RESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Tubeimoside-I (TBM) promotes various cancer cell death by increasing the reactive oxygen species (ROS) production. However, the specific molecular mechanisms of TBM and its impact on oxaliplatin-mediated anti-CRC activity are not yet fully understood. AIM OF THE STUDY: To elucidate the therapeutic effect and underlying molecular mechanism of TBM on oxaliplatin-mediated anti-CRC activity. MATERIALS AND METHODS: 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation, wound healing assays and flow cytometry were conducted to investigate the changes in cell phenotypes and ROS generation. Real-time quantitative PCR (qRT-PCR) and western blotting were performed to detect the expressions of related mRNA and proteins. Finally, mouse xenograft models demonstrated that synergistic anti-tumor effects of combined treatment with TBM and oxaliplatin. RESULTS: The synergistic enhancement of the anti-tumor effects of oxaliplatin in colon cancer cells by TBM involved in the regulation of ROS-mediated endoplasmic reticulum (ER) stress, C-jun-amino-terminal kinase (JNK), and p38 MAPK signaling pathways. Mechanistically, TBM increased ROS generation in colon cancer cells by inhibiting heat shock protein 60 (HSPD1) expression. Knocking down HSPD1 increased TBM-induced antitumor activity and ROS generation in colon cancer cells. The mouse xenograft tumor models further validated that the combination therapy exhibited stronger anti-tumor effects than monotherapy alone. CONCLUSIONS: Combined therapy with TBM and oxaliplatin might be an effective therapeutic strategy for some CRC patients.
Asunto(s)
Neoplasias Colorrectales , Sinergismo Farmacológico , Estrés del Retículo Endoplásmico , Oxaliplatino , Especies Reactivas de Oxígeno , Saponinas , Triterpenos , Animales , Humanos , Masculino , Ratones , Antineoplásicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Línea Celular Tumoral , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Estrés del Retículo Endoplásmico/efectos de los fármacos , Células HCT116 , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Ratones Endogámicos BALB C , Ratones Desnudos , Oxaliplatino/farmacología , Especies Reactivas de Oxígeno/metabolismo , Saponinas/farmacología , Triterpenos/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Mountain-cultivated Panax ginseng C.A.Mey. (MCG) with high market price and various properties was valuable special local product in Northeast of Asia. MCG has been historically used to mitigate heart failure (HF) for thousand years, HF is a clinical manifestation of deficiency of "heart-qi" in traditional Chinese medicine. However, there was little report focus on the activities of extracted residue of MCG. AIM OF THE STUDY: A novel glycopeptide (APMCG-1) was isolated from step ethanol precipitations of alkaline protease-assisted extract from MCG residue. MATERIALS AND METHODS: The molecular weight and subunit structure of APMCG-1 were determined by FT-IR, HPLC and GPC technologies, as well as the H9c2 cells, Tg (kdrl:EGFP) zebrafish were performed to evaluated the protective effect of APMCG-1. RESULTS: APMCG-1 was identified as a glycopeptide containing seven monosaccharides and seven amino acids via O-lined bonds. Further, in vitro, APMCG-1 significantly decreased reactive oxygen species production and lactate dehydrogenase contents in palmitic acid (PA)-induced H9c2 cells. APMCG-1 also attenuated endoplasmic reticulum stress and mitochondria-mediated apoptosis in H9c2 cells via the PI3K/AKT signaling pathway. More importantly, APMCG-1 reduced the blood glucose, lipid contents, the levels of heart injury, oxidative stress and inflammation of 5 days post fertilization Tg (kdrl:EGFP) zebrafish with type 2 diabetic symptoms in vivo. CONCLUSIONS: APMCG-1 protects PA-induced H9c2 cells while reducing cardiac dysfunction in zebrafish with type 2 diabetic symptoms. The present study provides a new insight into the development of natural glycopeptides as heart-related drug therapies.
Asunto(s)
Diabetes Mellitus Tipo 2 , Glicopéptidos , Insuficiencia Cardíaca , Panax , Pez Cebra , Animales , Panax/química , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/prevención & control , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Ratas , Línea Celular , Glicopéptidos/farmacología , Glicopéptidos/química , Apoptosis/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Extractos Vegetales/farmacología , Extractos Vegetales/química , Cardiotónicos/farmacología , Cardiotónicos/química , Cardiotónicos/aislamiento & purificación , Cardiotónicos/uso terapéutico , Miocitos Cardíacos/efectos de los fármacos , Estrés del Retículo Endoplásmico/efectos de los fármacosRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Melastoma dodecandrum Lour. (MD), a traditional Chinese medicine used by the She ethnic group, has been used to treat cerebral ischemia-reperfusion (CIR) injury due to its efficacy in promoting blood circulation and removing blood stasiss; however, the therapeutic effects and mechanisms of MD in treating CIR injury remain unclear. AIM: To investigate the protective effects of MD on CIR injury, in addition to its impact on oxidative stress, endoplasmic reticulum (ER) stress, and cell apoptosis. MATERIALS AND METHODS: The research was conducted using both cell experiments and animal experiments. The CCK-8 method, immunofluorescence staining, and flow cytometry were used to analyze the effects of MD-containing serum on oxygen-glucose deprivation/reperfusion (OGD/R)-induced PC12 cell viability, reactive oxygen species (ROS) clearance, anti-inflammatory, neuroprotection and inhibition of apoptosis. Furthermore, 2,3,5-Triphenyl tetrazolium chloride staining, hematoxylin and eosin staining, Nissl staining, and immunohistochemistry were used to detect infarct size, pathological changes, Nissl corpuscula and neuronal protein expression in middle cerebral artery occlusion (MCAO) rats. Polymerase chain reaction and Western Blotting were conducted in cell and animal experiments to detect the expression levels of ER stress-related genes and proteins. RESULTS: The MD extract enhanced the viability of PC12 cells under OGD/R modeling, reduced ROS and IL-6 levels, increased MBP levels, and inhibited cell apoptosis. Furthermore, MD improved the infarct area in MCAO rats, increased the number of Nissl bodies, and regulated neuronal protein levels including Microtubule-Associated Protein 2 (MAP-2), Myelin Basic Protein (MBP), Glial Fibrillary Acidic Protein (GFAP), and Neurofilament 200 (NF200). Additionally, MD could regulate the expression levels of oxidative stress proteins malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD), and catalase (CAT). Both cell and animal experiments demonstrated that MD could inhibit ER stress-related proteins (GRP78, ATF4, ATF6, CHOP) and reduce cell apoptosis. CONCLUSION: This study confirmed that the therapeutic mechanism of the MD extract on CIR injury was via the inhibition of oxidative stress and the ER stress pathway, in addition to the inhibition of apoptosis.
Asunto(s)
Apoptosis , Estrés del Retículo Endoplásmico , Fármacos Neuroprotectores , Estrés Oxidativo , Ratas Sprague-Dawley , Daño por Reperfusión , Animales , Estrés del Retículo Endoplásmico/efectos de los fármacos , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/metabolismo , Daño por Reperfusión/prevención & control , Estrés Oxidativo/efectos de los fármacos , Ratas , Células PC12 , Masculino , Fármacos Neuroprotectores/farmacología , Apoptosis/efectos de los fármacos , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Especies Reactivas de Oxígeno/metabolismo , Supervivencia Celular/efectos de los fármacos , Isquemia Encefálica/tratamiento farmacológico , Extractos Vegetales/farmacología , Extractos Vegetales/química , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéuticoRESUMEN
Bisphenol A (BPA) is an industrial pollutant that can cause immune impairment. Selenium acts as an antioxidant, as selenium deficiency often accompanies oxidative stress, resulting in organ damage. This study is the first to demonstrate that BPA and/or selenium deficiency induce pyroptosis and ferroptosis-mediated thymic injury in chicken and chicken lymphoma cell (MDCC-MSB-1) via oxidative stress-induced endoplasmic reticulum (ER) stress. We established a broiler chicken model of BPA and/or selenium deficiency exposure and collected thymus samples as research subjects after 42 days. The results demonstrated that BPA or selenium deficiency led to a decrease in antioxidant enzyme activities (T-AOC, CAT, and GSH-Px), accumulation of peroxides (H2O2 and MDA), significant upregulation of ER stress-related markers (GRP78, IER 1, PERK, EIF-2α, ATF4, and CHOP), a significant increase in iron ion levels, significant upregulation of pyroptosis-related gene (NLRP3, ASC, Caspase1, GSDMD, IL-18 and IL-1ß), significantly increase ferroptosis-related genes (TFRC, COX2) and downregulate GPX4, HO-1, FTH, NADPH. In vitro experiments conducted in MDCC-MSB-1 cells confirmed the results, demonstrating that the addition of antioxidant (NAC), ER stress inhibitor (TUDCA) and pyroptosis inhibitor (Vx765) alleviated oxidative stress, endoplasmic reticulum stress, pyroptosis, and ferroptosis. Overall, this study concludes that the combined effects of oxidative stress and ER stress mediate pyroptosis and ferroptosis in chicken thymus induced by BPA exposure and selenium deficiency.
Asunto(s)
Compuestos de Bencidrilo , Pollos , Estrés del Retículo Endoplásmico , Ferroptosis , Fenoles , Piroptosis , Especies Reactivas de Oxígeno , Selenio , Animales , Compuestos de Bencidrilo/toxicidad , Ferroptosis/efectos de los fármacos , Piroptosis/efectos de los fármacos , Estrés del Retículo Endoplásmico/efectos de los fármacos , Selenio/deficiencia , Fenoles/toxicidad , Especies Reactivas de Oxígeno/metabolismo , Timo/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacosRESUMEN
Cisplatin is a common anticancer drug, but its frequent nephrotoxicity limits its clinical use. Small GTP-binding protein GDP dissociation stimulator (smgGDS), a small GTPase chaperone protein, was considerably downregulated during cisplatin-induced acute kidney injury (CDDP-AKI), especially in renal tubular epithelial cells. SmgGDS-knockdown mice was established and found that smgGDS knockdown promoted CDDP-AKI, as demonstrated by an increase in serum creatine, blood urea nitrogen levels and the appearance of tubular patterns. RNA sequencing suggested that protein kinase RNA-like ER kinase (PERK), which bridges mitochondria-associated ER membranes, was involved in smgGDS knockdown following CDDP-AKI, and then identified that smgGDS knockdown increased phosphorylated-PERK in vivo and in vitro. Furthermore, we confirmed that smgGDS deficiency aggravated apoptosis and ER stress in vivo and in vitro. And the ER stress inhibitor 4-Phenylbutyric acid and the inhibition of PERK phosphorylation mitigated smgGDS deficiency-induced ER stress related apoptosis following cisplatin treatment, while the eIF2α phosphorylation inhibitor could not reverse the smgGDS deficiency accelerated cell death. Furthermore, the over-expression of smgGDS could reverse the ER stress and apoptosis caused by CDDP. Overall, smgGDS regulated PERK-dependent ER stress and apoptosis, thereby influencing renal damage. This study identified a target for diagnosing and treating cisplatin-induced acute kidney injury.
Asunto(s)
Lesión Renal Aguda , Cisplatino , Estrés del Retículo Endoplásmico , eIF-2 Quinasa , Cisplatino/efectos adversos , Cisplatino/toxicidad , Animales , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/patología , Lesión Renal Aguda/genética , eIF-2 Quinasa/metabolismo , eIF-2 Quinasa/genética , Estrés del Retículo Endoplásmico/efectos de los fármacos , Ratones , Masculino , Apoptosis/efectos de los fármacos , Ratones Endogámicos C57BL , Antineoplásicos/efectos adversos , Antineoplásicos/toxicidad , FosforilaciónRESUMEN
Pro-inflammatory cytokines in muscle play a pivotal role in physiological responses and in the pathophysiology of inflammatory disease and muscle atrophy. Lactobacillus delbrueckii (LD), as a kind of probiotics, has inhibitory effects on pro-inflammatory cytokines associated with various inflammatory diseases. This study was conducted to explore the effect of dietary LD on the lipopolysaccharide (LPS)-induced muscle inflammation and atrophy in piglets and to elucidate the underlying mechanism. A total of 36 weaned piglets (Duroc × Landrace × Large Yorkshire) were allotted into three groups with six replicates (pens) of two piglets: (1) Nonchallenged control; (2) LPS-challenged (LPS); (3) 0.2% LD diet and LPS-challenged (LD+LPS). On d 29, the piglets were injected intraperitoneally with LPS or sterilized saline, respectively. All piglets were slaughtered at 4 h after LPS or saline injection, the blood and muscle samples were collected for further analysis. Our results showed that dietary supplementation of LD significantly attenuated LPS-induced production of pro-inflammatory cytokines IL-6 and TNF-α in both serum and muscle of the piglets. Concomitantly, pretreating the piglets with LD also clearly inhibited LPS-induced nuclear translocation of NF-κB p65 subunits in the muscle, which correlated with the anti-inflammatory effects of LD on the muscle of piglets. Meanwhile, LPS-induced muscle atrophy, indicated by a higher expression of muscle atrophy F-box, muscle RING finger protein (MuRF1), forkhead box O 1, and autophagy-related protein 5 (ATG5) at the transcriptional level, whereas pretreatment with LD led to inhibition of these upregulations, particularly genes for MuRF1 and ATG5. Moreover, LPS-induced mRNA expression of endoplasmic reticulum stress markers, such as eukaryotic translational initiation factor 2α (eIF-2α) was suppressed by pretreatment with LD, which was accompanied by a decrease in the protein expression levels of IRE1α and GRP78. Additionally, LD significantly prevented muscle cell apoptotic death induced by LPS. Taken together, our data indicate that the anti-inflammatory effect of LD supply on muscle atrophy of piglets could be likely regulated by inhibiting the secretion of pro-inflammatory cytokines through the inactivation of the ER stress/NF-κB singling pathway, along with the reduction in protein degradation.
Asunto(s)
Estrés del Retículo Endoplásmico , Lactobacillus delbrueckii , Lipopolisacáridos , Atrofia Muscular , Animales , Lipopolisacáridos/toxicidad , Porcinos , Estrés del Retículo Endoplásmico/efectos de los fármacos , Atrofia Muscular/inducido químicamente , Atrofia Muscular/metabolismo , Atrofia Muscular/prevención & control , Atrofia Muscular/patología , Destete , Proteolisis , Probióticos/farmacología , Inflamación/metabolismo , Miositis/inducido químicamente , Miositis/metabolismo , Miositis/patología , Citocinas/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Músculo Esquelético/efectos de los fármacosRESUMEN
Antibiotic use is a risk factor for development of inflammatory bowel diseases (IBDs). IBDs are characterized by a damaged mucus layer, which does not separate the intestinal epithelium from the microbiota. Here, we hypothesized that antibiotics affect the integrity of the mucus barrier, which allows bacterial penetrance and predisposes to intestinal inflammation. We found that antibiotic treatment led to breakdown of the colonic mucus barrier and penetration of bacteria into the mucus layer. Using fecal microbiota transplant, RNA sequencing followed by machine learning, ex vivo mucus secretion measurements, and antibiotic treatment of germ-free mice, we determined that antibiotics induce endoplasmic reticulum stress in the colon that inhibits colonic mucus secretion in a microbiota-independent manner. This antibiotic-induced mucus secretion flaw led to penetration of bacteria into the colonic mucus layer, translocation of microbial antigens into circulation, and exacerbation of ulcerations in a mouse model of IBD. Thus, antibiotic use might predispose to intestinal inflammation by impeding mucus production.
Asunto(s)
Antibacterianos , Colon , Microbioma Gastrointestinal , Mucosa Intestinal , Moco , Animales , Antibacterianos/farmacología , Antibacterianos/efectos adversos , Ratones , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/patología , Microbioma Gastrointestinal/efectos de los fármacos , Colon/metabolismo , Colon/efectos de los fármacos , Colon/patología , Colon/microbiología , Moco/metabolismo , Enfermedades Inflamatorias del Intestino/inducido químicamente , Enfermedades Inflamatorias del Intestino/metabolismo , Enfermedades Inflamatorias del Intestino/patología , Enfermedades Inflamatorias del Intestino/microbiología , Estrés del Retículo Endoplásmico/efectos de los fármacos , Modelos Animales de Enfermedad , Trasplante de Microbiota Fecal , Ratones Endogámicos C57BL , HumanosRESUMEN
Microplastics (MPs), a brand-new class of worldwide environmental pollutant, have received a lot of attention. MPs are consumed by both humans and animals through water, food chain and other ways, which may cause potential health risks. However, the effects of MPs on embryonic development, especially placental function, and its related mechanisms still need to be further studied. We investigated the impact on fetal development and placental physiological function of pregnant mice by consecutive gavages of MPs at 0, 25, 50, 100 mg/kg body weight during gestational days (GDs 0-14). The results showed that continuous exposure to high concentrations of MP significantly reduced daily weight gain and impaired reproductive performance of pregnant mice. In addition, MPs could significantly induce oxidative stress and placental dysfunction in pregnant mice. On the other hand, MPs exposure significantly decreased placental barrier function and induced placental inflammation. Specifically, MPs treatment significantly reduced the expression of tight junction proteins in placentas, accompanied by inflammatory cell infiltration and increased mRNA levels of pro-inflammatory cytokines and chemokines in placentas. Finally, we found that MPs induced placental apoptosis and endoplasmic reticulum (ER) stress through the GRP78/IRE1α/JNK axis, leading to placental dysfunction and decreased reproductive performance in pregnant mice. We revealed for the first time that the effects of MPs on placental dysfunction in pregnant animals. Blocking the targets of MPs mediated ER stress will provide potential therapeutic ideas for the toxic effects of MPs on maternal pregnancy.
Asunto(s)
Apoptosis , Chaperón BiP del Retículo Endoplásmico , Estrés del Retículo Endoplásmico , Microplásticos , Placenta , Animales , Femenino , Embarazo , Chaperón BiP del Retículo Endoplásmico/metabolismo , Apoptosis/efectos de los fármacos , Estrés del Retículo Endoplásmico/efectos de los fármacos , Placenta/efectos de los fármacos , Placenta/metabolismo , Microplásticos/toxicidad , Ratones , Estrés Oxidativo/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas de Choque Térmico/metabolismo , Proteínas de Choque Térmico/genética , Retardo del Crecimiento Fetal/inducido químicamente , Ratones Endogámicos ICRRESUMEN
Bovine viral diarrhea-mucosal disease (BVD-MD) is a contagious disease in cattle, caused by the bovine viral diarrhea virus (BVDV). This virus continues to spread globally, exerting pressure on both public health and the economy. Despite its impact, there are currently no effective drugs for treating BVDV. This study utilized Madin-Darby bovine kidney (MDBK) cells as a model to investigate the antiviral effects of melatonin against Bovine Viral Diarrhea Virus (BVDV) and its connection with endoplasmic reticulum (ER) stress. Our results show that melatonin can suppress BVDV proliferation in MDBK cells by modulating the endoplasmic reticulum (ER) stress-mediated NF-κB pathway and autophagy. Specifically, melatonin alleviated ER stress, inhibited the activation of IκBα and p65, regulated autophagy, and reduced the expression levels of pro-inflammatory cytokines. Further, when we treated BVDV-infected cells with the ER stress inducer thapsigargin, it led to significant activation of the NF-κB pathway and autophagy. Conversely, treating the cells with the ER stress inhibitor 4-phenylbutyric acid reversed these effects. These findings suggest that melatonin exerts its antiviral effects primarily through the PERK-eIF2α-ATF4 of ER stress-mediated NF-κB pathway and autophagy. Overall, our study underscores the potential of melatonin as an effective protective and therapeutic option against BVDV, offering insights into its anti-infective mechanisms.
Asunto(s)
Antivirales , Autofagia , Virus de la Diarrea Viral Bovina , Estrés del Retículo Endoplásmico , Melatonina , FN-kappa B , Transducción de Señal , Replicación Viral , Melatonina/farmacología , Animales , Estrés del Retículo Endoplásmico/efectos de los fármacos , Autofagia/efectos de los fármacos , Bovinos , FN-kappa B/metabolismo , Replicación Viral/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Virus de la Diarrea Viral Bovina/efectos de los fármacos , Virus de la Diarrea Viral Bovina/fisiología , Línea Celular , Antivirales/farmacología , Diarrea Mucosa Bovina Viral/tratamiento farmacológico , Diarrea Mucosa Bovina Viral/virologíaRESUMEN
The immunosuppressive tumor microenvironment (TME) remains a major obstacle to tumor control and causes suboptimal responses to immune checkpoint blockade (ICB) therapy. Thus, developing feasible therapeutic strategies that trigger inflammatory responses in the TME could improve the ICB efficacy. Mitochondria play an essential role in inflammation regulation and tumor immunogenicity induction. Herein, we report the discovery and characterization of a class of small molecules that can recapitulate aqueous self-assembly behavior, specifically target cellular organelles (e.g., mitochondria), and invigorate tumor cell immunogenicity. Mechanistically, this nanoassembly platform dynamically rewires mitochondria, induces endoplasmic reticulum stress, and causes apoptosis/paraptosis-associated immunogenic cell death. After treatment, stressed and dying tumor cells can act as prophylactic or therapeutic cancer vaccines. In preclinical mouse models of cancers with intrinsic or acquired resistance to PD-1 blockade, the local administration of nanoassemblies inflames the immunologically silent TME and synergizes with ICB therapy, generating potent antitumor immunity. This chemically programmed small-molecule immune enhancer acts distinctly from regular cytotoxic therapeutics and offers a promising strategy for synchronous and dynamic tailoring of innate immunity to achieve traceless cancer therapy and overcome immunosuppression in cancers.
Asunto(s)
Mitocondrias , Neoplasias , Microambiente Tumoral , Animales , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Ratones , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología , Humanos , Línea Celular Tumoral , Neoplasias/inmunología , Neoplasias/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/farmacología , Estrés del Retículo Endoplásmico/efectos de los fármacos , Estrés del Retículo Endoplásmico/inmunología , Apoptosis/efectos de los fármacos , Femenino , Muerte Celular Inmunogénica/efectos de los fármacos , Ratones Endogámicos C57BL , Nanopartículas/química , Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/administración & dosificación , Inmunoterapia/métodosRESUMEN
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy that commonly affects children and adolescents with a poor prognosis. The terminal unfolded protein response (UPR) is an emerging anti-cancer approach, although its role in pediatric T-ALL remains unclear. In our pediatric T-ALL cohort from different centers, a lower QRICH1 expression was found associated with a worse prognosis of pediatric T-ALL. Overexpression of QRICH1 significantly inhibited cell proliferation and stimulated apoptosis of T-ALL both in vitro and in vivo. Upregulation of QRICH1 significantly downregulated 78 KDa glucose-regulated protein (GRP78) and upregulated CHOP, thus activating the terminal UPR. Co-overexpression of GRP78 in T-ALL cells overexpressing QRICH1 partially reverted the inhibited proliferation and stimulated apoptosis. QRICH1 bound to the residues Asp212 and Glu155 of the nucleotide-binding domain (NBD) of GRP78, thereby inhibiting its ATP hydrolysis activity. In addition, QRICH1 was associated with endoplasmic reticulum (ER) stress in T-ALL, and overexpression of QRICH1 reversed drug resistance. Overall, low QRICH1 expression is an independent risk factor for a poor prognosis of pediatric T-ALL. By inhibiting GRP78, QRICH1 suppresses pediatric T-ALL.
Asunto(s)
Apoptosis , Proliferación Celular , Chaperón BiP del Retículo Endoplásmico , Proteínas de Choque Térmico , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Chaperón BiP del Retículo Endoplásmico/metabolismo , Humanos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Proteínas de Choque Térmico/metabolismo , Proteínas de Choque Térmico/genética , Niño , Proliferación Celular/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Masculino , Línea Celular Tumoral , Femenino , Ratones , Estrés del Retículo Endoplásmico/efectos de los fármacos , Respuesta de Proteína Desplegada/efectos de los fármacos , Adolescente , Preescolar , PronósticoRESUMEN
Inflammatory bowel disease (IBD) is a chronic, debilitating condition with limited therapeutic options. Dietary components like blueberries have emerged as potential modulators of inflammation and tissue repair in gastrointestinal diseases. This study investigated endoplasmic reticulum (ER) stress-mediated apoptosis mediated protective effects of blueberries in ameliorating dextran sulfate sodium (DSS)-induced IBD. Firstly, a total of 86 anthocyanin compounds were identified in blueberry extract by LC-MS spectroscopy, including 35 cyanidin, 9 delphinidin, 14 malvidin, 10 peonidin, and 9 petunidin. Then, the animal study showed that blueberry supplementation notably ameliorated DSS-induced IBD symptoms, as evidenced by improved histopathological scores and a reduced disease activity index (DAI) score. Additionally, blueberries attenuated ER stress by inhibiting the colonic PERK/eIF2α/ATF4/CHOP signaling pathway. Furthermore, blueberries inhibited the expression of the pro-apoptotic protein, caspase-3, and decreased colonic apoptosis, as evidenced by TUNEL assay results. However, it did not affect the expression of anti-apoptotic proteins, bcl-2 and bcl-xl. Finally, blueberries enhanced the intestinal barrier by upregulating ZO-1, claudin-1, occludin, and E-cadherin. In conclusion, blueberries demonstrate therapeutic potential against DSS-induced IBD-like symptoms in mice, possibly by regulating ER stress-mediated apoptosis pathways. These findings suggest that blueberries might be an effective dietary intervention for IBD management.
Asunto(s)
Apoptosis , Arándanos Azules (Planta) , Colon , Sulfato de Dextran , Estrés del Retículo Endoplásmico , Enfermedades Inflamatorias del Intestino , Extractos Vegetales , Animales , Arándanos Azules (Planta)/química , Estrés del Retículo Endoplásmico/efectos de los fármacos , Apoptosis/efectos de los fármacos , Ratones , Extractos Vegetales/farmacología , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/inducido químicamente , Sulfato de Dextran/efectos adversos , Masculino , Colon/efectos de los fármacos , Colon/metabolismo , Colon/patología , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , HumanosRESUMEN
While 3-N-butylphthalide (NBP) has demonstrated notable cardioprotective effects, its precise role in mitigating myocardial arrhythmia following ischemia/reperfusion (IR) injury in diabetes remains unclear. This study aimed to explore the potential mechanisms through which NBP mitigates reperfusion-induced myocardial arrhythmia in diabetic rats, with a particular focus on mitochondrial function and biogenesis, endoplasmic reticulum (ER) stress, and oxidative/inflammatory responses. Sixty Sprague-Dawley rats were divided into non-diabetic and diabetic groups, subjected to in-vivo myocardial IR injury, and treated with NBP (100 mg/kg, intraperitoneally) through different modalities: preconditioning, postconditioning, or a combination of both. Electrocardiography (ECG) was employed to assess the incidence and severity of arrhythmia. Fluorometric, Western blotting and ELISA analyses were utilized to measure the mitochondrial, ER stress, and cellular outcomes. Treatment of non-diabetic rats with NBP in preconditioned, postconditioned, and combined approaches significantly reduced cardiotroponin-I and the frequency and severity of arrhythmias induced by IR injury. However, only the combined preconditioning plus postconditioning approach of NBP had protective and antiarrhythmic effects in diabetic rats, in an additive manner. Moreover, the NBP combined approach improved mitochondrial function and upregulated the expression of PGC-1?, Sirt1, and glutathione while concurrently downregulating ER stress and oxidative and pro-inflammatory-related proteins in diabetic rats. In conclusion, the combined approach of NBP treatment was effective in mitigating myocardial arrhythmia in diabetic rats. This approach coordinates interactions within the mitochondria-endoplasmic reticulum network and inhibits oxidative and inflammatory mediators, offering a promising strategy for managing myocardial arrhythmia in diabetic patients. Key words: Myocardial Infarction, Mitochondria, Arrhythmia, Reperfusion, Diabetes, Ischemia.
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Arritmias Cardíacas , Benzofuranos , Diabetes Mellitus Experimental , Estrés del Retículo Endoplásmico , Daño por Reperfusión Miocárdica , Estrés Oxidativo , Ratas Sprague-Dawley , Animales , Estrés Oxidativo/efectos de los fármacos , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/prevención & control , Benzofuranos/farmacología , Benzofuranos/uso terapéutico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/complicaciones , Masculino , Arritmias Cardíacas/etiología , Arritmias Cardíacas/prevención & control , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/tratamiento farmacológico , Ratas , Estrés del Retículo Endoplásmico/efectos de los fármacos , Antiarrítmicos/farmacología , Antiarrítmicos/uso terapéutico , Mitocondrias Cardíacas/metabolismo , Mitocondrias Cardíacas/efectos de los fármacos , Inflamación/metabolismo , Inflamación/tratamiento farmacológicoRESUMEN
This work reports a cyclic peptide appended self-assembled scaffold that recognizes the membrane protein EGFR and arrests the EGFR signaling through multivalent interactions by assembly-induced aggregation. When incubated with cells, the oligomers of PAD-1 first recognize the overexpressed EGFR on cancer cell membranes for arresting EGFR, which then initiates cellular uptake through endocytosis. The accumulation of PAD-1 and EGFR in the lysosome results in the formation of nanofibers, leading to the lysosomal membrane permeabilization (LMP). These processes disrupt the homeostasis of EGFR and inhibit the downstream signaling transduction of EGFR for cancer cell survival. Moreover, LMP induced the release of protein aggregates that could generate endoplasmic reticulum (ER) stress, resulting in cancer cell death selectively. In vivo studies indicate the efficient antitumor efficiency of PAD-1 in tumor-bearing mice. As a first example, this work provides an alternative strategy for controlling protein behavior for tuning cellular events in living cells.
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Receptores ErbB , Lisosomas , Transducción de Señal , Humanos , Animales , Transducción de Señal/efectos de los fármacos , Receptores ErbB/metabolismo , Ratones , Línea Celular Tumoral , Lisosomas/metabolismo , Péptidos Cíclicos/farmacología , Péptidos Cíclicos/química , Estrés del Retículo Endoplásmico/efectos de los fármacos , Neoplasias/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Endocitosis/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Proteínas de la Membrana/metabolismoAsunto(s)
Apoptosis , Atorvastatina , Modelos Animales de Enfermedad , Estrés del Retículo Endoplásmico , Hemorragia Subaracnoidea , Animales , Hemorragia Subaracnoidea/tratamiento farmacológico , Hemorragia Subaracnoidea/metabolismo , Hemorragia Subaracnoidea/patología , Atorvastatina/farmacología , Atorvastatina/uso terapéutico , Apoptosis/efectos de los fármacos , Ratas , Estrés del Retículo Endoplásmico/efectos de los fármacos , Lesiones Encefálicas/tratamiento farmacológico , Lesiones Encefálicas/metabolismo , Lesiones Encefálicas/patología , Lesiones Encefálicas/etiología , Ratas Sprague-Dawley , Masculino , HumanosRESUMEN
BACKGROUND: Cervical cancer ranks as one of the most prevalent malignancies among women worldwide and poses a significant threat to health and quality of life. MCL1 is an antiapoptotic protein closely linked to tumorigenesis, drug-resistance and poor prognosis in various cancers. Sanggenon C, a natural flavonoid derived from Morus albal., exhibits multiple activities, including anti-oxidant, anti-inflammatory, antivirus, and antitumor properties. However, the molecular mechanisms by which Sanggenon C exerts antitumor effects on in cervical cancer remain unclear. PURPOSE: To investigate the oncogenic role of MCL1 and elucidate the antitumor activity of Sanggenon C, along with its molecular mechanisms, in cervical cancer. METHODS: In vitro, the effects of Sanggenon C on proliferation, the cell cycle, apoptosis, and autophagy were explored. Transcriptome sequencing was employed to analyze critical genes and pathways. The expression of genes or proteins was evaluated via immunofluorescence, qRT-PCR, immunohistochemistry, and Western blotting. To identify targets of Sanggenon C, various techniques such as clinical database analysis, molecular docking, cellular thermal shift assays, co-immunoprecipitation, and ubiquitination assays were utilized. Additionally, Xenograft mouse models were established to further investigate Sanggenon C as a novel MCL1 inhibitor and its anti-tumor activity in vivo. RESULTS: Our investigation reveals that Sanggenon C effectively inhibits cervical cancer cell proliferation both in vitro and in vivo. Furthermore, Sanggenon C induces endoplasmic reticulum stress and triggers protective autophagy via activation of the ATF4-DDIT3-TRIB3-AKT-MTOR signaling axis. Furthermore, Sanggenon C specifically targets MCL1 to exert its antitumor effects by modulating MCL1 protein stability through SYVN1-mediated ubiquitination. Notably, MCL1 overexpression attenuates the Sanggenon C-induced decrease in cell viability and apoptosis. Our study further characterizes the role of MCL1 in cisplatin resistance and identifies MCL1 as a promising target for Sanggenon C, which effectively inhibits proliferation and induces apoptosis in cisplatin-resistant cervical cancer cells. Importantly, combining Sanggenon C with an autophagy inhibitor represents a promising strategy to enhance therapeutic outcomes in cisplatin-resistant cervical cancer cells. CONCLUSION: Our findings demonstrates that Sanggenon C induces endoplasmic reticulum stress and highlights the potential of targeting MCL1 to exploit vulnerabilities in drug-resistant cervical cancer cells. Sanggenon C emerges as a promising therapeutic agent against MCL1-driven adaptive chemoresistance through disruption of autophagy and endoplasmic reticulum stress in cervical cancer.
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Autofagia , Resistencia a Antineoplásicos , Estrés del Retículo Endoplásmico , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , Neoplasias del Cuello Uterino , Femenino , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/metabolismo , Humanos , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Estrés del Retículo Endoplásmico/efectos de los fármacos , Autofagia/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Ratones Desnudos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Células HeLa , Ratones Endogámicos BALB C , Ratones , Antineoplásicos Fitogénicos/farmacología , Simulación del Acoplamiento MolecularRESUMEN
Various factors, both internal and external, can disrupt endoplasmic reticulum (ER) homeostasis and increase the burden of protein folding, resulting in ER stress. While short periods of ER stress can help cells return to normal function, excessive or prolonged ER stress triggers a complex signaling network that negatively affects cells. Numerous studies have demonstrated the significant role of ER stress in various kidney diseases, such as immune-related kidney injury, diabetic kidney diseases, renal ischemia reperfusion injury, and renal fibrosis. To date, there is a severe shortage of medications for the treatment of acute and chronic kidney diseases of all causes. Natural products derived from various traditional Chinese medicines (TCM), which are a major source of new drugs, have garnered considerable attention. Recent research has revealed that many natural products have renoprotective effects by targeting ER stress-mediated events, such as apoptosis, oxidative stress, inflammation, autophagy, and epithelial-mesenchymal transition. This article provides a comprehensive review of the current research progress on natural products targeting ER stress for the treatment of kidney diseases.
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Productos Biológicos , Estrés del Retículo Endoplásmico , Enfermedades Renales , Medicina Tradicional China , Humanos , Estrés del Retículo Endoplásmico/efectos de los fármacos , Productos Biológicos/uso terapéutico , Productos Biológicos/farmacología , Medicina Tradicional China/métodos , Enfermedades Renales/tratamiento farmacológico , Medicamentos Herbarios Chinos/uso terapéutico , Medicamentos Herbarios Chinos/farmacología , Estrés Oxidativo/efectos de los fármacos , Autofagia/efectos de los fármacos , Apoptosis/efectos de los fármacos , Animales , Transducción de Señal/efectos de los fármacosRESUMEN
Macrophages show high plasticity and play a vital role in the progression of metabolic dysfunction-associated steatohepatitis (MASH). X-box binding protein 1 (XBP1), a key sensor of the unfolded protein response, can modulate macrophage-mediated pro-inflammatory responses in the pathogenesis of MASH. However, how XBP1 influences macrophage plasticity and promotes MASH progression remains unclear. Herein, we formulated an Xbp1 siRNA delivery system based on folic acid modified D-α-tocopheryl polyethylene glycol 1000 succinate nanoparticles (FT@XBP1) to explore the precise role of macrophage-specific Xbp1 deficiency in the progression of MASH. FT@XBP1 was specifically internalized into hepatic macrophages and subsequently inhibited the expression of spliced XBP1 both in vitro and in vivo. It promoted M1-phenotype macrophage repolarization to M2 macrophages, reduced the release of pro-inflammatory factors, and alleviated hepatic steatosis, liver injury, and fibrosis in mice with fat-, fructose- and cholesterol-rich diet-induced MASH. Mechanistically, FT@XBP1 promoted macrophage polarization toward the M2 phenotype and enhanced the release of exosomes that could inhibit the activation of hepatic stellate cells. A promising macrophage-targeted siRNA delivery system was revealed to pave a promising strategy in the treatment of MASH.
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Ácido Fólico , Macrófagos , ARN Interferente Pequeño , Proteína 1 de Unión a la X-Box , Animales , Masculino , Ratones , Estrés del Retículo Endoplásmico/efectos de los fármacos , Hígado Graso/metabolismo , Ácido Fólico/química , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Ratones Endogámicos C57BL , Nanopartículas/química , Proteína 1 de Unión a la X-Box/metabolismoRESUMEN
Chemicals are representative environmental factors that affect human health. Recently, external exposure to a chemical of rhododenol (RD) caused chemical leukoderma, an acquired patchy hypopigmentation, in about 20,000 Asian people. The development of a hazard assessment system for accurate determination of leukoderma-inducible chemicals is required for the prevention of such tragedies. Case studies in humans have shown 6 chemicals, including RD, with a constitutive leukoderma-inducible potency and 3 chemicals with a photosensitive but not a constitutive leukoderma-inducible potency. In this study, the 6 positive and 3 negative control chemicals with or without constitutive leukoderma-inducible potencies were investigated by our previously developed in vivo hazard assessment system using tail skin of mice. Based on the results of validation, this study aimed to develop an in vitro hazard assessment system to correctly determine chemicals with a constitutive leukoderma-inducible potency. As expected, external exposure to the 6 positive control chemicals, but not external exposure to the 3 negative control chemicals, resulted in development of constitutive leukoderma in mouse tail skin with a decreased level of skin melanin and decreased number of melanocytes. Moreover, the 6 positive and 3 negative control chemicals were correctly distinguished by the presence or absence of endoplasmic reticulum (ER) stress induction, but not by tyrosinase-dependent cell death or production of reactive oxygen species (ROS), in immortalized normal melanocytes. The hazard assessment system using tail skin could be a solid in vivo tool to reliably determine the chemical potency of a chemical for constitutive leukoderma induction. The hazard assessment system focusing on ER stress induction in normal melanocytes might be a novel and convenient in vitro tool for accurately evaluating chemicals with leukoderma-inducible potencies. Thus, this study contributed to environmentology through the development of a screening system for preventing an environmental factor-related disease.
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Hipopigmentación , Animales , Ratones , Hipopigmentación/inducido químicamente , Medición de Riesgo , Melanocitos/efectos de los fármacos , Piel/efectos de los fármacos , Estrés del Retículo Endoplásmico/efectos de los fármacos , Melaninas , Humanos , Pruebas de Toxicidad/métodos , ButanolesRESUMEN
Unfolded protein accumulation in the endoplasmic reticulum (ER) triggers ER stress, leading to a unique transcriptomic response called unfolded protein response (UPR). While ER stress is linked to various environmental stresses, its role in plant responses to heavy metal toxicity remains unclear. This study aimed to elucidate if heavy metals Fe, Zn, Cu, and As induce ER stress in plants. For this purpose, Arabidopsis thaliana seedlings were treated with Fe (200, 400 µM), Zn (500, 700 µM), Cu (25, 50 µM), and As (250, 500 µM) for 7 days, which resulted in 50-70% decrease in plant growth. All treatments increased insoluble protein levels, indicating unfolded protein accumulation, with the highest induction observed for 50 µM Cu treatment (fivefold). Expressions of genes involved in the perception and signaling of ER stress (IRE1, bZIP28, bZIP60, bZIP17) indicate that Zn toxicity specifically induces bZIP28 but not the IRE1 branch of UPR. All metals except Fe also induced genes associated with protein folding in the ER (BIP1, BIP3, and CNX) and ER-associated protein degradation (ERAD) (HRD1). This finding indicates Zn, Cu, and As but not Fe cause ER stress in plants. Furthermore, increased expression of ER oxidoreductase 1 (ERO1) suggests that metal toxicity also disrupts oxidative protein folding in the ER lumen. This study enhances our understanding of the intricate interplay between essential nutrients, metal toxicity, protein folding machinery, and ER stress, demonstrating that heavy metal toxicity has an ER stress component in plants alongside its established effects on energy metabolism, membrane integrity, and oxidative stress.