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1.
Zhongguo Zhong Yao Za Zhi ; 46(15): 3893-3899, 2021 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-34472265

RESUMO

To explore the protective effect and mechanism of ethyl acetate extract from Bidens bipinnata on hepatocyte damage induced by endoplasmic reticulum stress. Tunicamycin was used to establish the damage model in L02 cells. Methyl thiazolyl tetrazolium(MTT) colorimetric assay was used to investigate the survival rate of ethyl acetate extract from B. bipinnata in L02 cells injury induced by endoplasmic reticulum stress; the protein expressions of endoplasmic reticulum stress-related molecule glucose regulated protein 78(GRP78), PKR-like ER kinase(PERK), eukaryotic initiation factor-2(eIF2α), activating transcription factor 4(ATF4), C/EBP homologous protein(CHOP), B-cell CLL/lymphoma 2(Bcl-2), Bal-2 associated X apoptosis regulator(Bax) were examined by Wes-tern blot. The expressions of the above proteins were also detected after endoplasmic reticulum stress inhibitor(4-phenyl butyric acid) and CHOP shRNA-mediated knockdowns were added. The expressions of GRP78, PERK, CHOP in L02 cells were observed by immunofluorescence method. The results showed that ethyl acetate extract from B. bipinnata could significantly increase the survival rate of L02 cell injury caused by endoplasmic reticulum stress in a dose and time-dependent manner(P<0.05 or P<0.01). The expression levels of GRP78, PERK, eIF2α, ATF4, CHOP and Bax in the drug treatment groups were significantly down-regulated(P<0.05 or P<0.01), while Bcl-2 was significantly up-regulated(P<0.01). After endoplasmic reticulum stress inhibitor and CHOP shRNA-mediated knockdowns were added, the expression levels of GRP78, PERK, eIF2α, ATF4, CHOP, Bax in the drug treatment groups were significantly down-regulated(P<0.01), whereas Bcl-2 was significantly up-regulated(P<0.01). Immunofluorescence results showed that the expressions of GRP78, PERK, CHOP were consistent with the Western blot method. In conclusion, ethyl acetate extract from B. bipinnata has a significant protective effect on the damage of L02 cells caused by endoplasmic reticulum stress. The mechanism may be related to the inhibition of endoplasmic reticulum stress and the down-regulation of apoptosis in cells through the PERK/eIF2α/ATF4/CHOP signaling pathway.


Assuntos
Bidens , Estresse do Retículo Endoplasmático , Acetatos , Apoptose , Hepatócitos , Fator de Transcrição CHOP/genética , eIF-2 Quinase/genética
2.
Nanoscale ; 13(31): 13558, 2021 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-34477760

RESUMO

Correction for 'Furin-instructed molecular self-assembly actuates endoplasmic reticulum stress-mediated apoptosis for cancer therapy' by Chenxing Fu et al., Nanoscale, 2020, 12, 12126-12132, DOI: .


Assuntos
Estresse do Retículo Endoplasmático , Neoplasias , Apoptose , Furina , Humanos , Neoplasias/tratamento farmacológico
3.
Nat Commun ; 12(1): 5242, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34475398

RESUMO

Genome-wide association studies (GWAS) have linked single nucleotide polymorphisms (SNPs) at >250 loci in the human genome to type 2 diabetes (T2D) risk. For each locus, identifying the functional variant(s) among multiple SNPs in high linkage disequilibrium is critical to understand molecular mechanisms underlying T2D genetic risk. Using massively parallel reporter assays (MPRA), we test the cis-regulatory effects of SNPs associated with T2D and altered in vivo islet chromatin accessibility in MIN6 ß cells under steady state and pathophysiologic endoplasmic reticulum (ER) stress conditions. We identify 1,982/6,621 (29.9%) SNP-containing elements that activate transcription in MIN6 and 879 SNP alleles that modulate MPRA activity. Multiple T2D-associated SNPs alter the activity of short interspersed nuclear element (SINE)-containing elements that are strongly induced by ER stress. We identify 220 functional variants at 104 T2D association signals, narrowing 54 signals to a single candidate SNP. Together, this study identifies elements driving ß cell steady state and ER stress-responsive transcriptional activation, nominates causal T2D SNPs, and uncovers potential roles for repetitive elements in ß cell transcriptional stress response and T2D genetics.


Assuntos
Diabetes Mellitus Tipo 2/genética , Estresse do Retículo Endoplasmático/genética , Células Secretoras de Insulina/patologia , Polimorfismo de Nucleotídeo Único , Ativação Transcricional/genética , Alelos , Animais , Linhagem Celular , Cromatina/metabolismo , Diabetes Mellitus Tipo 2/patologia , Estudo de Associação Genômica Ampla , Humanos , Camundongos , Locos de Características Quantitativas , Elementos Nucleotídeos Curtos e Dispersos/genética
4.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 37(3): 266-271, 2021 May.
Artigo em Chinês | MEDLINE | ID: mdl-34374239

RESUMO

Objective: To investigate the effect of TGF-ß1/Smad signaling pathway on the apoptosis of HepG2 cells under endoplasmic reticulum stress (ERS). Methods: An ERS model was established firstly. Human hepatocellular carcinoma HepG2 cells were treated with 3 µmol/L tunicamycin (TM) for 24 h to induce ERS. Cells were divided into 6 groups, each with 3 replicate holes, and the experiment was repeated 3 times. The 6 groups included untreated group, TM group (3 µmol/L TM treatment group), TM + NC group(3 µmol/L TM + si-TGF-ß1 negative control group), TM + si-TGF-ß1 group(3 µmol/L TM + si-TGF-ß1 group), TM + pEX-3 group(3 µmol/L TM + plasmid control group), and TM + TGF-ß1 pEX-3 group(3 µmol/L TM + TGF-ß1 overexpressed plasmid group). HepG2 cells were transfected with TGF-ß1 small interfering RNA (TGF-ß1 si-RNA) and TGF-ß1 overexpressed plasmids (TGF-ß1 pEX-3) by Lipofectamine. Twenty-four hours after transfection, RT-qPCR and Western blot were used to detect the expression of TGF-ß1 and p-Smad2 in HepG2 cells of each group. CCK-8 and flow cytometry were used to analyze changes in the proliferation inhibition rate and apoptosis rate of HepG2 cells in each group. Results: Compared with the untreated group, the expressions of TGF-ß1 and p-Smad2 in TM group were significantly reduced (P<0.05). Compared with the TM group, the expressions of TGF-ß1 and p-Smad2, as well as the cell proliferation inhibition rate and apoptosis rate in TM + si-TGF-ß1 group were obviously decreased (P< 0.01), while the expressions of TGF-ß1 and p-Smad2, cell proliferation inhibition rate and apoptosis rate of TM + TGF-ß1 pEX-3 group were significantly increased (P<0.01). Conclusion: The TGF-ß1/Smad signaling pathway was inhibited in hepatocellular carcinoma HepG2 cells under ERS, when this pathway was activated, the apoptosis rate of HepG2 cells under ERS was increased significantly.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Apoptose , Estresse do Retículo Endoplasmático , Células Hep G2 , Humanos , Transdução de Sinais , Fator de Crescimento Transformador beta1
5.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 37(4): 359-364, 2021 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-34374254

RESUMO

Objective: To observe the effects of acupuncture on the endoplasmic reticulum (ER) functional enzymes sarcoplasmic reticulum Ca2+-ATPase (SERCA), protein disulfide isomerase (PDI), glucose-regulated protein 78(GRP78) and PERK pathways in rats with exercise-induced skeletal muscle damage, and to explore the mechanisms of acupuncture in preventing and treating exercise-induced skeletal muscle damage. Methods: Eight-week-old male SD rats were randomly divided into control group (group C, n=6), exercise group (group E, n=30), acupuncture group (group A, n=30) and exercise acupuncture group (group EA, n=30). Among them, the E and EA group were established an exercise-induced skeletal muscle damage model by a single eccentric exercise, and acupuncture intervention was applied 0.5 cm above the Achilles tendon of the rat's calf immediately after EA exercise, and in group A, acupuncture intervention was applied during the same period. Each group was divided into 0 h/12 h/24 h/48 h/72 h (n=6) according to different sampling time points after exercise and acupuncture intervention, and soleus muscle was collected at the corresponding time for index test. The ultrastructure of muscle fibers was observed by transmission electron microscopy; the contents of SERCA and PDI were determined by ELISA; and the expressions of ER stress marker proteins GRP78 and p-PERK and p-eIF2α were detected by Western blot. Results: Compared with group C, there were no significant differences in the indicators of group A at all time points (P> 0.05), the ultrastructure of muscle fibers in group E showed different damages, SERCA content was significantly decreased from 0 h to 48 h (P<0.05), PDI content was significantly increased from 0 h to 72 h (P<0.05), GRP78 expression was significantly increased from 0 h to 72 h (P<0.05), p-PERK expression was significantly increased from 0 h to 24 h (P<0.05), and p-eIF2α expression was consistent with p-PERK. Compared with the corresponding times in group E, the ultrastructure of muscle fibers in group EA was significantly alleviated, SERCA content was significantly increased from 48 h and 72 h (P<0.05), PDI content was significantly increased from 0 h to 72 h (P<0.05), and GRP78 expression was significantly decreased from 0 h to 72 h (P<0.05). Conclusion: Acupuncture can effectively ameliorate exercise-induced skeletal muscle damage and alleviate ER stress after a large load eccentric exercise. The mechanism of them may be related to the up-regulation of protein disulfide isomerase PDI and the inhibition of ER stress PERK pathway.


Assuntos
Terapia por Acupuntura , Condicionamento Físico Animal , Animais , Retículo Endoplasmático , Estresse do Retículo Endoplasmático , Masculino , Músculo Esquelético , Ratos , Ratos Sprague-Dawley
6.
Behav Neurol ; 2021: 6301458, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34336001

RESUMO

Prenatal exposure to buprenorphine renders offspring vulnerable to cerebral impairments. In this study, our data demonstrate, for the first time, that prenatal exposure to buprenorphine escalates astrocyte activation concurrent with indications of endoplasmic reticulum (ER) stress in the hippocampi of neonates, and this can be prevented by the coadministration of dextromethorphan with buprenorphine. Furthermore, dextromethorphan can inhibit the accumulation of GPR37 in the hippocampus of newborns caused by buprenorphine and is accompanied by the proapoptotic ER stress response that involves the procaspase-3/CHOP pathway. Primary astrocyte cultures derived from the neonates of the buprenorphine group also displayed aberrant ER calcium mobilization and elevated basal levels of cyclooxygenase-2 (COX-2) at 14 days in vitro while showing sensitivity to lipopolysaccharide-activated expression of COX-2. Similarly, these long-lasting defects in the hippocampus and astrocytes were abolished by dextromethorphan. Our findings suggest that prenatal exposure to buprenorphine might instigate long-lasting effects on hippocampal and astrocytic functions. The beneficial effects of prenatal coadministration of dextromethorphan might be, at least in part, attributed to its properties in attenuating astrocyte activation and hippocampal ER stress in neonates.


Assuntos
Buprenorfina , Efeitos Tardios da Exposição Pré-Natal , Apoptose , Astrócitos , Dextrometorfano/toxicidade , Estresse do Retículo Endoplasmático , Feminino , Humanos , Recém-Nascido , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente
7.
Ecotoxicol Environ Saf ; 223: 112596, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34352572

RESUMO

Ammonia (NH3) emission is a common threat to farm animals. Selenium (Se) is known for its antioxidant property and can resist several stressors affecting farm animals. The aims of this study were (Ⅰ) to determine how excess NH3 exert nephrotoxic effects in pigs and (Ⅱ) to investigate whether selenomethionine has an alleviative effect on NH3 toxicity. Two diets supplemented with different doses of Se (0.22 mg/kg or 0.50 mg/kg) and two concentrations of NH3 (< 5 mg/m3 or 89.8 mg/m3) were used in a 2 × 2 factorial design trial for a period of 30 days. The results showed that NH3 exposure caused apoptosis and increased the number of apoptotic cells in pig kidneys. Further, the activities of antioxidant enzymes were decreased, and the transcriptional and translational levels of endoplasmic reticulum stress-related genes, Bcl-2 and Caspase family members were increased under NH3 exposure. In addition, Wnt/ß-catenin signaling pathway was suppressed after NH3 treatment. Dietary supplement with selenomethionine appears to offer protection against NH3-induced kidney injury in pigs and the pathologic changes above were alleviated. Our findings provide additional insight into the mechanism of NH3 toxicity in pigs while elucidating the role of Se as a potential antidote against NH3 poisoning.


Assuntos
Antioxidantes , Selênio , Amônia , Animais , Apoptose , Estresse do Retículo Endoplasmático , Rim , Selênio/farmacologia , Selenometionina/farmacologia , Suínos
8.
Medicine (Baltimore) ; 100(33): e26879, 2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34414940

RESUMO

ABSTRACT: The current study aimed to investigate circulating glucose-regulated protein 78 (GRP78) as well as CCAAT/enhancer-binding protein homologous protein (CHOP) concentrations in Chinese type 2 diabetes mellitus (T2DM) patients, especially those with microalbuminuria. We recruited 67 patients with T2DM and 63 control subjects. We determined circulating GRP78 and CHOP concentrations by ELISA, collected anthropometric data, and measured biochemical parameters in a clinical laboratory. Compared with control groups, patients with T2DM showed decreased circulating levels of GRP78 (0.21 [0.16-0.24] vs 0.16 [0.16-0.19] ng/mL, P < .01) and CHOP ([0.29 ±â€Š0.02] vs [0.27 ±â€Š0.03]ng/mL, P < .01). Reduction in circulating GRP78 and CHOP levels was more pronounced in patients with more severe categories of albuminuria. Amounts of circulating GRP78 correlated directly with serum fasting c-peptide, cystatin-c (Cys-c), creatinine (Cr), blood urea nitrogen (BUN), and uric acid, and inversely with glomerular filtration rates. Circulating CHOP level was positively correlated with age, Cr, BUN, Cys-c, and urinary microalbumin/creatinine (UmALB/Cr). Circulating GRP78 was predicted independently by Cr, BUN, serum uric acid, estimated glomerular filtration rate, and Cys-c, while CHOP depended on age, Cr, BUN, estimated glomerular filtration rate, UmALB/Cr, and Cys-c. After controlling for confounding factors, circulating GRP78 and CHOP expression were significantly associated with diabetic kidney disease (binary logistic regression, P < .01). Patients with T2DM showed increased circulating GRP78 and CHOP concentrations. Receiver operating characteristic areas under the curve for predicting diabetic kidney disease based on GRP78 and CHOP were 0.686 (95% CI: 0.558-0.813) and 0.670 (0.524-0.816), respectively.


Assuntos
Diabetes Mellitus Tipo 2/sangue , Nefropatias Diabéticas/sangue , Estresse do Retículo Endoplasmático , Proteínas de Choque Térmico/sangue , Fator de Transcrição CHOP/sangue , Idoso , Grupo com Ancestrais do Continente Asiático , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
9.
Int J Mol Sci ; 22(16)2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34445555

RESUMO

Previous evidence links the formation of extranuclear inclusions of transcription factors, such as ERK, Jun, TDP-43, and REST, with oxidative, endoplasmic-reticulum, proteasomal, and osmotic stress. To further characterize its extranuclear location, we performed a high-content screening based on confocal microscopy and automatized image analyses of an epithelial cell culture treated with hydrogen peroxide, thapsigargin, epoxomicin, or sorbitol at different concentrations and times to recreate the stresses mentioned above. We also performed a subcellular fractionation of the brain from transgenic mice overexpressing the Q331K-mutated TARDBP, and we analyzed the REST-regulated mRNAs. The results show that these nuclear proteins exhibit a mitochondrial location, together with significant nuclear/extranuclear ratio changes, in a protein and stress-specific manner. The presence of these proteins in enriched mitochondrial fractions in vivo confirmed the results of the image analyses. TDP-43 aggregation was associated with alterations in the mRNA levels of the REST target genes involved in calcium homeostasis, apoptosis, and metabolism. In conclusion, cell stress increased the mitochondrial translocation of nuclear proteins, increasing the chance of proteostasis alterations. Furthermore, TDP-43 aggregation impacts REST target genes, disclosing an exciting interaction between these two transcription factors in neurodegenerative processes.


Assuntos
Encéfalo/patologia , Estresse do Retículo Endoplasmático , Glândulas Mamárias Humanas/patologia , Mitocôndrias/patologia , Estresse Oxidativo , Fatores de Transcrição/metabolismo , Animais , Encéfalo/metabolismo , Feminino , Humanos , Masculino , Glândulas Mamárias Humanas/metabolismo , Camundongos , Camundongos Transgênicos , Mitocôndrias/metabolismo
10.
Int J Mol Sci ; 22(16)2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34445569

RESUMO

Retinol dehydrogenase 12 (RDH12) is expressed in photoreceptor inner segments and catalyses the reduction of all-trans retinal (atRAL) to all-trans retinol (atROL), as part of the visual cycle. Mutations in RDH12 are primarily associated with autosomal recessive Leber congenital amaurosis. To further our understanding of the disease mechanisms, HEK-293 cell lines expressing wildtype (WT) and mutant RDH12 were created. The WT cells afforded protection from atRAL-induced toxicity and oxidative stress. Mutant RDH12 cells displayed reduced protein expression and activity, with an inability to protect cells from atRAL toxicity, inducing oxidative and endoplasmic reticulum (ER) stress, with upregulation of sXBP1, CHOP, and ATF4. Pregabalin, a retinal scavenger, attenuated atRAL-induced ER stress in the mutant RDH12 cell lines. A zebrafish rdh12 mutant model (rdh12u533 c.17_23del; p.(Val6AlafsTer5)) was generated through CRISPR-Cas9 gene editing. Mutant fish showed disrupted phagocytosis through transmission electron microscopy, with increased phagosome size at 12 months post-fertilisation. Rhodopsin mislocalisation and reduced expression of atg12 and sod2 indicated early signs of a rod-predominant degeneration. A lack of functional RDH12 results in ER and oxidative stress representing key pathways to be targeted for potential therapeutics.


Assuntos
Oxirredutases do Álcool/metabolismo , Apoptose , Estresse do Retículo Endoplasmático , Mutação , Estresse Oxidativo , Doenças Retinianas/patologia , Oxirredutases do Álcool/antagonistas & inibidores , Oxirredutases do Álcool/genética , Animais , Autofagia , Sistemas CRISPR-Cas , Células HEK293 , Humanos , Doenças Retinianas/etiologia , Doenças Retinianas/metabolismo , Peixe-Zebra
11.
ACS Chem Neurosci ; 12(16): 3101-3111, 2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34338497

RESUMO

The IRE1/XBP1 signaling pathway is the most conserved component of the endoplasmic reticulum unfolded protein response (UPRER). Activating this branch to correct defects in ER proteostasis is regarded as a promising anti-Parkinson's disease (PD) strategy. P-53 is a marine-derived xyloketal B analog which exhibited potential neuroprotective activities in previous research studies; however, the molecular mechanism underneath its protective effect remains unknown. Herein, a transcriptomic approach was introduced to explore the protective mechanism of P-53. RNA microarray profiling was conducted based on an MPP+-induced C. elegans PD model, and bioinformatics analyses including GO enrichment and PPI network analysis were subsequently performed. In particular, the recovery of the impaired UPRER was highlighted as a main physiological change caused by P-53, and a cluster of genes including abu and hsp family genes which are involved in the IRE1/XBP1 branch of the UPRER were identified as the key genes related to its neuroprotective effect. The transcription levels of these key genes were validated by RT-qPCR assays. Further results showed that P-53 enhanced the phosphorylation of IRE1, the splicing of xbp-1 mRNA, and the translation of XBP1S and boosted the expression level of the downstream targets of the IRE1/XBP1 signaling pathway. Moreover, it was also demonstrated that P-53 accelerated the scavenging of misfolded α-synuclein and attenuated the correlative mitochondrial dysfunction. Finally, the protective effect of P-53 against MPP+-induced dopaminergic neuronal loss was assessed. Taken together, these results revealed that P-53 plays its neuroprotective role through regulating of the IRE1/XBP1 signaling pathway and laid the foundation for its further development as an ER proteostasis-regulating agent.


Assuntos
Caenorhabditis elegans , Endorribonucleases , Proteínas Serina-Treonina Quinases , Proteína 1 de Ligação a X-Box , Animais , Proteínas de Caenorhabditis elegans , Estresse do Retículo Endoplasmático , Endorribonucleases/genética , Endorribonucleases/metabolismo , Neurônios/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Resposta a Proteínas não Dobradas , Proteína 1 de Ligação a X-Box/genética , Proteína 1 de Ligação a X-Box/metabolismo
12.
Nutrients ; 13(7)2021 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-34371808

RESUMO

Endoplasmic reticulum stress (ERS) and autophagy pathways are implicated in disuse muscle atrophy. The effects of high eicosapentaenoic (EPA) or high docosahexaenoic (DHA) fish oils on soleus muscle ERS and autophagy markers were investigated in a rat hindlimb suspension (HS) atrophy model. Adult Wistar male rats received daily by gavage supplementation (0.3 mL per 100 g b.w.) of mineral oil or high EPA or high DHA fish oils (FOs) for two weeks. Afterward, the rats were subjected to HS and the respective treatments concomitantly for an additional two-week period. After four weeks, we evaluated ERS and autophagy markers in the soleus muscle. Results were analyzed using two-way analysis of variance (ANOVA) and Bonferroni post hoc test. Gastrocnemius muscle ω-6/ω-3 fatty acids (FAs) ratio was decreased by both FOs indicating the tissue incorporation of omega-3 fatty acids. HS altered (p < 0.05) the protein content (decreasing total p38 and BiP and increasing p-JNK2/total JNK2 ratio, and caspase 3) and gene expressions (decreasing BiP and increasing IRE1 and PERK) of ERS and autophagy (decreasing Beclin and increasing LC3 and ATG14) markers in soleus. Both FOs attenuated (p < 0.05) the increase in PERK and ATG14 expressions induced by HS. Thus, both FOs could potentially attenuate ERS and autophagy in skeletal muscles undergoing atrophy.


Assuntos
Autofagia/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Óleos de Peixe/farmacologia , Músculo Esquelético/metabolismo , Atrofia Muscular/terapia , Animais , Biomarcadores/metabolismo , Modelos Animais de Doenças , Ácidos Docosa-Hexaenoicos/farmacologia , Ácido Eicosapentaenoico/farmacologia , Elevação dos Membros Posteriores , Masculino , Atrofia Muscular/etiologia , Atrofia Muscular/metabolismo , Ratos , Ratos Wistar
13.
FASEB J ; 35(9): e21777, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34403519

RESUMO

Mycobacterium bovis is the causative agent of bovine tuberculosis and also responsible for serious threat to public health. Koumiss is a fermented mare's milk product, used as traditional drink. Here, we explored the effect of koumiss on gut microbiota and the host immune response against M bovis infection. Therefore, mice were treated with koumiss and fresh mare milk for 14 days before M bovis infection and continue for 5 weeks after infection. The results showed a clear change in the intestinal flora of mice treated with koumiss, and the lungs of mice treated with koumiss showed severe edema, inflammatory infiltration, and pulmonary nodules in M bovis-infected mice. Notably, we found that the content of short-chain fatty acids was significantly lower in the koumiss-treated group compared with the control group. However, the expression of endoplasmic reticulum stress and apoptosis-related proteins in the lungs of koumiss-treated mice were significantly decreased. Collectively, these findings suggest that koumiss treatment disturb the intestinal flora of, which is associated with disease severity and the possible mechanism that induces lungs pathology. Our current findings can be exploited further to establish the "gut-lung" axis which might be a novel strategy for the control of tuberculosis.


Assuntos
Estresse do Retículo Endoplasmático/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Kumis/efeitos adversos , Mycobacterium bovis/efeitos dos fármacos , Tuberculose Pulmonar/microbiologia , Tuberculose Pulmonar/patologia , Animais , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Ácidos Graxos/análise , Fezes/química , Fezes/microbiologia , Feminino , Microbioma Gastrointestinal/imunologia , Cavalos , Pulmão/efeitos dos fármacos , Pulmão/microbiologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Mycobacterium bovis/imunologia , Tuberculose Pulmonar/dietoterapia , Tuberculose Pulmonar/metabolismo
14.
Ageing Res Rev ; 70: 101417, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34339860

RESUMO

One evident hallmark of Alzheimer's disease (AD) is the irregular accumulation of proteins due to changes in proteostasis involving endoplasmic reticulum (ER) stress. To alleviate ER stress and reinstate proteostasis, cells undergo an integrated signaling cascade called the unfolded protein response (UPR) that reduces the number of misfolded proteins and inhibits abnormal protein accumulation. Aging is associated with changes in the expression of ER chaperones and folding enzymes, leading to the impairment of proteostasis, and accumulation of misfolded proteins. The disrupted initiation of UPR prevents the elimination of unfolded proteins, leading to ER stress. In AD, the accumulation of misfolded proteins caused by sustained cellular stress leads to neurodegeneration and neuronal death. Current research has revealed that ER stress can trigger an inflammatory response through diverse transducers of UPR. Although the involvement of a neuroinflammatory component in AD has been documented for decades, whether it is a contributing factor or part of the neurodegenerative events is so far unknown. Besides, a feedback loop occurs between neuroinflammation and ER stress, which is strongly associated with neurodegenerative processes in AD. In this review, we focus on the current research on ER stress and UPR in cellular aging and neuroinflammatory processes, leading to memory impairment and synapse dysfunction in AD.


Assuntos
Doença de Alzheimer , Doença de Alzheimer/metabolismo , Senescência Celular , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático , Humanos , Resposta a Proteínas não Dobradas
15.
Molecules ; 26(16)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34443600

RESUMO

Organotin(IV) compounds are a class of non-platinum metallo-conjugates exhibiting antitumor activity. The effects of different organotin types has been related to several mechanisms, including their ability to modify acetylation protein status and to promote apoptosis. Here, we focus on triorganotin(IV) complexes of butyric acid, a well-known HDAC inhibitor with antitumor properties. The conjugated compounds were synthesized and characterised by FTIR spectroscopy, multi-nuclear (1H, 13C and 119Sn) NMR, and mass spectrometry (ESI-MS). In the triorganotin(IV) complexes, an anionic monodentate butyrate ligand was observed, which coordinated the tin atom on a tetra-coordinated, monomeric environment similar to ester. FTIR and NMR findings confirm this structure both in solid state and solution. The antitumor efficacy of the triorganotin(IV) butyrates was tested in colon cancer cells and, among them, tributyltin(IV) butyrate (BT2) was selected as the most efficacious. BT2 induced G2/M cell cycle arrest, ER stress, and apoptotic cell death. These effects were obtained using low concentrations of BT2 up to 1 µM, whereas butyric acid alone was completely inefficacious, and the parent compound TBT was poorly effective at the same treatment conditions. To assess whether butyrate in the coordinated form maintains its epigenetic effects, histone acetylation was evaluated and a dramatic decrease in acetyl-H3 and -H4 histones was found. In contrast, butyrate alone stimulated histone acetylation at a higher concentration (5 mM). BT2 was also capable of preventing histone acetylation induced by SAHA, another potent HDAC inhibitor, thus suggesting that it may activate HDACs. These results support a potential use of BT2, a novel epigenetic modulator, in colon cancer treatment.


Assuntos
Apoptose/genética , Ácido Butírico/química , Neoplasias do Colo/patologia , Estresse do Retículo Endoplasmático/genética , Epigênese Genética/efeitos dos fármacos , Compostos de Trialquitina/química , Compostos de Trialquitina/farmacologia , Acetilação/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Histona Desacetilases/metabolismo , Humanos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos
16.
Int J Mol Sci ; 22(12)2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34207084

RESUMO

Advanced glycation end products (AGEs) are formed via nonenzymatic reactions between reducing sugars and proteins. Recent studies have shown that methylglyoxal, a potent precursor for AGEs, causes a variety of biological dysfunctions, including diabetes, inflammation, renal failure, and cancer. However, little is known about the function of methylglyoxal-derived AGEs (AGE4) in kidney cells. Therefore, we verified the expression of endoplasmic reticulum (ER) stress-related genes and apoptosis markers to determine the effects of AGE4 on human proximal epithelial cells (HK-2). Moreover, our results showed that AGE4 induced the expression of apoptosis markers, such as Bax, p53, and kidney injury molecule-1, but downregulated Bcl-2 and cyclin D1 levels. AGE4 also promoted the expression of NF-κB, serving as a transcription factor, and the phosphorylation of c-Jun NH2-terminal kinase (JNK), which induced cell apoptosis and ER stress mediated by the JNK inhibitor. Furthermore, AGE4 induced mitochondrial dysfunction by inducing the permeabilization of the mitochondrial membrane and ATP synthesis. Through in vitro and in vivo experiments, this study provides a new perspective on renal dysfunction with regard to the AGE4-induced RAGE /JNK signaling pathway, which leads to renal cell apoptosis via the imbalance of mitochondrial function and ER stress in kidney damage.


Assuntos
Apoptose , Estresse do Retículo Endoplasmático , Produtos Finais de Glicação Avançada/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Mitocôndrias/metabolismo , Aldeído Pirúvico/metabolismo , Transdução de Sinais , Animais , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Células Epiteliais/metabolismo , Produtos Finais de Glicação Avançada/farmacologia , Humanos , Rim/metabolismo , Camundongos , Mitocôndrias/efeitos dos fármacos , Modelos Biológicos , NF-kappa B/metabolismo , Espécies Reativas de Oxigênio , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição/metabolismo
17.
Artigo em Inglês | MEDLINE | ID: mdl-34299918

RESUMO

Chenopodium ambrosioides L. (C. ambrosioides) has been used as dietary condiments and as traditional medicine in South America. The oil of Chenopodium ambrosioides L. (C. ambrosioides) can be used as a natural antioxidant in food processing. It also has analgesic, sedating, and deworming effects, and can be used along with the whole plant for its medical effects: decongestion, as an insecticide, and to offer menstruation pain relief. This study was conducted to investigate the cytotoxicity and apoptosis effects of an essential oil from C. ambrosioides in vitro. The cytotoxicity evaluation of the essential oil from C. ambrosioides on human normal liver cell line L02 was assessed by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay. AO/EB dual fluorescent staining assay and Annexin V-FITC were used for apoptosis analysis. The changes in mitochondrial membrane potential (MMP) were analyzed with 5,5,6,6'-tetrachloro-1,1,3,3,-tetraethyl-imidacarbocyanine iodide (JC-1) dye under a fluorescence microscope. The level of apoptosis related protein expression was quantified by Western blot. The L02 cells were treated with the essential oil from C. ambrosioides at 24, 48, and 72 h, and the IC50 values were 65.45, 58.03, and 35.47 µg/mL, respectively. The AO/EB staining showed that viable apoptotic cells, non-viable apoptotic cells, and non-viable non-apoptotic cells appeared among the L02 cells under the fluorescence microscope. Cell cycle arrest at the S phase and cell apoptosis increased through flow cytometry in the L02 cells treated with the essential oil. MMP decreased in a concentration-dependent manner, as seen through JC-1 staining under the fluorescence microscope. In the L02 cells as shown by Western blot and qPCR, the amount of the apoptosis-related proteins and the mRNA expression levels of cytochrome C, Bax, Caspase-9, and Caspase-3 increased, Bcl-2 decreased, and Caspase-12, which is expressed in the endoplasmic reticulum, showed no obvious changes in protein amount or mRNA expression level. The essential oil form C. ambrosioides had a cytotoxic effect on L02 cells. It could inhibit L02 cell proliferation, arrest the cell cycle at the S phase, and induce L02 cell apoptosis through the endogenous mitochondrial pathway.


Assuntos
Chenopodium ambrosioides , Óleos Voláteis , Apoptose , Linhagem Celular , Estresse do Retículo Endoplasmático , Feminino , Humanos , Fígado , Óleos Voláteis/toxicidade
18.
Aquat Toxicol ; 237: 105903, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34229255

RESUMO

Ammonia is a major pollutant in the water environment, which could cause severe harm to aquatic organisms. To explore the pathological and physiological effects of ammonia in Chinese striped-necked turtles (Mauremys sinensis), the individuals (body mass: 218.26 ± 12.65 g) were divided into two groups: control group and ammonia exposed group (6.25 mM total ammonia), then the expression levels of signaling factors involved in the endoplasmic reticulum stress and apoptotic pathways were determined. The results showed that ammonia exposure up-regulated the transcriptional and protein levels of endoplasmic reticulum stress marker gene Bip. Meanwhile, the relative mRNA levels of key genes (PERK, ATF6, eIF2α, ATF4, IRE1α and XBP1) involved in unfolded protein response up-regulated, and the phosphorylation levels of PERK, eIF2α and IRE1α increased correspondingly. In addition, the protein and transcriptional levels of CHOP and JNK related to apoptotic pathway induced by unfolded protein reaction increased under ammonia exposure. Moreover, Bcl-2 mRNA expression levels and protein levels decreased, whereas BAX and caspase-3 showed an opposite trend, and the cleaved protein of caspase-3 appeared when the turtles in the elevated ammonia. Furthermore, the apoptotic cells in liver increased after ammonia exposure. These results suggested ammonia exposure induced endoplasmic reticulum stress, then activated unfolded protein response, followed by apoptosis in M. sinensis. The results will contribute to a better understanding of the toxicity mechanism of ammonia to aquatic turtles.


Assuntos
Tartarugas , Poluentes Químicos da Água , Amônia/toxicidade , Animais , Apoptose , China , Estresse do Retículo Endoplasmático , Poluentes Químicos da Água/toxicidade
19.
FASEB J ; 35(8): e21821, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34325487

RESUMO

Skeletal muscle atrophy is a debilitating complication of many chronic disease states and disuse conditions including denervation. However, molecular and signaling mechanisms of muscle wasting remain less understood. Here, we demonstrate that the levels of several toll-like receptors (TLRs) and their downstream signaling adaptor, myeloid differentiation primary response 88 (MyD88), are induced in skeletal muscle of mice in response to sciatic nerve denervation. Muscle-specific ablation of MyD88 mitigates denervation-induced skeletal muscle atrophy in mice. Targeted ablation of MyD88 suppresses the components of ubiquitin-proteasome system, autophagy, and FOXO transcription factors in skeletal muscle during denervation. We also found that specific inhibition of MyD88 reduces the activation of canonical nuclear factor-kappa (NF-κB) pathway and expression of receptors for inflammatory cytokines in denervated muscle. In contrast, inhibition of MyD88 stimulates the activation of non-canonical NF-κB signaling in denervated skeletal muscle. Ablation of MyD88 also inhibits the denervation-induced increase in phosphorylation of AMPK without having any effect on the phosphorylation of mTOR. Moreover, targeted ablation of MyD88 inhibits the activation of a few components of the unfolded protein response (UPR) pathways, especially X-box protein 1 (XBP1). Importantly, myofiber-specific ablation of XBP1 mitigates denervation-induced skeletal muscle atrophy in mice. Collectively, our experiments suggest that TLR-MyD88 signaling mediates skeletal muscle wasting during denervation potentially through the activation of canonical NF-κB signaling, AMPK and UPR pathways.


Assuntos
Músculo Esquelético/inervação , Atrofia Muscular/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais/fisiologia , Animais , Biomarcadores/sangue , Estresse do Retículo Endoplasmático/fisiologia , Regulação da Expressão Gênica/fisiologia , Camundongos , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/genética , NF-kappa B/genética , Receptores Toll-Like/genética , Receptores Toll-Like/metabolismo , Resposta a Proteínas não Dobradas
20.
Sci Transl Med ; 13(604)2021 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-34321322

RESUMO

Type 2 diabetes (T2D) is a metabolic disorder characterized by hyperglycemia, hyperinsulinemia, and insulin resistance (IR). During the early phase of T2D, insulin synthesis and secretion by pancreatic ß cells is enhanced, which can lead to proinsulin misfolding that aggravates endoplasmic reticulum (ER) protein homeostasis in ß cells. Moreover, increased circulating insulin may contribute to fatty liver disease. Medical interventions aimed at alleviating ER stress in ß cells while maintaining optimal insulin secretion are therefore an attractive therapeutic strategy for T2D. Previously, we demonstrated that germline Chop gene deletion preserved ß cells in high-fat diet (HFD)-fed mice and in leptin receptor-deficient db/db mice. In the current study, we further investigated whether targeting Chop/Ddit3 specifically in murine ß cells conferred therapeutic benefits. First, we showed that Chop deletion in ß cells alleviated ß cell ER stress and delayed glucose-stimulated insulin secretion (GSIS) in HFD-fed mice. Second, ß cell-specific Chop deletion prevented liver steatosis and hepatomegaly in aged HFD-fed mice without affecting basal glucose homeostasis. Third, we provide mechanistic evidence that Chop depletion reduces ER Ca2+ buffering capacity and modulates glucose-induced islet Ca2+ oscillations, leading to transcriptional changes of ER chaperone profile ("ER remodeling"). Last, we demonstrated that a GLP1-conjugated Chop antisense oligonucleotide strategy recapitulated the reduction in liver triglycerides and pancreatic insulin content. In summary, our results demonstrate that Chop depletion in ß cells provides a therapeutic strategy to alleviate dysregulated insulin secretion and consequent fatty liver disease in T2D.


Assuntos
Diabetes Mellitus Tipo 2 , Fígado Gorduroso , Células Secretoras de Insulina , Animais , Diabetes Mellitus Tipo 2/metabolismo , Dieta Hiperlipídica/efeitos adversos , Estresse do Retículo Endoplasmático , Insulina/metabolismo , Secreção de Insulina , Células Secretoras de Insulina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL
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