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1.
Free Radic Biol Med ; 2024 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-39053861

RESUMO

Vascular calcification is frequently seen in patients with chronic kidney disease (CKD), and significantly increases cardiovascular mortality and morbidity. Sirt7, a NAD+-dependent histone deacetylases, plays a crucial role in cardiovascular disease. However, the role of Sirt7 in vascular calcification remains largely unknown. Using in vitro and in vivo models of vascular calcification, this study showed that Sirt7 expression was significantly reduced in calcified arteries from mice administered with high dose of vitamin D3 (vD3). We found that knockdown or inhibition of Sirt7 promoted vascular smooth muscle cell (VSMC), aortic ring and vascular calcification in mice, whereas overexpression of Sirt7 had opposite effects. Intriguingly, this protective effect of Sirt7 on vascular calcification is dependent on its deacetylase activity. Unexpectedly, Sirt7 did not alter the osteogenic transition of VSMCs. However, our RNA-seq and subsequent studies demonstrated that knockdown of Sirt7 in VSMCs resulted in increased intracellular reactive oxygen species (ROS) accumulation, and induced an Nrf-2 mediated oxidative stress response. Treatment with the ROS inhibitor N-acetylcysteine (NAC) significantly attenuated the inhibitory effect of Sirt7 on VSMC calcification. Furthermore, we found that knockdown of Sirt7 delayed cell cycle progression and accelerated cellular senescence of VSMCs. Taken together, our results indicate that Sirt7 regulates vascular calcification at least in part through modulation of ROS and cellular senescence of VSMCs. Sirt7 may be a potential therapeutic target for vascular calcification.

2.
J Nanobiotechnology ; 22(1): 190, 2024 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-38637808

RESUMO

Acute lung injury (ALI) is generally caused by severe respiratory infection and characterized by overexuberant inflammatory responses and inefficient pathogens-containing, the two major processes wherein alveolar macrophages (AMs) play a central role. Dysfunctional mitochondria have been linked with distorted macrophages and hence lung disorders, but few treatments are currently available to correct these defects. Plant-derive nanovesicles have gained significant attention because of their therapeutic potential, but the targeting cells and the underlying mechanism remain elusive. We herein prepared the nanovesicles from Artemisia annua, a well-known medicinal plant with multiple attributes involving anti-inflammatory, anti-infection, and metabolism-regulating properties. By applying three mice models of acute lung injury caused by bacterial endotoxin, influenza A virus (IAV) and SARS-CoV-2 pseudovirus respectively, we showed that Artemisia-derived nanovesicles (ADNVs) substantially alleviated lung immunopathology and raised the survival rate of challenged mice. Macrophage depletion and adoptive transfer studies confirmed the requirement of AMs for ADNVs effects. We identified that gamma-aminobutyric acid (GABA) enclosed in the vesicles is a major molecular effector mediating the regulatory roles of ADNVs. Specifically, GABA acts on macrophages through GABA receptors, promoting mitochondrial gene programming and bioenergy generation, reducing oxidative stress and inflammatory signals, thereby enhancing the adaptability of AMs to inflammation resolution. Collectively, this study identifies a promising nanotherapeutics for alleviating lung pathology, and elucidates a mechanism whereby the canonical neurotransmitter modifies AMs and mitochondria to resume tissue homeostasis, which may have broader implications for treating critical pulmonary diseases such as COVID-19.


Assuntos
Lesão Pulmonar Aguda , Plantas Medicinais , Pneumonia Viral , Pneumonia , Camundongos , Animais , Macrófagos Alveolares/metabolismo , Pulmão/metabolismo , Pneumonia Viral/tratamento farmacológico , Lesão Pulmonar Aguda/patologia , Mitocôndrias/patologia , Ácido gama-Aminobutírico/metabolismo , Pneumonia/metabolismo
3.
Int J Biol Sci ; 19(13): 4082-4102, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37705749

RESUMO

Epalrestat, an aldose reductase inhibitor (ARI), has been clinically adopted in treating diabetic neuropathy in China and Japan. Apart from the involvement in diabetic complications, AR has been implicated in inflammation. Here, we seek to investigate the feasibility of clinically approved ARI, epalrestat, for the treatment of rheumatoid arthritis (RA). The mRNA level of AR was markedly upregulated in the peripheral blood mononuclear cells (PBMCs) of RA patients when compared to those of healthy donors. Besides, the disease activity of RA patients is positively correlated with AR expression. Epalrestat significantly suppressed lipopolysaccharide (LPS) induced TNF-α, IL-1ß, and IL-6 in the human RA fibroblast-like synoviocytes (RAFLSs). Unexpectedly, epalrestat treatment alone markedly exaggerated the disease severity in adjuvant induced arthritic (AIA) rats with elevated Th17 cell proportion and increased inflammatory markers, probably resulting from the increased levels of 4-hydroxy-2-nonenal (4-HNE) and malondialdehyde (MDA). Interestingly, the combined treatment of epalrestat with N-Acetylcysteine (NAC), an anti-oxidant, to AIA rats dramatically suppressed the production of 4-HNE, MDA and inflammatory cytokines, and significantly improved the arthritic condition. Taken together, the anti-arthritic effect of epalrestat was diminished or even overridden by the excessive accumulation of toxic 4-HNE or other reactive aldehydes in AIA rats due to AR inhibition. Co-treatment with NAC significantly reversed epalrestat-induced upregulation of 4-HNE level and potentiated the anti-arthritic effect of epalrestat, suggesting that the combined therapy of epalrestat with NAC may sever as a potential approach in treating RA. Importantly, it could be regarded as a safe intervention for RA patients who need epalrestat for the treatment of diabetic complications.


Assuntos
Acetilcisteína , Artrite Reumatoide , Humanos , Animais , Ratos , Acetilcisteína/uso terapêutico , Leucócitos Mononucleares , Aldeídos , Artrite Reumatoide/tratamento farmacológico
4.
FASEB J ; 37(10): e23182, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37682013

RESUMO

A link between increased glycolysis and vascular calcification has recently been reported, but it remains unclear how increased glycolysis contributes to vascular calcification. We therefore investigated the role of PFKFB3, a critical enzyme of glycolysis, in vascular calcification. We found that PFKFB3 expression was upregulated in calcified mouse VSMCs and arteries. We showed that expression of miR-26a-5p and miR-26b-5p in calcified mouse arteries was significantly decreased, and a negative correlation between Pfkfb3 mRNA expression and miR-26a-5p or miR-26b-5p was seen in these samples. Overexpression of miR-26a/b-5p significantly inhibited PFKFB3 expression in VSMCs. Intriguingly, pharmacological inhibition of PFKFB3 using PFK15 or knockdown of PFKFB3 ameliorated vascular calcification in vD3 -overloaded mice in vivo or attenuated high phosphate (Pi)-induced VSMC calcification in vitro. Consistently, knockdown of PFKFB3 significantly reduced glycolysis and osteogenic transdifferentiation of VSMCs, whereas overexpression of PFKFB3 in VSMCs induced the opposite effects. RNA-seq analysis and subsequent experiments revealed that silencing of PFKFB3 inhibited FoxO3 expression in VSMCs. Silencing of FoxO3 phenocopied the effects of PFKFB3 depletion on Ocn and Opg expression but not Alpl in VSMCs. Pyruvate or lactate supplementation, the product of glycolysis, reversed the PFKFB3 depletion-mediated effects on ALP activity and OPG protein expression in VSMCs. Our results reveal that blockade of PFKFB3-mediated glycolysis inhibits vascular calcification in vitro and in vivo. Mechanistically, we show that FoxO3 and lactate production are involved in PFKFB3-driven osteogenic transdifferentiation of VSMCs. PFKFB3 may be a promising therapeutic target for the treatment of vascular calcification.


Assuntos
Proteína Forkhead Box O3 , MicroRNAs , Fosfofrutoquinase-2 , Calcificação Vascular , Animais , Camundongos , Glicólise , Ácido Láctico , Músculo Liso Vascular , Monoéster Fosfórico Hidrolases , Calcificação Vascular/genética , Fosfofrutoquinase-2/metabolismo , Proteína Forkhead Box O3/metabolismo
5.
Front Cell Neurosci ; 17: 1193362, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37534043

RESUMO

Tumor suppressor gene p53 and its aggregate have been found to be involved in many angiogenesis-related pathways. We explored the possible p53 aggregation formation mechanisms commonly occur after ischemic stroke, such as hypoxia and the presence of reactive oxygen species (ROS). The angiogenic pathways involving p53 mainly occur in nucleus or cytoplasm, with one exception that occurs in mitochondria. Considering the high mitochondrial density in brain and endothelial cells, we proposed that the cyclophilin D (CypD)-dependent vascular endothelial cell (VECs) necrosis pathway occurring in the mitochondria is one of the major factors that affects angiogenesis. Hence, targeting p53 aggregation, a key intermediate in the pathway, could be an alternative therapeutic target for post-stroke management.

7.
NAR Cancer ; 5(1): zcad012, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36879684

RESUMO

Immune checkpoint inhibitors (ICIs) have led to durable responses in cancer patients, yet their efficacy varies significantly across cancer types and patients. To stratify patients based on their potential clinical benefits, there have been substantial research efforts in identifying biomarkers and computational models that can predict the efficacy of ICIs, and it has become difficult to keep track of all of them. It is also difficult to compare findings of different studies since they involve different cancer types, ICIs, and various other details. To make it easy to access the latest information about ICI efficacy, we have developed a knowledgebase and a corresponding web-based portal (https://iciefficacy.org/). Our knowledgebase systematically records information about latest publications related to ICI efficacy, predictors proposed, and datasets used to test them. All information recorded is checked carefully by a manual curation process. The web-based portal provides functions to browse, search, filter, and sort the information. Digests of method details are provided based on the original descriptions in the publications. Evaluation results of the effectiveness of the predictors reported in the publications are summarized for quick overviews. Overall, our resource provides centralized access to the burst of information produced by the vibrant research on ICI efficacy.

8.
Vascul Pharmacol ; 146: 107096, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35952961

RESUMO

Recent studies have shown that short-chain fatty acids (SCFAs), primarily acetate, propionate and butyrate, play a crucial role in the pathogenesis of cardiovascular disease. Whether SCFAs regulate vascular calcification, a common pathological change in cardiovascular tissues, remains unclear. This study aimed to investigate the potential role of SCFAs in vascular calcification. Using cellular and animal models of vascular calcification, we showed that butyrate significantly enhanced high phosphate (Pi)-induced calcification and osteogenic transition of vascular smooth muscle cells (VSMC) in vitro, whereas acetate and propionate had no effects. Subsequent studies confirmed that butyrate significantly promoted high Pi-induced aortic ring calcification ex vivo and high dose vitamin D3 (vD3)-induced mouse vascular calcification in vivo. Mechanistically, butyrate significantly inhibited histone deacetylase (HDAC) expression in VSMCs, and a pan HDAC inhibitor Trichostatin A showed similar inductive effects on calcification and osteogenic transition of VSMCs to butyrate. In addition, the SCFA sensing receptors Gpr41 and Gpr109a were primarily expressed by VSMCs, and butyrate induced the rapid activation of NF-κB, Wnt and Akt signaling in VSMCs. Intriguingly, the NF-κB inhibitor SC75741 significantly attenuated butyrate-induced calcification and the osteogenic gene Msx2 expression in VSMCs. We showed that knockdown of Gpr41 but not Gpr109a attenuated butyrate-induced VSMC calcification. This study reveals that butyrate accelerates vascular calcification via its dual effects on HDAC inhibition and NF-κB activation. Our data provide novel insights into the role of microbe-host interaction in vascular calcification, and may have implications for the development of potential therapy for vascular calcification.


Assuntos
NF-kappa B , Calcificação Vascular , Animais , Butiratos/metabolismo , Butiratos/farmacologia , Células Cultivadas , Inibidores de Histona Desacetilases/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Camundongos , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , NF-kappa B/metabolismo , Fosfatos , Propionatos/metabolismo , Propionatos/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Calcificação Vascular/patologia , Vitamina D
9.
Front Pharmacol ; 12: 692431, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34744705

RESUMO

Vascular calcification (VC) in macrovascular and peripheral blood vessels is one of the main factors leading to diabetes mellitus (DM) and death. Apart from the induction of vascular calcification, advanced glycation end products (AGEs) have also been reported to modulate autophagy and apoptosis in DM. Autophagy plays a role in maintaining the stabilization of the external and internal microenvironment. This process is vital for regulating arteriosclerosis. However, the internal mechanisms of this pathogenic process are still unclear. Besides, the relationship among autophagy, apoptosis, and calcification in HASMCs upon AGEs exposure has not been reported in detail. In this study, we established a calcification model of SMC through the intervention of AGEs. It was found that the calcification was upregulated in AGEs treated HASMCs when autophagy and apoptosis were activated. In the country, AGEs-activated calcification and apoptosis were suppressed in Atg7 knockout cells or pretreated with wortmannin (WM), an autophagy inhibitor. These results provide new insights to conduct further investigations on the potential clinical applications for autophagy inhibitors in the treatment of diabetes-related vascular calcification.

10.
Pharmacol Res ; 170: 105697, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34062240

RESUMO

With the increase in human lifespan, population aging is one of the major problems worldwide. Aging is an irreversible progressive process that affects humans via multiple factors including genetic, immunity, cellular oxidation and inflammation. Progressive neuroinflammation contributes to aging, cognitive malfunction, and neurodegenerative diseases. However, precise mechanisms or drugs targeting age-related neuroinflammation and cognitive impairment remain un-elucidated. Traditional herbal plants have been prescribed in many Asian countries for anti-aging and the modulation of aging-related symptoms. In general, herbal plants' efficacy is attributed to their safety and polypharmacological potency via the systemic manipulation of the body system. Radix polygalae (RP) is a herbal plant prescribed for anti-aging and the relief of age-related symptoms; however, its active components and biological functions remained un-elucidated. In this study, an active methanol fraction of RP containing 17 RP saponins (RPS), was identified. RPS attenuates the elevated C3 complement protein in aged mice to a level comparable to the young control mice. The active RPS also restates the aging gut microbiota by enhancing beneficial bacteria and suppressing harmful bacteria. In addition, RPS treatment improve spatial reference memory in aged mice, with the attenuation of multiple molecular markers related to neuroinflammation and aging. Finally, the RPS improves the behavior and extends the lifespan of C. elegans, confirming the herbal plant's anti-aging ability. In conclusion, through the mouse and C. elegas models, we have identified the beneficial RPS that can modulate the aging process, gut microbiota diversity and rectify several aging-related phenotypes.


Assuntos
Envelhecimento/efeitos dos fármacos , Caenorhabditis elegans/efeitos dos fármacos , Complemento C3/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Extratos Vegetais/farmacologia , Polygala , Saponinas/farmacologia , Fatores Etários , Envelhecimento/genética , Envelhecimento/imunologia , Envelhecimento/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Caenorhabditis elegans/genética , Caenorhabditis elegans/crescimento & desenvolvimento , Caenorhabditis elegans/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo , Longevidade/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Doenças Neuroinflamatórias/genética , Doenças Neuroinflamatórias/imunologia , Doenças Neuroinflamatórias/metabolismo , Doenças Neuroinflamatórias/prevenção & controle , Fármacos Neuroprotetores/isolamento & purificação , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/isolamento & purificação , Raízes de Plantas , Polygala/química , Saponinas/isolamento & purificação , Memória Espacial/efeitos dos fármacos , Transcriptoma
11.
Cancer Biol Med ; 17(4): 986-1001, 2020 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-33299648

RESUMO

Objective: Delivery of chemotherapeutic drugs to the brain has remained a major obstacle in the treatment of glioma, owing to the presence of the blood-brain barrier and the activity of P-gp, which pumps its substrate back into the systemic circulation. The aim of the present study was to develop an intravenous formulation of HM30181A (HM) to inhibit P-gp in the brain to effectively deliver paclitaxel (PTX) for the treatment of malignant glioma. Methods: Two formulations of solubilized HM were designed on the basis of different solid dispersion strategies: i) spray-drying [polyvinlypyrrolidone (PVP)-HM] and ii) solvent evaporation [HP-ß-cyclodextrin (cyclodextrin)-HM]. The P-gp inhibition of these 2 formulations was assessed on the basis of rhodamine 123 uptake in cancer cells. Blood and brain pharmacokinetic parameters were also determined, and the antitumor effect of cyclodextrin-HM with PTX was evaluated in an orthotopic glioma xenograft mouse model. Results: Although both PVP-HM and cyclodextrin-HM formulations showed promising P-gp inhibition activity in vitro, cyclodextrin-HM had a higher maximum tolerated dose in mice than did PVP-HM. Pharmacokinetic study of cyclodextrin-HM revealed a plasma concentration plateau at 20 mg/kg, and the mice began to lose weight at doses above this level. Cyclodextrin-HM (10 mg/kg) administered with PTX at 10 mg/kg showed optimal antitumor activity in a mouse model, according to both tumor volume measurement and survival time (P < 0.05). Conclusions: In a mouse orthotopic brain tumor model, the intravenous co-administration of cyclodextrin-HM with PTX showed potent antitumor effects and therefore may have potential for glioma therapy in humans.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Antineoplásicos Fitogênicos/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Glioma/tratamento farmacológico , Paclitaxel/administração & dosagem , Administração Oral , Animais , Antineoplásicos Fitogênicos/farmacocinética , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Experimentais/tratamento farmacológico , Paclitaxel/farmacocinética , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Cell Death Dis ; 11(8): 621, 2020 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-32796841

RESUMO

Increased energy metabolism is responsible for supporting the abnormally upregulated proliferation and biosynthesis of cancer cells. The key cellular energy sensor AMP-activated protein kinase (AMPK) and the glycolytic enzyme alpha-enolase (α-enolase) have been identified as the targets for active components of ginseng. Accordingly, ginseng or ginsenosides have been demonstrated with their potential values for the treatment and/or prevention of cancer via the regulation of energy balance. Notably, our previous study demonstrated that the R-form derivative of 20(R)-Rh2, 20(R)-Rh2E2 exhibits specific and potent anti-tumor effect via suppression of cancer energy metabolism. However, the uncertain pharmacological effect of S-form derivative, 20(S)-Rh2E2, the by-product during the synthesis of 20(R)-Rh2E2 from parental compound 20(R/S)-Rh2 (with both R- and S-form), retarded the industrialized production, research and development of this novel effective candidate drug. In this study, 20(S)-Rh2E2 was structurally modified from pure 20(S)-Rh2, and this novel compound was directly compared with 20(R)-Rh2E2 for their in vitro and in vivo antitumor efficacy. Results showed that 20(S)-Rh2E2 effectively inhibited tumor growth and metastasis in a lung xenograft mouse model. Most importantly, animal administrated with 20(S)-Rh2E2 up to 320 mg/kg/day survived with no significant body weight lost or observable toxicity upon 7-day treatment. In addition, we revealed that 20(S)-Rh2E2 specifically suppressed cancer cell energy metabolism via the downregulation of metabolic enzyme α-enolase, leading to the reduction of lactate, acetyl-coenzyme (acetyl CoA) and adenosine triphosphate (ATP) production in Lewis lung cancer cells (LLC-1), but not normal cells. These findings are consistent to the results obtained from previous studies using a similar isomer 20(R)-Rh2E2. Collectively, current results suggested that 20(R/S)-Rh2E2 isomers could be the new and safe anti-metabolic agents by acting as the tumor metabolic suppressors, which could be generated from 20(R/S)-Rh2 in industrialized scale with low cost.


Assuntos
Metabolismo Energético/efeitos dos fármacos , Ginsenosídeos/farmacologia , Neoplasias/metabolismo , Neoplasias/patologia , Adenilato Quinase/metabolismo , Animais , Apoptose/efeitos dos fármacos , Biomarcadores Tumorais/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Respiração Celular/efeitos dos fármacos , Quinases Ciclina-Dependentes/metabolismo , Ciclinas/metabolismo , Regulação para Baixo/efeitos dos fármacos , Ginsenosídeos/química , Glicólise/efeitos dos fármacos , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Invasividade Neoplásica , Metástase Neoplásica , Neoplasias/enzimologia , Fosfopiruvato Hidratase/metabolismo , Fase S/efeitos dos fármacos , Proteínas Quinases Associadas a Fase S/metabolismo , Estatmina/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Pharmacol Res ; 153: 104660, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31982489

RESUMO

Multidrug resistance (MDR) represents an obstacle in anti-cancer therapy. MDR is caused by multiple mechanisms, involving ATP-binding cassette (ABC) transporters such as P-glycoprotein (P-gp), which reduces intracellular drug levels to sub-therapeutic concentrations. Therefore, sensitizing agents retaining effectiveness against apoptosis- or drug-resistant cancers are desired for the treatment of MDR cancers. The sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) pump is an emerging target to overcome MDR, because of its continuous expression and because the calcium transport function is crucial to the survival of tumor cells. Previous studies showed that SERCA inhibitors exhibit anti-cancer effects in Bax-Bak-deficient, apoptosis-resistant and MDR cancers, whereas specific P-gp inhibitors reverse the MDR phenotype of cancer cells by blocking efflux of chemotherapeutic agents. Here, we unraveled SERCA and P-gp as double targets of the triterpenoid, celastrol to reverse MDR. Celastrol inhibited both SERCA and P-gp to stimulate calcium-mediated autophagy and ATP depletion, thereby induced collateral sensitivity in MDR cancer cells. In vivo studies further confirmed that celastrol suppressed tumor growth and metastasis by SERCA-mediated calcium mobilization. To the best of our knowledge, our findings demonstrate collateral sensitivity in MDR cancer cells by simultaneous inhibition of SERCA and P-gp for the first time.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Trifosfato de Adenosina/antagonistas & inibidores , Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/antagonistas & inibidores , Triterpenos/farmacologia , Animais , Autofagia/genética , Proteína 7 Relacionada à Autofagia/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Hepatócitos/efeitos dos fármacos , Hepatócitos/patologia , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos Endogâmicos C57BL , Triterpenos Pentacíclicos , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Pharmacol Ther ; 208: 107480, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31972182

RESUMO

Chronic inflammation of the central nervous system (CNS) is critical to the pathogenesis of neuropsychiatric disorders (NPDs) that affect the global population. Current therapeutics for NPDs are limited to relieving symptoms and induce many adverse effects. Therefore, the discovery of novel therapeutic agents from natural sources is urgently needed. Intriguingly, the immune responses of peripheral organs are closely linked through the molecular communication between resident and blood-borne cellular components, which shape the neuroinflammatory phenotypes of NPDs. Since the gut and spleen are the two largest immunological organs of the body, the brain-gut-microbiome and brain-spleen axes have been implicated in the connection between the CNS and the peripheral immune system. Accordingly, it has been proposed that the local CNS inflammation observed in NPDs is regulated via the manipulation of the systemic immune system by targeting the gut and spleen. Additionally, the complexity of the signalling network underlying the communication between the CNS and the systemic immune system suggests a strong potential for treating NPDs through a polypharmacological approach. The close association between systemic immunity and the homeostasis of the CNS points to the concept of repurposing interventions for systemic immune disorders to treat NPDs. Notably, natural products represent a promising source of such effective compounds due to both their pharmacological potency and safety. This review discusses the complex implications of dysregulated systemic immunity mediated by the brain-spleen and brain-gut-microbiome axes in NPDs, such as Alzheimer's disease, Parkinson's disease, schizophrenia and major depressive disorder. In addition, the potential of repurposing natural product-based bioactive compounds for treating NPDs via modulating systemic immune disorders is intensively discussed.


Assuntos
Produtos Biológicos/uso terapêutico , Fatores Imunológicos/uso terapêutico , Transtornos Mentais/tratamento farmacológico , Doenças Neurodegenerativas/tratamento farmacológico , Animais , Humanos , Sistema Imunitário/efeitos dos fármacos , Inflamação/tratamento farmacológico , Transtornos Mentais/imunologia , Polifarmacologia
15.
Sci Rep ; 9(1): 20034, 2019 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-31882989

RESUMO

Resistance of cancer cells to chemotherapy is a significant clinical concern and mechanisms regulating cell death in cancer therapy, including apoptosis, autophagy or necrosis, have been extensively investigated over the last decade. Accordingly, the identification of medicinal compounds against chemoresistant cancer cells via new mechanism of action is highly desired. Autophagy is important in inducing cell death or survival in cancer therapy. Recently, novel autophagy activators isolated from natural products were shown to induce autophagic cell death in apoptosis-resistant cancer cells in a calcium-dependent manner. Therefore, enhancement of autophagy may serve as additional therapeutic strategy against these resistant cancers. By computational docking analysis, biochemical assays, and advanced live-cell imaging, we identified that neferine, a natural alkaloid from Nelumbo nucifera, induces autophagy by activating the ryanodine receptor and calcium release. With well-known apoptotic agents, such as staurosporine, taxol, doxorubicin, cisplatin and etoposide, utilized as controls, neferine was shown to induce autophagic cell death in a panel of cancer cells, including apoptosis-defective and -resistant cancer cells or isogenic cancer cells, via calcium mobilization through the activation of ryanodine receptor and Ulk-1-PERK and AMPK-mTOR signaling cascades. Taken together, this study provides insights into the cytotoxic mechanism of neferine-induced autophagy through ryanodine receptor activation in resistant cancers.


Assuntos
Apoptose/efeitos dos fármacos , Morte Celular Autofágica/efeitos dos fármacos , Benzilisoquinolinas/farmacologia , Cálcio/metabolismo , Neoplasias/patologia , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Linhagem Celular Tumoral , Medicamentos de Ervas Chinesas , Humanos , Neoplasias/metabolismo
16.
Front Pharmacol ; 10: 912, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31551763

RESUMO

The pro-apoptotic proteins BAX and BAK are critical regulatory factors constituting the apoptosis machinery. Downregulated expression of BAX and BAK in human colorectal cancer lead to chemotherapeutic failure and poor survival rate in patients. In this study, isogenic DLD-1 colon cancer cells and the BAX and BAK double knockout counterpart were used as the cellular model to investigate the role of BAX/BAK-associated signaling network and the corresponding downstream effects in the development of drug resistance. Our data suggested that DLD-1 colon cancer cells with BAX/BAK double-knockout were selectively resistant to a panel of FDA-approved drugs (27 out of 66), including etoposide. PCR array analysis for the transcriptional profiling of genes related to human cancer drug resistance validated the altered level of 12 genes (3 upregulated and 9 downregulated) in DLD-1 colon cancer cells lack of BAX and BAK expression. Amongst these genes, XPC responsible for DNA repairment and cellular respiration demonstrated the highest tolerance towards etoposide treatment accompanying upregulated glycolysis as revealed by metabolic stress assay in DLD-1 colon cancer cells deficient with XPC. Collectively, our findings provide insight into the search of novel therapeutic strategies and pharmacological targets to against cancer drug resistance genetically associated with BAX, BAK, and XPC, for improving the therapy of colorectal cancer via the glycolytic pathway.

17.
Br J Pharmacol ; 176(16): 2922-2944, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31124139

RESUMO

BACKGROUND AND PURPOSE: Celastrol exhibits anti-arthritic effects in rheumatoid arthritis (RA), but the role of celastrol-mediated Ca2+ mobilization in treatment of RA remains undefined. Here, we describe a regulatory role for celastrol-induced Ca2+ signalling in synovial fibroblasts of RA patients and adjuvant-induced arthritis (AIA) in rats. EXPERIMENTAL APPROACH: We used computational docking, Ca2+ dynamics and functional assays to study the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase pump (SERCA). In rheumatoid arthritis synovial fibroblasts (RASFs)/rheumatoid arthritis fibroblast-like synoviocytes (RAFLS), mechanisms of Ca2+ -mediated autophagy were analysed by histological, immunohistochemical and flow cytometric techniques. Anti-arthritic effects of celastrol, autophagy induction, and growth rate of synovial fibroblasts in AIA rats were monitored by microCT and immunofluorescence staining. mRNA from joint tissues of AIA rats was isolated for transcriptional analysis of inflammatory genes, using siRNA methods to study calmodulin, calpains, and calcineurin. KEY RESULTS: Celastrol inhibited SERCA to induce autophagy-dependent cytotoxicity in RASFs/RAFLS via Ca2+ /calmodulin-dependent kinase kinase-ß-AMP-activated protein kinase-mTOR pathway and repressed arthritis symptoms in AIA rats. BAPTA/AM hampered the in vitro and in vivo effectiveness of celastrol. Inflammatory- and autoimmunity-associated genes down-regulated by celastrol in joint tissues of AIA rat were restored by BAPTA/AM. Knockdown of calmodulin, calpains, and calcineurin in RAFLS confirmed the role of Ca2+ in celastrol-regulated gene expression. CONCLUSION AND IMPLICATIONS: Celastrol triggered Ca2+ signalling to induce autophagic cell death in RASFs/RAFLS and ameliorated arthritis in AIA rats mediated by calcium-dependent/-binding proteins facilitating the exploitation of anti-arthritic drugs based on manipulation of Ca2+ signalling.


Assuntos
Artrite Experimental/metabolismo , Artrite Reumatoide/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Triterpenos/farmacologia , Animais , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Autofagia/efeitos dos fármacos , Células Cultivadas , Fibroblastos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Camundongos Knockout , Triterpenos Pentacíclicos , Ratos Sprague-Dawley , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Membrana Sinovial/citologia , Triterpenos/uso terapêutico
18.
Bioorg Chem ; 83: 450-460, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30448723

RESUMO

Eleven dauricine derivatives were synthesized and evaluated for their anti-cancer effect in different cancer cells and their autophagic activity in HeLa model cell. Among these newly synthesized compounds, carbamates 2a, 2b, carbonyl ester 3a and sulfonyl ester 4a exhibited potent cytotoxic effects on tested cancer cells with IC50 values ranged from 2.72 to 12.53 µM, which were more potent than that of dauricine (higher than 15.53 µM). The above four derivatives are validated to induce autophagy-dependent cell death in HeLa cancer cells. These findings offer us a promising source for generating novel autophagic enhancers for anti-cancer therapy.


Assuntos
Antineoplásicos/farmacologia , Benzilisoquinolinas/farmacologia , Tetra-Hidroisoquinolinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Autofagia/efeitos dos fármacos , Benzilisoquinolinas/síntese química , Benzilisoquinolinas/química , Células HeLa , Humanos , Proteínas Associadas aos Microtúbulos/metabolismo , Tetra-Hidroisoquinolinas/síntese química , Tetra-Hidroisoquinolinas/química
20.
Front Pharmacol ; 9: 710, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30018557

RESUMO

Adenosine 5'-monophsphate-activated protein kinase (AMPK) is a crucial energy sensor for maintaining cellular homeostasis. Targeting AMPK may provide an alternative approach in treatment of various diseases like cancer, diabetes, and neurodegenerations. Accordingly, novel AMPK activators are frequently identified from natural products in recent years. However, most of such AMPK activators are interacting with AMPK in an indirect manner, which may cause off-target effects. Therefore, the search of novel direct AMPK modulators is inevitable and effective screening methods are needed. In this report, a rapid and straightforward method combining the use of in silico and in vitro techniques was established for selecting and categorizing huge amount of compounds from chemical library for targeting AMPK modulators. A new class of direct AMPK modulator have been discovered which are anilides or anilide-like compounds. In total 1,360,000 compounds were virtually screened and 17 compounds were selected after biological assays. Lipinski's rule of five assessment suggested that, 13 out of the 17 compounds are demonstrating optimal bioavailability. Proton acceptors constituting the structure of these compounds and hydrogen bonds with AMPK in the binding site appeared to be the important factors determining the efficacy of these compounds.

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