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Background: Despite the potential demonstrated by targeted plasma metabolite modulators in halting the progression of chronic kidney disease (CKD), a lingering uncertainty persists concerning the causal relationship between distinct plasma metabolites and the onset and progression of CKD. Methods: A genome-wide association study was conducted on 1,091 metabolites and 309 metabolite ratios derived from a cohort of 8,299 unrelated individuals of European descent. Employing a bidirectional two-sample Mendelian randomization (MR) analysis in conjunction with colocalization analysis, we systematically investigated the associations between these metabolites and three phenotypes: CKD, creatinine-estimated glomerular filtration rate (creatinine-eGFR), and urine albumin creatinine ratio (UACR). In the MR analysis, the primary analytical approach employed was inverse variance weighting (IVW), and sensitivity analysis was executed utilizing the MR-Egger method and MR-pleiotropy residual sum and outlier (MR-PRESSO). Heterogeneity was carefully evaluated through Cochrane's Q test. To ensure the robustness of our MR results, the leave-one-out method was implemented, and the strength of causal relationships was subjected to scrutiny via Bonferroni correction. Results: Our thorough MR analysis involving 1,400 plasma metabolites and three clinical phenotypes yielded a discerning identification of 21 plasma metabolites significantly associated with diverse outcomes. Specifically, in the forward MR analysis, 6 plasma metabolites were determined to be causally associated with CKD, 16 with creatinine-eGFR, and 7 with UACR. Substantiated by robust evidence from colocalization analysis, 6 plasma metabolites shared causal variants with CKD, 16 with creatinine-eGFR, and 7 with UACR. In the reverse analysis, a diminished creatinine-eGFR was linked to elevated levels of nine plasma metabolites. Notably, no discernible associations were observed between other plasma metabolites and CKD, creatinine-eGFR, and UACR. Importantly, our analysis detected no evidence of horizontal pleiotropy. Conclusion: This study elucidates specific plasma metabolites causally associated with CKD and renal functions, providing potential targets for intervention. These findings contribute to an enriched understanding of the genetic underpinnings of CKD and renal functions, paving the way for precision medicine applications and therapeutic strategies aimed at impeding disease progression.
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Estudo de Associação Genômica Ampla , Taxa de Filtração Glomerular , Análise da Randomização Mendeliana , Insuficiência Renal Crônica , Humanos , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/metabolismo , Feminino , Masculino , Creatinina/sangue , Polimorfismo de Nucleotídeo Único , Biomarcadores/sangue , Estudos de Coortes , Rim/metabolismo , Pessoa de Meia-IdadeRESUMO
Importance: Many patients with diabetic peripheral neuropathic pain (DPNP) experience inadequate relief, despite best available medical treatments. There are no approved and effective therapies for patients with DPNP in China. Objective: To evaluate the efficacy and safety of capsules containing γ-aminobutyric acid (GABA) analogue HSK16149 in the treatment of Chinese patients with DPNP. Design, Setting, and Participants: This phase 2 to 3 adaptive randomized clinical trial was multicenter, double blind, and placebo and pregabalin controlled. The trial started on December 10, 2020, and concluded on July 8, 2022. In stage 1, various doses of HSK16149 were evaluated to determine safety and efficacy for stage 2. The second stage then validated the efficacy and safety of the recommended dose. Intervention: In stage 1, enrolled patients (n = 363) were randomized 1:1:1:1:1:1 to 4 HSK16149 doses (40, 80, 120, or 160 mg/d), pregabalin (300 mg/d), or placebo. In stage 2, patients (n = 362) were randomized 1:1:1 to receive HSK16149, 40 or 80 mg/d, or placebo. The final efficacy and safety analysis pooled data from patients receiving the same treatment. Main Outcomes and Measures: The primary efficacy end point in stage 1 was the change from baseline in average daily pain score (ADPS) at week 5. The primary efficacy end point in stage 2 was the change from baseline in ADPS at week 13. When the final statistical analysis was performed, the P values calculated from the independent data of each phase were combined using the weighted inverse normal method to make statistical inferences. Results: Of 725 randomized patients in the full-analysis set (393 men [54.2%]; mean [SD] age, 58.80 [9.53] years; 700 [96.6%] of Han Chinese ethnicity), 177 received placebo; 178, HSK16149, 40 mg/d; 179, HSK16149, 80 mg/d; 66, HSK16149, 120 mg/d; 63, HSK16149, 160 mg/d; and 62, pregabalin, 300 mg/d. A total of 644 patients (88.8%) completed the study. The 40- and 80-mg/d doses of HSK16149 were recommended in stage 2. At week 13, the ADPS mean (SD) change from baseline was -2.24 (1.55) for the 40-mg/d and -2.16 (1.79) for 80-mg/d groups and -1.23 (1.68) for the placebo group, showing statistical significance for both HSK16149 doses vs placebo (both P < .001). In a safety set (n = 726), 545 patients (75.1%) had adverse events, which were generally mild to moderate, with dizziness and somnolence being the most common. Conclusions and Relevance: Forty- and eighty-mg/d doses of HSK16149 were recommended for treating patients with DPNP in China. The efficacy of HSK16149 capsules was superior to placebo in all groups for relieving DPNP and appeared well tolerated. Trial Registration: ClinicalTrials.gov Identifier: NCT04647773.
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Neuropatias Diabéticas , Pregabalina , Ácido gama-Aminobutírico , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Neuropatias Diabéticas/tratamento farmacológico , Método Duplo-Cego , Ácido gama-Aminobutírico/análogos & derivados , Ácido gama-Aminobutírico/uso terapêutico , Ácido gama-Aminobutírico/administração & dosagem , Ácido gama-Aminobutírico/efeitos adversos , China , Pregabalina/uso terapêutico , Idoso , Adulto , Analgésicos/uso terapêutico , Resultado do Tratamento , Medição da Dor , População do Leste AsiáticoRESUMO
Electrochromic devices (ECDs), which are capable of modulating optical properties in the visible and long-wave infrared (LWIR) spectra under applied voltage, are of great significance for military camouflage. However, there are a few materials that can modulate dual frequency bands. In addition, the complex and specialized structural design of dual-band ECDs poses significant challenges. Here, we propose a novel approach for a bendable ECD capable of modulating LWIR radiation and displaying multiple colors. Notably, it eliminates the need for a porous electrode or a grid electrode, thereby improving both the response speed and fabrication feasibility. The device employs multiwalled carbon nanotubes (MWCNTs) as both the transparent electrode and the LWIR modulator, polyaniline (PANI) as the electrochromic layer, and ionic liquids (HMIM[TFSI]) as the electrolyte. The ECD is able to reduce its infrared emissivity (Δε = 0.23) in a short time (resulting in a drop in infrared temperature from 50 to 44 °C) within a mere duration of 0.78 ± 0.07 s while changing its color from green to yellow within 3 s when a positive voltage of 4 V is applied. In addition, it exhibits excellent flexibility, even under bending conditions. This simplified structure provides opportunities for applications such as wearable adaptive camouflage and multispectral displays.
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RATIONALE: Inflammatory pseudotumor-like follicular dendritic cell sarcoma (IPT-like FDCS) of the liver is rare. It was previously believed that Epstein-Barr virus (EBV) positivity was a necessary criterion for pathological diagnosis. However, we found that there were also cases of EBV negativity. Therefore, clinicians and pathologists are reminded that EBV positivity is not a necessary condition for diagnosis. PATIENT CONCERNS: A 70-year-old female underwent computed tomography (CT) examination for upper abdominal discomfort, which revealed the presence of a liver tumor. Follow-up revealed that the tumor had progressively increased in size. DIAGNOSIS: The final diagnosis was an IPT-like follicular cell sarcoma, based on CT, MRI, HE staining, and immunohistochemical staining. INTERVENTIONS: The patient underwent a laparoscopic left hemihepatectomy. OUTCOMES: The patient has not undergone any special treatment, such as radiotherapy and chemotherapy, and has been followed up for over 3 years without experiencing any recurrence. LESSONS: IPT-like FDCS is a rare tumor that lacks definitive criteria, and its diagnosis mainly relies on pathological findings. Previously, it was believed that being EBV-positive was an important condition for diagnosis. Primary IPT-like FDCS in the liver is even rarer, and the patient in this case tested negative for EBV. It may be necessary for pathologists to consider the role of EBV in the diagnosis of IPT-like FDCS.
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Sarcoma de Células Dendríticas Foliculares , Infecções por Vírus Epstein-Barr , Granuloma de Células Plasmáticas , Feminino , Humanos , Idoso , Sarcoma de Células Dendríticas Foliculares/diagnóstico , Sarcoma de Células Dendríticas Foliculares/cirurgia , Sarcoma de Células Dendríticas Foliculares/patologia , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/diagnóstico , Granuloma de Células Plasmáticas/diagnóstico , Granuloma de Células Plasmáticas/cirurgia , Granuloma de Células Plasmáticas/patologia , Herpesvirus Humano 4 , Fígado/diagnóstico por imagem , Fígado/patologiaRESUMO
As a self-degrading and highly conserved survival mechanism, autophagy plays an important role in maintaining cell survival and recycling. The discovery of autophagy-related (ATG) genes has revolutionized our understanding of autophagy. Lysosomal membrane proteins (LMPs) are important executors of lysosomal function, and increasing evidence has demonstrated their role in the induction and regulation of autophagy. In addition, the functional dysregulation of the process mediated by LMPs at all stages of autophagy is closely related to neurodegenerative diseases and cancer. Here, we review the role of LMPs in autophagy, focusing on their roles in vesicle nucleation, vesicle elongation and completion, the fusion of autophagosomes and lysosomes, and degradation, as well as their broad association with related diseases.
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INTRODUCTION: The study aimed to explore the efficacy and safety of low-dose (LD) and regular-dose (RD) prednisone (PDN) for the treatment of subacute thyroiditis (SAT). MATERIAL AND METHODS: Patients were randomly allocated using the block randomization method to the 2 groups. The primary outcome was the time required for PDN treatment. Secondary outcomes included percentages of relapse, mean score for the Morisky Medication Adherence Scale-8© (MMAS-8), time required for symptoms to resolve, cumulative PDN dose (mg), and mean erythrocyte sedimentation rate (ESR) at 2 weeks and at baseline. RESULTS: The study cohort included 77 patients, randomized 74 participants, and 68 completed the study. There was no significant difference in the treatment duration between the LD and RD groups (55.31 ± 14.05 vs. 61.25 ± 19.95 days, p = 0.053). The mean difference in the time required for PDN treatment between the LD and RD groups was -1.86 [95% confidence interval (CI) = -10.64 to 6.92] days, which was within the non-inferiority margin of 7 days. There was a significant difference in the mean score for MMAS-8 between the LD and RD groups (5.84 ± 0.88 vs. 5.33 ± 1.12, p = 0.031). Also, there was a significant difference in the cumulative PDN dose between the LD and RD groups (504.22 ± 236.86 vs. 1002.28 ± 309.86, p = 0.046). The ESR at 2 weeks was statistically significant compared to baseline values in both groups, with pre-treatment and post-treatment ESRs of 49.91 ± 24.95 and 17.91 ± 12.60/mm/h, (p < 0.0001) in the LD group and 65.08 ± 21.77 and 17.23 ± 13.61/mm/h (p < 0.0001) in the RD group. CONCLUSION: Low-dose PDN therapy may be sufficient to achieve complete recovery and better outcomes for SAT. This study is registered with the Chinese Clinical Trial Registry (02/10/2021 ChiCTR2100051762).
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Tireoidite Subaguda , Humanos , Prednisona/uso terapêutico , Tireoidite Subaguda/tratamento farmacológico , Estudos Prospectivos , Resultado do Tratamento , Recidiva Local de NeoplasiaRESUMO
Background: Currently, there are many surgical options for patellar dislocation. The purpose of this study is to perform a network meta-analysis of the randomized controlled trials (RCTs) and cohort studies to determine the better treatment. Method: We searched the Pubmed, Embase, Cochrane Central Register of Controlled Trials, Web of Science, clinicaltrials.gov and who.int/trialsearch. Clinical outcomes included Kujala score, Lysholm score, International Knee Documentation Committee (IKDC) score, redislocation or recurrent instability. We conducted pairwise meta-analysis and network meta-analysis respectively using the frequentist model to compare the clinical outcomes. Results: There were 10 RCTs and 2 cohort studies with a total of 774 patients included in our study. In network meta-analysis, double-bundle medial patellofemoral ligament reconstruction (DB-MPFLR) achieved good results on functional scores. According to the surface under the cumulative ranking (SUCRA), DB-MPFLR had the highest probabilities of their protective effects on outcomes of Kujala score (SUCRA 96.5 %), IKDC score (SUCRA 100.0%) and redislocation (SUCRA 67.8%). However, DB-MPFLR (SUCRA 84.6%) comes second to SB-MPFLR (SUCRA 90.4%) in Lyshlom score. It is (SUCRA 70%) also inferior to vastus medialis plasty (VM-plasty) (SUCRA 81.9%) in preventing Recurrent instability. The results of subgroup analysis were similar. Conclusion: Our study demonstrated that MPFLR showed better functional scores than other surgical options.
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Litotripsia , Ureter , Cálculos Ureterais , Humanos , Cálculos Ureterais/cirurgia , Ureter/cirurgia , Rim , Resultado do TratamentoRESUMO
The SID1 transmembrane family, member 2, namely, Sidt2, is a highly glycosylated multichannel lysosomal transmembrane protein, but its specific physiological function remains unknown. Lysosomal membrane proteins are very important for the executive functioning of lysosomes. As an important part of the lysosomal membrane, Sidt2 can maintain the normal morphology of lysosomes and help stabilize them from the acidic pH environment within. As a receptor/transporter, it binds and transports nucleic acids and mediates the uptake and degradation of RNA and DNA by the lysosome. During glucose metabolism, deletion of Sidt2 can cause an increase in fasting blood glucose and the impairment of grape tolerance, which is closely related to the secretion of insulin. During lipid metabolism, the loss of Sidt2 can cause hepatic steatosis and lipid metabolism disorders and can also play a role in signal regulation and transport. Here, we review the function of the lysosomal membrane protein Sidt2, and focus on its role in glucose and lipid metabolism, autophagy and nucleotide (DNA/RNA) transport.
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Proteínas de Membrana , RNA , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , RNA/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Lisossomos/metabolismo , Proteínas de Membrana Lisossomal/metabolismo , DNA/metabolismo , AutofagiaRESUMO
BACKGROUND: Lower urinary tract symptoms are very common in elderly women, and transvaginal delivery and multiple deliveries have been confirmed to be risk factors. Transvaginal delivery and multiple deliveries may lead to an increase in pubic symphysis degeneration. CASE PRESENTATION: A 79-year-old woman consulted a urologist because of worsening lower urinary tract symptoms such as frequent urination and urodynia. Color ultrasound and cystoscopy suggested the possibility of a bladder mass. A lump on the anterior wall of the bladder was observed although the surface mucosa was normal. Physical examination showed obvious tenderness in the posterior area of the pubic symphysis. Further urological computed tomography (CT) and pelvic magnetic resonance imaging (MRI) showed a nodular bony protuberance in the posterior part of the pubic symphysis, which was more obvious than before, with compression changes near the anterior wall of bladder. Open pelvic surgery showed that nodular bone tissue originating from the pubic symphysis significantly oppressed the anterior wall of the bladder behind the pubic symphysis. After resection of the nodule, the lower urinary tract symptoms were relieved significantly. CONCLUSIONS: Pubic symphysis degeneration caused by transvaginal delivery may be an important cause of lower urinary tract symptoms in women. Pelvic CT or MRI is necessary to diagnosis this condition.
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Sintomas do Trato Urinário Inferior , Sínfise Pubiana , Idoso , Cistoscopia , Feminino , Humanos , Sintomas do Trato Urinário Inferior/etiologia , Imageamento por Ressonância Magnética/métodos , Sínfise Pubiana/diagnóstico por imagem , Tomografia Computadorizada por Raios XRESUMO
Disintegrin and metalloproteinase 12 (ADAM12) is thought to trigger the occurrence and development of numerous tumours, including colorectal, breast, and pancreatic cancers. On the basis of The Cancer Genome Atlas (TCGA) datasets, in this study, the relationship between ADAM12 gene expression and hepatocellular carcinoma (HCC), the prognostic value of this relationship, and the potential mechanisms influencing HCC development were evaluated. The results showed that the ADAM12 gene was significantly and highly expressed in liver cancer tissue. The high expression of the ADAM12 gene in liver cancer tissue significantly and positively correlated with T stage, pathological stage, and residual tumour. Kaplan-Meier and Cox regression analyses revealed that ADAM12 gene expression is an independent risk factor influencing the prognosis of patients with liver cancer. Pathway analyses of ADAM12 in HCC revealed ADAM12-correlated signalling pathways, and the expression level of ADAM12 was associated with immune cell infiltration. In vitro experiments demonstrated that the expression level of ADAM12 in Huh-7 and Hep3B cells was significantly higher than that in other HCC cells. ShRNA transfection experiments confirmed that the expression levels of TGF-ß and Notch pathway-related proteins were significantly decreased. An EdU cell proliferation assay showed that a low level of ADAM12 gene expression significantly inhibited the proliferative activity of HCC cells. Cell cycle experiments showed that low ADAM12 expression blocked the G1/S phase transition. Overall, this research revealed that high ADAM12 gene expression implies a poor prognosis for patients with primary liver cancer. In addition, it is a potential indicator for the diagnosis of liver cancer.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Proteína ADAM12/genética , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Ciclo Celular , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/patologia , PrognósticoRESUMO
The regulation and homeostasis of autophagy are essential for maintaining organ morphology and function. As a lysosomal membrane protein, the effect of Sidt2 on kidney structure and renal autophagy is still unknown. In this study, we found that the kidneys of Sidt2-/- mice showed changes in basement membrane thickening, foot process fusion, and mitochondrial swelling, suggesting that the structure of the kidney was damaged. Increased urine protein at 24 h indicated that the kidney function was also damaged. At the same time, the absence of Sidt2 caused a decrease in the number of acidic lysosomes, a decrease in acid hydrolase activity and expression in the lysosome, and an increase of pH in the lysosome, suggesting that lysosomal function was impaired after Sidt2 deletion. The accumulation of autophagolysosomes, increased LC3-II and P62 protein levels, and decreased P62 mRNA levels indicated that the absence of the Sidt2 gene caused abnormal autophagy pathway flow. Chloroquine experiment, immunofluorescence autophagosome, and lysosome fusion assay, and Ad-mcherry-GFP-LC3B further indicated that, after Sidt2 deletion, the production of autophagosomes did not increase, but the fusion of autophagosomes and lysosomes and the degradation of autophagolysosomes were impaired. When incubating Sidt2-/- cells with the autophagy activator rapamycin, we found that it could activate autophagy, which manifested as an increase in autophagosomes, but it could not improve autophagolysosome degradation. Meanwhile, it further illustrated that the Sidt2 gene plays an important role in the smooth progress of autophagolysosome processes. In summary, the absence of the Sidt2 gene caused impaired lysosome function and a decreased number of acidic lysosomes, leading to formation and degradation disorders of the autophagolysosomes, which eventually manifested as abnormal kidney structure and function. Sidt2 is essential in maintaining the normal function of the lysosomes and the physiological stability of the kidneys.
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Lisossomos/metabolismo , Proteínas de Transporte de Nucleotídeos/metabolismo , Animais , Autofagia , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , TransfecçãoRESUMO
The detection of rail surface defects is an important tool to ensure the safe operation of rail transit. Due to the complex diversity of track surface defect features and the small size of the defect area, it is difficult to obtain satisfying detection results by traditional machine vision methods. The existing deep learning-based methods have the problems of large model sizes, excessive parameters, low accuracy and slow speed. Therefore, this paper proposes a new method based on an improved YOLOv4 (You Only Look Once, YOLO) for railway surface defect detection. In this method, MobileNetv3 is used as the backbone network of YOLOv4 to extract image features, and at the same time, deep separable convolution is applied on the PANet layer in YOLOv4, which realizes the lightweight network and real-time detection of the railway surface. The test results show that, compared with YOLOv4, the study can reduce the amount of the parameters by 78.04%, speed up the detection by 10.36 frames per second and decrease the model volume by 78%. Compared with other methods, the proposed method can achieve a higher detection accuracy, making it suitable for the fast and accurate detection of railway surface defects.
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Lysosomes have long been regarded as the "garbage dump" of the cell. More recently, however, researchers have revealed novel roles for lysosomal membranes in autophagy, ion transport, nutrition sensing, and membrane fusion and repair. With active research into lysosomal membrane proteins (LMP), increasing evidence has become available showing that LMPs are inextricably linked to glucose and lipid metabolism, and this relationship represents mutual influence and regulation. In this review, we summarize the roles of LMPs in relation to glucose and lipid metabolism, and describe their roles in glucose transport, glycolysis, cholesterol transport, and lipophagy. The role of transport proteins can be traced back to the original discoveries of GLUT8, NPC1, and NPC2, which were all found to have significant roles in the pathways involved in glucose and lipid metabolism. CLC-5 and SIDT2-knockout animals show serious phenotypic disorders of metabolism, and V-ATPase and LAMP-2 have been found to interact with proteins related to glucose and lipid metabolism. These findings all emphasize the critical role of LMPs in glycolipid metabolism and help to strengthen our understanding of the independent and close relationship between LMPs and glycolipid metabolism.
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Glucose/metabolismo , Metabolismo dos Lipídeos , Proteínas de Membrana Lisossomal/metabolismo , Animais , HumanosRESUMO
Diabetic nephropathy (DN) is one of the most lethal complications of diabetes mellitus with chronic inflammation. We have examined the role of the inflammatory chemokine CCL24 in DN. We observed that serum levels of CCL24 were significantly elevated in patients with DN. Not only that, the expression of CCL24 was significantly increased in the kidneys of DN mice. The kidney of DN mice showed increased renal fibrosis and inflammation. We characterized an in vitro podocyte cell model with high glucose. Western blot analysis showed that expression of CCL24 was significantly increased under high-glucose conditions. Stimulation with high glucose (35 mmol/L) resulted in an increase in CCL24 expression in the first 48 hours but changed little after 72 hours. Moreover, with glucose stimulation, the level of podocyte fibrosis gradually increased, the expression of the proinflammatory cytokine IL-1ß was upregulated, and the expression of the glucose transporter GLUT4, involved in the insulin signal regulation pathway, also increased. It is suggested that CCL24 is involved in the pathogenesis of DN. In order to study the specific role of CCL24 in this process, we used the CRISPR-Cas9 technique to knock out CCL24 expression in podocytes. Compared with the control group, the podocyte inflammatory response induced by high glucose after CCL24 knockout was significantly increased. These results suggest that CCL24 plays a role in the development of early DN by exerting an anti-inflammatory effect, at least, in podocytes.
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Quimiocina CCL24/sangue , Quimiocina CCL2/sangue , Nefropatias Diabéticas/metabolismo , Glucose/efeitos adversos , Podócitos/citologia , Regulação para Cima , Idoso , Animais , Técnicas de Cultura de Células , Quimiocina CCL2/genética , Quimiocina CCL24/genética , Nefropatias Diabéticas/imunologia , Nefropatias Diabéticas/patologia , Modelos Animais de Doenças , Feminino , Fibrose , Técnicas de Inativação de Genes , Transportador de Glucose Tipo 4/metabolismo , Humanos , Interleucina-1beta/metabolismo , Testes de Função Renal , Masculino , Camundongos , Pessoa de Meia-Idade , Podócitos/efeitos dos fármacos , Podócitos/metabolismo , Podócitos/patologiaRESUMO
In recent years, abnormal liver lipid metabolism has emerged as one of the important pathogenesis pathways of primary liver cancer. It is highly important to identify the mechanisms to explore potential prevention and treatment targets. Apolipoprotein M is specifically expressed in the liver and participates in liver lipid metabolism, but the evidence that ApoM affects primary liver cancer is insufficient. The Cancer Genome Atlas (TCGA) database and clinical case analysis, as well as animal level and cell level analysis suggest that the expression level of ApoM gene in cancer tissues is lower than that in paracarcinoma tissues. Further experimental research found that the deletion of ApoM significantly increased the proliferation of mouse liver cancer cells (Hepa1-6) and inhibited the level of apoptosis induced by cisplatin. In addition, mouse liver cancer cells lacking ApoM showed stronger migration and invasion capabilities in transwell experiments. In contrast, overexpression of ApoM in Hepa1-6 cells and Huh-7 cells showed an inhibition of proliferation, up-regulation apoptosis and reduced migration and invasion. In vivo, the deletion of the ApoM accelerated tumorigenesis in nude mice and allowed the mice to develop liver tumor mutations more quickly under the induction of N-nitrosodiethylamine and the survival time of mice was shorter than that control. Therefore, ApoM may be a potential protective factor to inhibit the occurrence and development of primary liver cancer.
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BACKGROUND: Xanthoceraside is a component obtained in the husks of Xanthoceras sorbifolia Bunge. Series of researches proved that xanthoceraside had functions of anti-inflammation and anti-tumor effects. However, the mechanisms of xanthoceraside against bladder cancer are unclear. Accordingly, we proposed to investigate xanthoceraside's impacts and potential mechanisms in cells of bladder cancer. METHODS: By using the CCK-8 assay, we measured the viability of cells. With the use of 4,6-diamidino-2-phenylindole (DAPI) staining, we examined nuclear fragmentation and chromatin condensation in the nuclei of apoptotic cells. By using flow cytometry, we measured cell apoptosis. By using Western blotting, we tested the expressions of Caspase-9, Caspase-8, Caspase-3, Bcl-xL, P53, and PI3K/Akt/Bcl-2/Bax. RESULTS: The proliferation of cell lines of human bladder cancer T24 and 5637 was suppressed by xanthoceraside significantly in a time- and concentration-dependent way. When cell lines 5637 and T24 were incubated as the xanthoceraside dose increased, the rates of cell apoptosis were upregulated, which was dependent on dose. According to further analysis, xanthoceraside induced apoptosis by upregulating Bax and downregulating the expression of Bcl-xL and Bcl-2. However, xanthoceraside did not change the expression of Caspase-9, Caspase-8, and Caspase-3. Interestingly, xanthoceraside also downregulated the expression of p-PI3K and p-Akt, and upregulated P53. CONCLUSIONS: Xanthoceraside induces cell apoptosis through downregulation of the PI3K/Akt/Bcl-2/Bax signaling pathway in cell lines of human bladder cancer.
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Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Saponinas/farmacologia , Triterpenos/farmacologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Caspase 3/metabolismo , Caspase 8/metabolismo , Caspase 9/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , Proteína X Associada a bcl-2/metabolismoRESUMO
Imaging-guided phototherapy, including photothermal therapy and photodynamic therapy, has been emerging as a promising avenue for precision cancer treatment. However, the utilization of a single laser to induce combination phototherapy and multiple-model imaging remains a great challenge. Herein, we report, the first of its kind, a covalent-organic framework (COF)-based magnetic core-shell nanocomposite, Fe3O4@COF-DhaTph, that is used as a multifunctional nanoagent for cancer theranostics under single 660 nm NIR irradiation. Besides significant photothermal and photodynamic effects, it still permits triple-modal magnetic resonance/photoacoustic/near-infrared thermal (IR) imaging due to its unequaled magnetic and optical performance. We believe that the results obtained herein could obviously promote the application of COF-based multifunctional nanomaterials in cancer theranostics.
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Lasers , Estruturas Metalorgânicas/química , Fototerapia/métodos , Óxido Ferroso-Férrico/química , Imagem Multimodal , Nanocompostos/químicaRESUMO
The role of Sidt2 in the process of glucose and lipid metabolism has been recently reported. However, whether Sidt2 is involved in the metabolic regulation in skeletal muscle remains unknown. In this study, for the first time, using skeletal muscle-selective Sidt2 knockout mice, we found that Sidt2 was vital for the quality control of mitochondria in mouse skeletal muscle. These mice showed significantly reduced muscle tolerance and structurally abnormal mitochondria. Deletion of the Sidt2 gene resulted in decreased expression of mitochondrial fusion protein 2 (Mfn2) and Dynamin-related protein 1 (Drp1), as well as peroxisome proliferator-activated receptor γ coactivator-1 (PGC1-α). In addition, the clearance of damaged mitochondria in skeletal muscle was inhibited upon Sidt2 deletion, which was caused by blockade of autophagy flow. Mechanistically, the fusion of autophagosomes and lysosomes was compromised in Sidt2 knockout skeletal muscle cells. In summary, the deletion of the Sidt2 gene not only interfered with the quality control of mitochondria, but also inhibited the clearance of mitochondria and caused the accumulation of a large number of damaged mitochondria, ultimately leading to the abnormal structure and function of skeletal muscle.
Assuntos
Membrana Celular , Lisossomos , Músculo Esquelético/metabolismo , Proteínas de Transporte de Nucleotídeos/metabolismo , Animais , Autofagia/fisiologia , Linhagem Celular , Regulação da Expressão Gênica , Predisposição Genética para Doença , Camundongos , Camundongos Knockout , Microscopia Eletrônica de Transmissão , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/citologia , Doenças Musculares/genética , Proteínas de Transporte de Nucleotídeos/genéticaRESUMO
The purpose of this meta-analysis was to evaluate the beneficial and adverse effects of tripterygium glycosides (TGs) combined with angiotensin II receptor blocker (ARB) on diabetic nephropathy (DN). We searched for randomized controlled trials (RCTs) in PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science, China National Knowledge Infrastructure (CNKI), Wanfang Data, Chinese Biomedical Literature Database, China Science and Technology Journal Database up to June 2017. Weighted mean difference (WMD) and standardized mean difference (SMD) were used for continuous variables and all variables were expressed by 95% confidence interval (CI). Twenty-three studies with 1810 DN patients were included in this meta-analysis. TG combined with ARB statistically significantly improved 24-h urinary total protein (24-h UTP) (SMD = -1.46; 95% CI = -1.84 to -1.09; P<0.00001), urinary albumin excretion rate (UAER) (SMD = -6.9; 95% CI = -9.65 to -4.14, P<0.00001), serum creatinine (SCr) (WMD = -7.65.14; 95% CI = -12.99 to -2.31; P=0.005) and albumin (Alb) (WMD = 5.7; 95% CI = 4.44 to 6.96; P<0.00001) more than did ARB alone. TG combined with ARB statistically significantly affected the level of serum glutamic pyruvic transaminase (SGPT) (WMD = 1.08; 95% CI = 0.04 to 2.12, P=0.04) more than did ARB alone. Compared with ARB alone, TG combined with ARB showed no significant difference in improving blood urea nitrogen (BUN) and hemoglobin A1c (HbA1c). Minor side effects from the combined treatment were observed and mainly focused on the abnormal liver function. TG combined with ARB offers a novel concept in treating DN, more high-quality RCTs are needed for better understanding and applying the combined treatment in DN.