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1.
Oxid Med Cell Longev ; 2022: 4674215, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36111165

RESUMO

Lipotoxicity can lead to beta-cell dysfunction and apoptosis because it induces oxidative stress. Recent studies have found that Irisin prevents pancreatic beta-cell dysfunction induced by palmitic acid (PA). However, an association between the protection against oxidative stress conferred by Irisin and beta-cell dysfunction has not been fully elucidated. In this study, we observed that Irisin treatment prevented INS-1 cell apoptosis induced by PA treatment and preserved the insulin-secreting function of INS-1 cells in vitro. These effects probably resulted from the Irisin-induced decrease in intracellular ROS levels triggered by PA treatment. In addition, PA treatment induced oxidative stress partially by inhibiting the activation of thioredoxin 2 (Trx2) through its increase of thioredoxin-interacting protein (Txnip) expression. However, Irisin administration blocked the increase in Txnip expression, which reversed the PA-induced inactivation of Trx2. Irisin also increased the nuclear translocation of Stat3, and the inhibition of Stat3 by siRNAs blocked Irisin-induced Trx2 expression, indicating that both Txnip and Stat3 are involved in Irisin-induced activation of Trx2. Furthermore, blockade of Stat3 by siRNAs led to the decreased gene expression of MafA and Ins and to cessation of glucose-induced insulin secretion that had been enhanced by Irisin. In vivo, HFD treatment led to reduced glucose tolerance and an increase in the level of the oxidative marker malondialdehyde (MDA) compared to that in the control group. However, these effects were ameliorated by Irisin injection due to the inhibition of beta-cell apoptosis and the activation of Trx2, probably through Txnip inhibition and Stat3 activation. In conclusion, our results reveal a possible mechanism for Irisin-induced beta-cell protection, which is mediated through Txnip inhibition and activation of the Stat3-Trx2 pathway.


Assuntos
Fibronectinas , Tiorredoxinas , Fibronectinas/metabolismo , Glucose/toxicidade , Insulina/metabolismo , Malondialdeído/metabolismo , Estresse Oxidativo , Ácido Palmítico/toxicidade , RNA Interferente Pequeno/metabolismo , Espécies Reativas de Oxigênio/farmacologia , Tiorredoxinas/metabolismo
3.
Cardiovasc Diabetol ; 21(1): 186, 2022 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-36114538

RESUMO

BACKGROUND AND AIMS: The effect of dapagliflozin (DAPA) on the prognosis of patients with acute myocardial infarction (AMI) is unclear. The present study was conducted to evaluate the association between DAPA administration and adverse events in patients with AMI undergoing percutaneous coronary intervention (PCI). METHODS: This single-center retrospective analysis study included a total of 786 patients with AMI from January 2019 to August 2021 who were or were not administered DAPA at discharge. The primary endpoint was the composite of major adverse cardiovascular events (MACE), including overall deaths, heart failure, nonfatal MI, nonfatal stroke, and unplanned repeat revascularization (URR). Differences in the triglyceride glucose (TyG) index and the atherogenic index of plasma (AIP) both during hospitalization and 12 months after discharge (if achievable) were also compared. RESULTS: During a median follow-up of 23 months, 130 patients had MACE (118 in the DAPA-free group and 12 in the DAPA group). Kaplan-Meier survival analyses revealed that the cumulative incidence of MACE (log-rank test, p = 0.009), heart failure (p = 0.003), nonfatal MI (p = 0.005), and URR (p = 0.031) was higher in the DAPA-free group. In addition, the multivariate Cox analysis showed that DAPA was significantly associated with the reduced risk of MACE (hazard ratio = 0.170, 95% confidence interval = 0.078-0.373, p < 0.001). Considering each specific adverse event, the DAPA-free group was associated with heart failure, nonfatal MI, and URR in multivariate Cox regression analyses. Stratification analyses suggested that DAPA has a strong protective effect in patients with AMI of advanced age with concomitant diabetes or those who are not on angiotensin receptor enkephalinase inhibitors. Furthermore, the TyG index and AIP of the patients 12 months after DAPA administration at discharge were significantly lower than those during hospitalization. CONCLUSIONS: DAPA is an independent protective factor against MACE and may provide incremental prognostic information in patients with AMI undergoing PCI.


Assuntos
Insuficiência Cardíaca , Infarto do Miocárdio , Intervenção Coronária Percutânea , Compostos Benzidrílicos , Glucose , Glucosídeos , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/tratamento farmacológico , Neprilisina , Intervenção Coronária Percutânea/efeitos adversos , Prognóstico , Receptores de Angiotensina , Estudos Retrospectivos , Triglicerídeos
4.
Biomed Res Int ; 2022: 2193895, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36119933

RESUMO

Objective: To evaluate the clinical and radiological outcomes of percutaneous kyphoplasty (PKP) versus posterior fixation combined with vertebroplasty PF+VP for treating stage III Kümmell's disease (KD) patients without neurological deficits. Methods: From April 2016 to February 2020, a total of 88 patients with single-level stage III KD without neurological deficits, including 45 patients treated by PKP and 43 patients who underwent posterior fixation combined with vertebroplasty PF+VP, were retrospectively studied. The outcome parameters, including blood loss, operative time, kyphotic Cobb angle, height of vertebrae, Oswestry Disability Index (ODI), and visual analog scale (VAS) score, were compared between the PKP group and the PF+VP group. Results: The mean follow-up time was 29.3 ± 7.0 months, ranging from 24 to 48 months. The kyphotic angle and vertebral height in both groups were significantly improved compared with those before surgery at three days, 3 months and the final follow-up. The estimated blood loss, operative time, and length of stay were significantly lower in the PKP group than in the PF+VP group (P < 0.001). The FP+VP group showed better results in kyphotic angle correction than the PKP group (P = 0.024). In the short-term follow-up (up to 3 months), the PKP group had lower VAS and ODI scores than the PF+VP group. In contrast, there were no significant differences between the two groups (P > 0.05) at the final follow-up. The average cost of PKP was lower than that of PF+VP. Conclusion: The results of our study showed that both PKP and PF+VP were safe and effective for stage III KD patients without neurological deficits. Although PF+VP presents better performance in kyphotic angle correction, PKP was associated with less surgical trauma, quicker pain relief, and lower expense than PF+VP. Therefore, it can be considered an alternative option for patients with advanced KD.


Assuntos
Cifoplastia , Cifose , Fraturas da Coluna Vertebral , Vertebroplastia , Humanos , Cifoplastia/métodos , Cifose/diagnóstico por imagem , Cifose/cirurgia , Estudos Retrospectivos , Fraturas da Coluna Vertebral/diagnóstico por imagem , Fraturas da Coluna Vertebral/cirurgia , Vertebroplastia/métodos
5.
Oxid Med Cell Longev ; 2022: 7727006, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36148414

RESUMO

Osteoporosis is a disorder of bone metabolism that is extremely common in elderly patients as well as in postmenopausal women. The main manifestation is that the bone resorption capacity is greater than the bone formation capacity, which eventually leads to a decrease in bone mass, increasing the risk of fracture. There is growing evidence that inhibiting osteoclast formation and resorption ability can be effective in treating and preventing the occurrence of osteoporosis. Our study is the first time to explore the role of the mitochondrial calcium uniporter (MCU) and its inhibitor ruthenium red (RR) in bone metabolism, clarifying the specific mechanism by which it inhibits osteoclast formation in vitro and plays a therapeutic role in osteoporosis in vivo. We verified the suppressive effects of RR on the receptor activator of nuclear factor-κB ligand (RANKL-)-induced differentiation and bone resorption function of osteoclasts in vitro. The reactive oxygen species (ROS) production stimulated by RANKL and the expression level of P38 MAPK/NFATc1 were also found to be inhibited by RR. Moreover, the promotion of RR on osteogenesis differentiation was investigated by alkaline phosphatase (ALP) and alizarin red S (ARS) staining and the detection of osteogenesis-specific gene expression levels by quantitative polymerase chain reaction (qPCR) and western blotting. Moreover, in ovariectomy (OVX-)-induced osteoporosis models, RR can downregulate the expression and function of the MCU, relieving bone loss and promoting osteogenesis to present a therapeutic effect on osteoporosis. This new finding will provide an important direction for the study of RR and MCU in the study of bone metabolism therapy targets.

6.
Infect Drug Resist ; 15: 4899-4906, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36060233

RESUMO

Background: Potent immune-suppressive therapy has been demonstrated to increase the risk of infective endocarditis (IE) in renal recipients. Reports of Corynebacterium striatum (C. striatum) endocarditis in renal recipients are scarce, thus limiting understanding of the disease. Case Presentation: We describe a case of native valve endocarditis caused by C. striatum in a 35-year-old male patient. The young man with end-stage renal failure underwent kidney transplantation because of autosomal dominant polycystic kidney disease. Ceftazidime was administered after the surgery according to routine procedures, and the patient was discharged on the 14th day after the surgery without any evidence of infection. The patient experienced fever on the 56th day, and Corynebacterium was cultured from the patient's blood, in agreement with the results of testing of the donor kidney preservation solution. On the 64th day, multiple thromboses were found in the right external iliac artery, particularly around the anastomotic orifice of the transplanted renal artery. Vegetation was found in the posterior mitral valve tip on the 65th day. The patient had symptoms of persistent angina pectoris and chest tightness and underwent mitral valve replacement and vegetative resection. The patient eventually died. C. striatum was detected in the mitral valve and vegetation tissue with metagenomic next-generation sequencing. Conclusion: C. striatum may cause endocarditis and endanger patients' lives and thus warrants greater attention. Genotypic assays such as metagenomic next-generation sequencing are demonstrated to be effective in confirming species identity. Adequate anti-infection therapy and early surgery are required after IE is discovered.

7.
Front Pharmacol ; 13: 927653, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36091791

RESUMO

Pulmonary fibrosis (PF) is a group of interstitial lung diseases that seriously endanger human life and health. Despite the current advances in research on the pathogenesis and treatment of PF, the overall quality of survival and survival rates of PF patients remain low, prompting the search for more effective therapeutic approaches. Exosomes are nanoscale vesicles with diameters ranging from approximately 30-150 nm, capable of transporting a variety of molecules in the body and mediating intercellular communication. There is an increasing number of studies focusing on the role of exosomes in PF. This review demonstrates the significance of exosomes in the pathogenesis, diagnosis, and treatment of PF. Exosomes are able to influence inflammatory, immune, and extracellular matrix deposition processes in PF and regulate the corresponding cytokines. Some exosomes detected in sputum, blood, and bronchoalveolar lavage fluid may be used as potential diagnostic and prognostic biomarkers for PF. Exosomes derived from several cells, such as mesenchymal stem cells, have demonstrated potential as PF therapeutic agents. Drug delivery systems using exosomes may also provide new insights into PF therapy.

8.
ACS Omega ; 7(35): 30773-30781, 2022 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-36092619

RESUMO

The kinetic effects of co-feeding of dimethyl disulfide (DMDS) and hydrogen on propane dehydrogenation (PDH) over the Pt-Sn-K/Al2O3 catalyst were investigated by the response surface method. The 3-level Box-Behnken design for 4 factors (reaction temperature, propene, hydrogen, and DMDS flow rate) was used to design the experiment. The initial propane conversion, propene selectivity, and coking amount were chosen as responses and the results were fitted by quadratic models. The fresh and coked catalysts were characterized by high-angle annular dark-field scanning transmission electron microscopy (HAADF-STEM), scanning electron microscopy and energy dispersive X-ray spectroscopy (SEM-EDS), thermogravimetry (TG), N2 physisorption, and Fourier-transform infrared spectroscopy (FT-IR). Analysis of variance (ANOVA) results showed that the DMDS flow rate is significant for propane conversion and coking amount while hydrogen flow rate is only significant for the conversion. By using the fitted model for the response surface, it is found that DMDS can significantly reduce the coking amount at the expense of propane conversion, and hydrogen weakly affects the selectivity and coking amount. The optimal conditions to achieve maximum conversion and selectivity and minimum coking amount are not consistent. The DMDS and hydrogen flow rate should be optimized to obtain the maximum economic profit out of the propane dehydrogenation (PDH) process.

9.
Transl Androl Urol ; 11(8): 1130-1147, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36092848

RESUMO

Background: Ferroptosis-related genes (FRGs) play vital roles in survival and prognosis of prostate cancer (PCa) patients. We establish a ferroptosis-related prediction model through bioinformatics analysis for overall survival (OS) and disease-free survival (DFS), so as to evaluate the clinical survival status through the characteristics of immune cell infiltration (ICI), which could provide information for treatment monitoring. Methods: At first, 268 FRGs were obtained from previous studies. Differentially expressed FRGs were identified based on The Cancer Genome Atlas (TCGA) database, and FRG enrichment analysis was performed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). We then performed univariate, least absolute shrinkage and selection operator (LASSO), and multivariate Cox regression analyses to establish OS- and DFS-related prognostic prediction models. The association of the model and clinicopathological features was further analyzed. Subsequently, unique genomic signatures of immune cell subsets were obtained through the KEGG database. Based on specific genes associated with ferroptosis and their association with ICI, immune infiltration was assessed in patients in different risk groups. Results: We constructed an OS- and an DFS-prognostic model through bioinformatics analysis. The predicted values of OS and DFS-related models were higher in T3-4 than in T1-2 (P=0.0057, P<0.001), and the predicted value of the DFS model in N0 stage was higher than that in N1 stage (P=0.0136). Results of Single-sample gene set enrichment analysis (ssGSEA) on the basis of the KEGG dataset showed p53 signaling being the most enriched signal in the high-risk group, while endocytosis was the most enriched signal in the low-risk group. M2 macrophages (P=0.007) and neutrophils (P=0.024) were enriched in the high-risk group, and CD4-activated memory T cells were significantly accumulated in the low-risk group (P=0.017). Conclusions: The OS- and DFS-related model based on FRGs and ICI create new insights into the disease state assessment of PCa patients., which may aid in the development of individualized and precise treatment in the future.

10.
Mol Cell Proteomics ; : 100408, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-36058520

RESUMO

The mouse is a valuable model organism for biomedical research. Here, we established a comprehensive spectral library and the DIA-based quantitative proteome maps for 41 mouse organs, including some rarely reported organs such as the cornea, retina, and nine paired organs. The mouse spectral library contained 178,304 peptides from 12,320 proteins, including 1678 proteins not reported in previous mouse spectral libraries. Our data suggested that organs from the nervous system and immune system expressed the most distinct proteome compared with other organs. We also found characteristic protein expression of immune-privileged organs, which may help understanding possible immune rejection after organ transplantation. Each tissue type expressed characteristic high-abundance proteins related to its physiological functions. We also uncovered some tissue-specific proteins which have not been reported previously. The testis expressed highest number of tissue-specific proteins. By comparison of nine paired organs including kidneys, testes, and adrenal glands, we found left organs exhibited higher levels of antioxidant enzymes. We also observed expression asymmetry for proteins related to the apoptotic process, tumor suppression, and organ functions between the left and right sides. This study provides a comprehensive spectral library and a quantitative proteome resource for mouse studies.

11.
Cell Discov ; 8(1): 85, 2022 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-36068205

RESUMO

Determination of malignancy in thyroid nodules remains a major diagnostic challenge. Here we report the feasibility and clinical utility of developing an AI-defined protein-based biomarker panel for diagnostic classification of thyroid nodules: based initially on formalin-fixed paraffin-embedded (FFPE), and further refined for fine-needle aspiration (FNA) tissue specimens of minute amounts which pose technical challenges for other methods. We first developed a neural network model of 19 protein biomarkers based on the proteomes of 1724 FFPE thyroid tissue samples from a retrospective cohort. This classifier achieved over 91% accuracy in the discovery set for classifying malignant thyroid nodules. The classifier was externally validated by blinded analyses in a retrospective cohort of 288 nodules (89% accuracy; FFPE) and a prospective cohort of 294 FNA biopsies (85% accuracy) from twelve independent clinical centers. This study shows that integrating high-throughput proteomics and AI technology in multi-center retrospective and prospective clinical cohorts facilitates precise disease diagnosis which is otherwise difficult to achieve by other methods.

12.
Front Nutr ; 9: 961207, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36071933

RESUMO

Objective: Nitrogen balance (NB) is a commonly used nutrition indicator in clinical practice, while its relation to the interpretation of protein malnutrition and outcomes in critically ill patients remains unclear. This study aimed to evaluate the impact of NB on prognosis in such a patient population. Methods: We searched for relevant studies in PubMed, EMBASE, and the Cochrane Database up to May 10, 2022. Meta-analyses were performed to evaluate the relationship between NB (initial, final, or absolute change of NB levels) and prognosis and important clinical outcomes in critically ill patients. Pooled odds ratios (ORs) and mean differences (MDs) together with their 95% confidence intervals (CIs) were calculated. We also conducted subgroup analyses to explore the sources of heterogeneity. Results: Eight studies with 1,409 patients were eligible. These studies were moderate to high quality. When pooled, the initial NB was comparable between the survival and non-survival groups (five studies, MD 1.20, 95% CI, -0.70 to 3.11, I 2 = 77%; P = 0.22), while a significantly higher final NB in the survival group than that in the death group (two studies, MD 3.69, 95% CI, 1.92-5.46, I 2 = 55%; P < 0.0001). Two studies provided the absolute change of NB over time and suggested survival patients had more increased NB (MD 4.16 g/day, 95% CI, 3.70-4.61, I 2 = 0%; P < 0.00001). Similarly, for studies utilizing multivariate logistic regression, we found an improved NB (four studies, OR 0.85, 95% CI, 0.73-0.99, I 2 = 61%; P = 0.04) but not an initial NB (two studies, OR 0.92, 95% CI 0.78-1.08, I 2 = 55%; P = 0.31) was significantly associated the risk of all-cause mortality. These results were further confirmed in subgroup analyses. In addition, patients with improved NB had more protein and calorie intake and a similar length of stay in hospital than those without. Conclusions: Our results suggested that an improved NB but not the initial NB level was associated with all-cause mortality in critically ill patients. This highlights the requirement for dynamic monitoring of NB during nutrition treatment. Further randomized clinical trials examining the impact of NB-guided protein intake on clinical outcomes in critically ill patients are warranted. Systematic review registration: INPLASY202250134, https://doi.org/10.37766/inplasy2022.5.0134.

13.
Front Genet ; 13: 921306, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36081987

RESUMO

Circular RNAs (circRNAs) are recognized as a novel type of single-stranded endogenous noncoding RNA molecule with the characteristics of tissue specificity, sequence conservation and structural stability. Accumulating studies have shown that circRNAs play a unique biological role in different kinds of diseases. CircRNAs can affect tumor proliferation, migration, metastasis and other behaviors by modulating the expression of downstream genes. CircSMARCA5, an example of a circRNA, is dysregulated in various noninfectious diseases, such as tumors, osteoporosis, atherosclerosis and coronary heart disease. Furthermore, recent studies have demonstrated that circSMARCA5 is associated with the occurrence and development of a variety of tumors, including gastric cancer, glioblastoma, hepatocellular carcinoma, multiple myeloma, colorectal cancer, breast cancer and osteosarcoma. Mechanistically, circSMARCA5 primarily acts as a sponge of miRNAs to regulate the expression of downstream genes, and can serve as a potential biomarker for the diagnosis of malignant tumors. This review summarizes the biological roles of circSMARCA5 and its molecular mechanism of action in various diseases. Moreover, the meta-analysis of some publications showed that the expression of circSMARCA5 was significantly correlated with the prognosis of patients and tumor TNM stage, showing that circSMARCA5 has the potential to be a prognostic marker.

14.
Water Res ; 224: 119045, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-36108396

RESUMO

Microplastics are widely present in global ecosystems, threatening both marine and freshwater species. Given this problem, it is vital to research where land-based microplastics originate and how they are transmitted to receiving waters in urban agglomerations. Research results should inform systemic mitigation efforts to prevent future contamination. This study established the multi-directional transmission network of a microplastic mass balance system using a source-pathway-receptor framework, and involving annual source stocks and pathway flows with considerable variations under dry and wet weather patterns. Details of a baseline scenario quantifying the occurrence and spread of microplastics in an urban agglomeration were also determined in the context of current environmental management practices. We demonstrated that the total stock of the six major pollution sources amounted to 5317.7 ± 2175.3 and 3320.1 ± 953.6 tons/a in dry and wet weather, respectively; and 2347.8 ± 766.9 and 1991.8 ± 701.8 tons/a flows directly entered the sewer system and receiving water in Shanghai, China, respectively. Prominent microplastic stocks were found in atmospheric fallout, industrial wastewater, and domestic sewage. These stocks were much higher compared to crop farming wastewater, aquacultural wastewater, and livestock and poultry breeding wastewater. Total microplastic flows entering receiving water reached 3207.4 ± 1071.6 tons/a; the largest contributions were from wet weather overflow (23.7%), direct atmospheric fallout (21.7%), wastewater treatment plant effluent (14.2%), industrial wastewater (14.1%), and surface runoff (10.4%). Weather patterns led to divergent microplastic transmission pathways and mass flows, revealing a lagging timeline mode and illustrating the basic spatiotemporal features of microplastic contamination in urban agglomerations. Terminal disposal practices retained about two-fifths of the microplastic flows that would have otherwise been transmitted into receiving water. Of these, land surface sweep contributed half of the retained flow. Improvements in WWTP removal efficiency, storm sewage interception rate, industrial wastewater collection rate, and sewer sediment dredge rate could further enhance the systemic benefits.

15.
Micromachines (Basel) ; 13(9)2022 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-36144096

RESUMO

Recently, robots have assisted and contributed to the biomedical field. Scaling down the size of robots to micro/nanoscale can increase the accuracy of targeted medications and decrease the danger of invasive operations in human surgery. Inspired by the motion pattern and collective behaviors of the tiny biological motors in nature, various kinds of sophisticated and programmable microrobots are fabricated with the ability for cargo delivery, bio-imaging, precise operation, etc. In this review, four types of propulsion-magnetically, acoustically, chemically/optically and hybrid driven-and their corresponding features have been outlined and categorized. In particular, the locomotion of these micro/nanorobots, as well as the requirement of biocompatibility, transportation efficiency, and controllable motion for applications in the complex human body environment should be considered. We discuss applications of different propulsion mechanisms in the biomedical field, list their individual benefits, and suggest their potential growth paths.

16.
Elife ; 112022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-36048712

RESUMO

Amyloid aggregation of phosphorylated Tau (pTau) into neurofibrillary tangles is closely associated with Alzheimer's disease (AD). Several molecular chaperones have been reported to bind Tau and impede its pathological aggregation. Recent findings of elevated levels of Hsp27 in the brains of patients with AD suggested its important role in pTau pathology. However, the molecular mechanism of Hsp27 in pTau aggregation remains poorly understood. Here, we show that Hsp27 partially co-localizes with pTau tangles in the brains of patients with AD. Notably, phosphorylation of Tau by microtubule affinity regulating kinase 2 (MARK2), dramatically enhances the binding affinity of Hsp27 to Tau. Moreover, Hsp27 efficiently prevents pTau fibrillation in vitro and mitigates neuropathology of pTau aggregation in a Drosophila tauopathy model. Further mechanistic study reveals that Hsp27 employs its N-terminal domain to directly interact with multiple phosphorylation sites of pTau for specific binding. Our work provides the structural basis for the specific recognition of Hsp27 to pathogenic pTau, and highlights the important role of Hsp27 in preventing abnormal aggregation and pathology of pTau in AD.


Assuntos
Doença de Alzheimer , Proteínas de Choque Térmico/metabolismo , Chaperonas Moleculares/metabolismo , Tauopatias , Proteínas tau/metabolismo , Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Humanos , Microtúbulos/metabolismo , Fosforilação , Tauopatias/patologia
17.
Biology (Basel) ; 11(7)2022 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-36101404

RESUMO

Breastfeeding offers a broad spectrum of health benefits for infants. However, overnutrition and a steady increase in maternal obesity in the U.S. have made it harder for many mothers to produce and express breastmilk, and the quality of milk from obese mothers is also frequently compromised. Adipocytes, the primary cell type in the non-lactating breast, display a drastic morphological and functional change during lactation in mice. Lipid-filled adipocytes undergo lipolysis, and lipid droplets disappear to provide fatty acids and energy for breastmilk production. Once the animal stops lactation, these lipid-depleted adipocytes return as lipid-laden cells. This dynamic remodeling of the tissue is likely the result of active intercellular communications. Connexin43 (Cx43) is the most abundant connexin in the mammary adipose tissue that makes up the gap junctions for direct intercellular communications. Its expression is increased during lactation and reduced in obese mammary adipose tissue, which is resistant to lactation-induced remodeling. However, whether Cx43 is required for adipocyte remodeling and breastmilk production to support neonates' growth has not been established. In this study, we used doxycycline-inducible adipocyte-specific Cx43-deleted mice and demonstrated that adipocyte Cx43 played a vital role in determining the carbohydrate levels in breastmilk, which may subsequently affect neonates' growth.

18.
Mol Cell ; 2022 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-36113479

RESUMO

RNA polymerase II (RNA Pol II) subunits are thought to be involved in various transcription-associated processes, but it is unclear whether they play different regulatory roles in modulating gene expression. Here, we performed nascent and mature transcript sequencing after the acute degradation of 12 mammalian RNA Pol II subunits and profiled their genomic binding sites and protein interactomes to dissect their molecular functions. We found that RNA Pol II subunits contribute differently to RNA Pol II cellular localization and transcription processes and preferentially regulate RNA processing (such as RNA splicing and 3' end maturation). Genes sensitive to the depletion of different RNA Pol II subunits tend to be involved in diverse biological functions and show different RNA half-lives. Sequences, associated protein factors, and RNA structures are correlated with RNA Pol II subunit-mediated differential gene expression. These findings collectively suggest that the heterogeneity of RNA Pol II and different genes appear to depend on some of the subunits.

20.
Cell Mol Life Sci ; 79(9): 507, 2022 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-36059036

RESUMO

Patients with autism spectrum disorder (ASD) typically experience substantial social isolation, which may cause secondary adverse effects on their brain development. miR-124 is the most abundant miRNA in the human brain, acting as a pivotal molecule regulating neuronal fate determination. Alterations of miR-124 maturation or expression are observed in various neurodevelopmental, neuropsychiatric, and neurodegenerative disorders. In the present study, we analyzed a panel of brain-enriched microRNAs in serums from 2 to 6 year old boys diagnosed with ASD. The hsa-miR-124 level was found significantly elevated in ASD boys than in age and sex-matched healthy controls. In an isolation-reared weanling mouse model, we evidenced elevated mmu-miR-124 level in the serum and the medial prefrontal cortex (mPFC). These mice displayed significant sociability deficits, as well as myelin abnormality in the mPFC, which was partially rescued by expressing the miR-124 sponge in the bilateral mPFC, ubiquitously or specifically in oligodendroglia. In cultured mouse oligodendrocyte precursor cells, introducing a synthetic mmu-miR-124 inhibited the differentiation process through suppressing expression of nuclear receptor subfamily 4 group A member 1 (Nr4a1). Overexpressing Nr4a1 in the bilateral mPFC also corrected the social behavioral deficits and myelin impairments in the isolation-reared mice. This study revealed an unanticipated role of the miR-124/Nr4a1 signaling in regulating early social experience-dependent mPFC myelination, which may serve as a potential therapy target for social neglect or social isolation-related neuropsychiatric disorders.


Assuntos
Transtorno do Espectro Autista , MicroRNAs , Animais , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/metabolismo , Encéfalo/metabolismo , Criança , Pré-Escolar , Humanos , Masculino , Camundongos , MicroRNAs/metabolismo , Bainha de Mielina/genética , Bainha de Mielina/metabolismo , Córtex Pré-Frontal/metabolismo
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