-inflammatory cytokines. However, its pharmaceutical importance and therapeutic utility are underexplored due to intrinsic physicochemical characteristics such as inadequate biological stability, short half-life, low hydrophilicity, and less systemic availability. Tamanu oil-stabilised nanostructured lipid carriers (TQ-NLCs) were prepared and optimised using Box-Behnken design (BBD) with the size of 153.9 ± 0.52 nm and surface charge of -30.71 mV. The % entrapment efficiency and drug content were found to be 84.6 ± 0.50% and 14.75 ± 0.52%, respectively. Furthermore, the TQ-loaded NLCs (TQ-NLCs) assayed for skin permeation for transdermal delivery which significantly (p < 0.05) increased skin enhancement ratio 14.6 times compared to the aqueous solution of TQ. Tamanu oil displayed the synergistic anti-inflammatory potential with TQ in comparison to pure TQ, as evidenced against carrageenan (CRG)-induced paw oedema model and Freund's adjuvant-induced arthritic model. The arthritic and X-ray scores significantly (p < 0.05) reduced in TQ-NLCs and standard formulation-treated groups. Moreover, serum pro-inflammatory marker TNF-α and IL-6 levels were also significantly (p < 0.05) reduced in TQ-NLCs gel-treated group compared to the arthritic control group.
Subject(s)
Antirheumatic Agents , Arthritis, Rheumatoid , Anti-Inflammatory Agents/pharmacology , Arthritis, Rheumatoid/drug therapy , Down-Regulation , Drug Carriers/chemistry , Interleukin-6 , Quinones/therapeutic use , Tumor Necrosis Factor-alpha/metabolism , AnimalsABSTRACT
Inflammatory bowel diseases (IBD) are chronic, recurring gastrointestinal diseases that severely impair health and quality of life. Although therapeutic options have significantly expanded in recent years, there is no effective therapy for a complete and permanent cure for IBD. Well tolerated dietary interventions to improve gastrointestinal health in IBD would be a welcome advance especially with anticipated favorable tolerability and affordability. Soluble protein hydrolysate (SPH) is produced by the enzymatic hydrolysis of commercial food industry salmon offcuts (consisting of the head, backbone and skin) and contains a multitude of bioactive peptides including those with anti-oxidant properties. This study aimed to investigate whether SPH ameliorates gastrointestinal injury in 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced mouse colitis model. Mice were randomly assigned to four groups: Control (no colitis), Colitis, Colitis/CP (with control peptide treatment), and Colitis/SPH (with SPH treatment). Colitis was induced by cutaneous sensitization with 1% TNBS on day -8 followed by 2.5% TNBS enema challenge on day 0. Control peptides and SPH were provided to the mice in the Colitis/CP or Colitis/SPH group respectively by drinking water at the final concentration of 2% w/v daily from day -10 to day 4. Then, the colon was harvested on day 4 and examined macro- and microscopically. Relevant measures included disease activity index (DAI), colon histology injury, immune cells infiltration, pro- and anti-inflammatory cytokines and anti-oxidative gene expression. It was found that SPH treatment decreased the DAI score and colon tissue injury when compared to the colitis-only and CP groups. The protective mechanisms of SPH were associated with reduced infiltration of CD4+ T, CD8+ T and B220+ B lymphocytes but not macrophages, downregulated pro-inflammatory cytokines (tumor necrosis factor-α and interleukin-6), and upregulated anti-inflammatory cytokines (transforming growth factor-ß1 and interleukin-10) in the colon tissue. Moreover, the upregulation of anti-oxidative genes, including ferritin heavy chain 1, heme oxygenase 1, NAD(P)H quinone oxidoreductase 1, and superoxide dismutase 1, in the colons of colitis/SPH group was observed compared with the control peptide treatment group. In conclusion, the protective mechanism of SPH is associated with anti-inflammatory and anti-oxidative effects as demonstrated herein in an established mice model of colitis. Clinical studies with SPH as a potential functional food for the prevention or as an adjuvant therapy in IBD may add an effective and targeted diet-based approach to IBD management in the future.
Subject(s)
Colitis , Drinking Water , Inflammatory Bowel Diseases , Animals , Anti-Inflammatory Agents/therapeutic use , Antioxidants/therapeutic use , Apoferritins , Colitis/chemically induced , Colitis/drug therapy , Colitis/pathology , Cytokines/metabolism , Drinking Water/adverse effects , Heme Oxygenase-1/metabolism , Inflammation/drug therapy , Inflammatory Bowel Diseases/metabolism , Interleukin-10/metabolism , Interleukin-6/metabolism , Mice , NAD/metabolism , Protein Hydrolysates/metabolism , Quality of Life , Quinones/therapeutic use , Superoxide Dismutase-1/metabolism , Transforming Growth Factor beta1/metabolism , Trinitrobenzenes , Trinitrobenzenesulfonic Acid/adverse effects , Tumor Necrosis Factor-alpha/metabolismABSTRACT
NAD(P)H:quinone oxidoreductase 1 (NQO1) is an enzyme significantly overexpressed in pancreatic ductal adenocarcinoma (PDAC) tumors compared to the associated normal tissues. NQO1 bioactivatable drugs, such as ß-lapachone (ß-lap), can be catalyzed to generate reactive oxygen species (ROS) for direct tumor killing. However, the extremely narrow therapeutic window caused by methemoglobinemia and hemolytic anemia severely restricts its further clinical translation despite considerable efforts in the past 20 years. Previously, we demonstrated that albumin could be utilized to deliver cytotoxic drugs selectively into KRAS-mutant PDAC with a much expanded therapeutic window due to KRAS-enhanced macropinocytosis and reduced neonatal Fc receptor (FcRn) expression in PDAC. Herein, we analyzed the expression patterns of albumin and FcRn across major organs in LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre (KPC) mice. The tumors were the predominant tissues with both elevated albumin and reduced FcRn expression, thus making them an ideal target for albumin-based drug delivery. Quantitative proteomics analysis of tissue samples from 5 human PDAC patients further confirmed the elevated albumin/FcRn ratio. Given such a compelling biological rationale, we designed a nanoparticle albumin-bound prodrug of ß-lap, nab-(pro-ß-lap), to achieve PDAC targeted delivery and expand the therapeutic window of ß-lap. We found that nab-(pro-ß-lap) uptake was profoundly enhanced by KRAS mutation. Compared to the solution formulation of the parent drug ß-lap, nab-(pro-ß-lap) showed enhanced safety due to much lower rates of methemoglobinemia and hemolytic anemia, which was confirmed both in vitro and in vivo. Furthermore, nab-(pro-ß-lap) significantly inhibited tumor growth in subcutaneously implanted KPC xenografts and enhanced the pharmacodynamic endpoints (e.g., PARP1 hyperactivation, γ-H2AX). Thus, nab-(pro-ß-lap), with improved safety and antitumor efficacy, offers a drug delivery strategy with translational viability for ß-lap in pancreatic cancer therapy.
Subject(s)
Carcinoma, Pancreatic Ductal , Methemoglobinemia , Naphthoquinones , Pancreatic Neoplasms , Prodrugs , Albumins/metabolism , Animals , Carcinoma, Pancreatic Ductal/drug therapy , Cell Line, Tumor , Humans , Methemoglobinemia/drug therapy , Mice , NAD/metabolism , NAD/therapeutic use , NAD(P)H Dehydrogenase (Quinone)/genetics , NAD(P)H Dehydrogenase (Quinone)/metabolism , Naphthoquinones/pharmacology , Naphthoquinones/therapeutic use , Pancreatic Neoplasms/pathology , Proto-Oncogene Proteins p21(ras)/metabolism , Quinones/therapeutic use , Reactive Oxygen Species/metabolism , Pancreatic NeoplasmsABSTRACT
OBJECTIVE: Astragalus and Safflower are commonly used in the treatment of stroke. Studies have shown that their two active components, hydroxysafflor yellow A (HSYA) and calycosin (CA), have protective effects on cerebral ischemia-reperfusion injury (I/R). However, the pharmacokinetic-pharmacodynamic (PK-PD) modeling study of the combination of the two components has not been reported in rats. The study aimed to perform combined PK-PD modeling of HSYA and CA in normal and cerebral ischemia model rats to explain quantitatively their time-concentration-effect relationship. METHODS: To make the middle cerebral artery occlusion (MCAO) model. SD rats were randomly divided into normal treated group (NTG) (n = 6), model group (MDG) (n = 6) and model treated group (MTG) (n = 6). Plasma was collected from the mandibular vein after 0, 2, 5, 10, 15, 20, 30, 45, 60, 75, 90, 120, 180, and 240 min after intravenous administration. Rats in NTG and MTG were administered the same dose of HSYA (5 mg/kg) and CA (8 mg/kg) by tail vein injection. HPLC-VWD method was used for detection and analysis. Simultaneously, ELISA was performed to detect the levels of IL-1ß and caspase-9 in rat plasma at different time points. The improvement in the above indicators was compared after administration. Lastly, after combining the pharmacokinetic parameters and pharmacodynamic indicators in vivo, DAS 3.2.6 software was used to fit the PK-PD model. RESULTS: The MCAO model was successfully established. Compared to NTG, there was a significant difference (P < 0.05) in t1/2α, t1/2ß, V1, V2, CL1, CL2, AUC(0-t), AUC (0-∞), and K12 of MTG for HSYA, and there was a significant difference (P < 0.05) in t1/2α, V1, CL1, AUC(0-t), AUC (0-∞), and K10 of MTG for CA. Compared to NTG, the PK parameters of t1/2α, V1, V2, CL1, and K10 were higher for HSYA in MTG, while AUC(0-t), AUC (0-∞), K12, and K21 were lower; the PK parameters of t1/2α, V1, V2, AUC(0-t), and AUC(0-∞) were higher for CA in MTG, while CL1, CL2, K10, K12, and K21 were lower. Also, the results of PD showed extremely significant differences in the levels of caspase-9 and IL-1ß at the different time points in MTG (P < 0.01) compared with 0 min. The levels of caspase-9 and IL-1ß in NTG rats showed little fluctuation and were relatively stable; however, their levels in MTG showed a downward trend with time. There were highly significant differences in the levels of each of the pharmacodynamic indicators at every time point between NTG and MTG (P < 0.01). CONCLUSION: The PK-PD model of the combined administration of HSYA and CA was successfully established in rats, and the differences in pharmacodynamic and pharmacokinetic properties between the normal and cerebral ischemic rats were evaluated. Based on comprehensive data analysis, we found that the combination of HSYA and CA may exert protective effects against I/R injury in rats via anti-apoptotic and anti-inflammatory pathways. The study provided additional insights into the development of drugs for ischemic stroke as well as the design of appropriate dosing regimens.
Subject(s)
Chalcone , Animals , Caspase 9 , Chalcone/analogs & derivatives , Chalcone/pharmacology , Chalcone/therapeutic use , Infarction, Middle Cerebral Artery/drug therapy , Isoflavones , Quinones/pharmacology , Quinones/therapeutic use , Rats , Rats, Sprague-DawleyABSTRACT
NAD(P)H:quinine oxidoreductase (NQO1) is a class of flavoprotein enzymes commonly expressed in eukaryotic cells. It actively participates in the metabolism of various quinones and their in vivo bioactivation through electron reduction reactions. The expression level of NQO1 is highly upregulated in many solid tumor cells compared with that in normal cells. NQO1 has been considered a candidate molecular target because of its overexpression and bioactivity in different tumors. NQO1-responsive prodrugs and nanocarriers have recently been identified as effective objectives for achieving controlled drug release, reducing adverse reactions and improving clinical efficacy. This review systematically introduces the research advances in applying NQO1-responsive prodrugs and nanocarriers to cancer treatment. It also discusses the existing problems and the developmental prospects of these two antitumor drug delivery systems.
Subject(s)
Drug Carriers/chemistry , NAD(P)H Dehydrogenase (Quinone)/metabolism , Nanoparticles/chemistry , Prodrugs/chemistry , Animals , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , Humans , NAD(P)H Dehydrogenase (Quinone)/antagonists & inhibitors , Neoplasms/drug therapy , Neoplasms/pathology , Prodrugs/metabolism , Prodrugs/therapeutic use , Quinones/chemistry , Quinones/metabolism , Quinones/therapeutic useABSTRACT
The DYRK (Dual-specificity tyrosine phosphorylation-regulated kinase) family of protein kinases is involved in the pathogenesis of several neurodegenerative diseases. Among them, the DYRK1A protein kinase is thought to be implicated in Alzheimer's disease (AD) and Down syndrome, and as such, has emerged as an appealing therapeutic target. DYRKs are a subset of the CMGC (CDK, MAPKK, GSK3 and CLK) group of kinases. Within this group of kinases, the CDC2-like kinases (CLKs), such as CLK1, are closely related to DYRKs and have also sparked great interest as potential therapeutic targets for AD. Based on inhibitors previously described in the literature (namely TG003 and INDY), we report in this work a new class of dihydroquinolines exhibiting inhibitory activities in the nanomolar range on hDYRK1A and hCLK1. Moreover, there is overwhelming evidence that oxidative stress plays an important role in AD. Pleasingly, the most potent dual kinase inhibitor 1p exhibited antioxidant and radical scavenging properties. Finally, drug-likeness and molecular docking studies of this new class of DYRK1A/CLK1 inhibitors are also discussed in this article.
Subject(s)
Protein Kinase Inhibitors , Quinones , Humans , Alzheimer Disease/drug therapy , Down Syndrome/drug therapy , Glycogen Synthase Kinase 3/metabolism , Molecular Docking Simulation , Phosphorylation , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Quinones/chemistry , Quinones/pharmacology , Quinones/therapeutic use , Dyrk KinasesABSTRACT
Dihydrotanshinone (DIH) is an extract of Salvia miltiorrhiza Bunge. It has been reported that DIH could regulate NF-κB signaling pathway. The aim of this study was to investigate whether DIH could protect mice from lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. In this study, sixty mice were randomly divided into five groups, one group as blank control group, the second group as LPS control group, and the last three groups were pre-injected with different doses of DIH and then inhaled LPS for experimental comparison. After 12 h of LPS treatment, the wet-dry ratio, histopathlogical changes, and myeloperoxidase (MPO) activity of lungs were measured. In addition, ELISA kits were used to measure the levels of TNF-α and IL-1ß inflammatory cytokines in bronchoalveolar lavage fluids (BALF), and western blot analysis was used to measure the activity of NF-κB signaling pathway. The results demonstrated that DIH could effectively reduce pulmonary edema, MPO activity, and improve the lung histopathlogical changes. Furthermore, DIH suppressed the levels of inflammatory cytokines in BALF, such as TNF-α and IL-1ß. In addition, DIH could also downregulate the activity of NF-κB signaling pathway. We also found that DIH dose-dependently increased the expression of LXRα. In addition, DIH could inhibit LPS-induced IL-8 production and NF-κB activation in A549 cells. And the inhibitory effects were reversed by LXRα inhibitor geranylgeranyl pyrophosphate (GGPP). Therefore, we speculate that DIH regulates LPS-induced ALI in mice by increasing LXRα expression, which subsequently inhibiting NF-κB signaling pathway.
Subject(s)
Acute Lung Injury/drug therapy , Anti-Inflammatory Agents/pharmacology , Furans/pharmacology , Liver X Receptors/metabolism , Phenanthrenes/pharmacology , Plant Extracts/pharmacology , Quinones/pharmacology , Up-Regulation/drug effects , Acute Lung Injury/etiology , Acute Lung Injury/metabolism , Animals , Anti-Inflammatory Agents/therapeutic use , Biomarkers/metabolism , Furans/therapeutic use , Lipopolysaccharides , Male , Mice , Mice, Inbred BALB C , NF-kappa B/metabolism , Phenanthrenes/therapeutic use , Plant Extracts/therapeutic use , Quinones/therapeutic use , Random Allocation , Signal TransductionABSTRACT
Hydroxysafflor yellow A (HSYA), a nutraceutical compound derived from safflower (Carthamus tinctorius), has been shown as an effective therapeutic agent in cardiovascular diseases, cancer, and diabetes. Our previous study showed that the effect of HSYA on high-glucose-induced podocyte injury is related to its anti-inflammatory activities via macrophage polarization. Based on the information provided on PubMed, Scopus and Wanfang database, we currently aim to provide an updated overview of the role of HSYA in antidiabetic research from the following points: pharmacological actions, molecular mechanisms, pharmacokinetic progressions, and clinical applications. The pharmacokinetic research of HSYA has laid foundations for the clinical applications of HSYA injection in diabetic nephropathy, diabetic retinopathy, and diabetic neuropathy. The application of HSYA as an antidiabetic oral medicament has been investigated based on its recent oral delivery system research. In vivo and in vitro pharmacological research indicated that the antidiabetic activities of HSYA were based mainly on its antioxidant and anti-inflammatory mechanisms via JNK/c-jun pathway, NOX4 pathway, and macrophage differentiation. Further anti-inflammatory exploration related to NF-κB signaling, MAPK pathway, and PI3K/Akt/mTOR pathway might deserve attention in the future. The anti-inflammatory activities of HSYA related to diabetes and diabetic complications will be a highlight in our following research.