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The energy required for spin-orbit excitation plays a critical role in understanding translational-to-electronic energy conversion, particularly in chemical reactions involving changes in spin states. This is particularly important for transition metal atoms possessing d-orbitals, which result in multiple spin-orbit split energy levels at low energies. The accurate identification and characterization of spin-orbit transitions in such species require advanced experimental techniques and theoretical support. In this study, the spin-orbit excited collisions of Y(2D3/2) with rare gas atoms Ne, Ar, and Kr leading to Y(2D5/2) were observed using laser-ablated crossed-beam and time-sliced ion velocity mapping imaging techniques. Through a comparison of the forward angular distributions of Y(2D3/2) to the backward and sideway scattering distributions of Y(2D5/2) from elastic and inelastic collisions of Y(2D) with rare gas atoms, this study reveals that the spin-orbit electronic excitation occurs with high collision energy and low impact parameters from backward and sideway collisions. The effectiveness of the spin-orbit excitation process is strongly dependent on the collision energy or temperature, suggesting that energy requirements of the process have to be considered in chemical reactions involving changes in spin states.
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This article describes a digital technique for acquiring a 3-dimensional (3D) diagnostic cast with authentic tooth shade and translucency using an open source nondental computer-aided design (CAD) software program detailing the operational methods and parameters. The resultant 3D diagnostic cast can be transmitted to a dental laboratory for the fabrication of deï¬nitive prostheses.
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PURPOSE: In patients with gallstones complicated by common bile duct (CBD) stones, both normal and dilated common bile ducts have been reported. The goal of this study was to investigate the efficacy and safety of primary suturing after microincision of the cystic duct confluence in treating these patients. METHOD: Between July 2018 and December 2021, 104 patients were admitted to the Department of General Surgery at Guannan County People's Hospital with gallstone complications, and their records were reviewed retrospectively. The patients were divided into 2 groups: normal CBD group (n=70, CBD diameter: 6.0 to 8.0 mm) and dilated CBD group (n=34, CBD diameter: >8.0 mm). In these 104 patients, there were 75 cases of CBD stones with acute cholangitis, 12 cases of CBD stones without cholangitis, and 17 cases of mild biliary pancreatitis with CBD stones (including 2 cases of biliary pancreatitis with cholangitis). Among all patients, there were 37 cases with jaundice, 67 cases without jaundice, and 5 cases of emergency surgery. All patients underwent microincision of the cystic duct confluence followed by primary suturing. Both groups were compared on a variety of general and perioperative indicators. RESULT: All patients underwent laparoscopy combined with choledochoscopy; there were no cases of biliary tract injury or conversion to laparotomy. There was no statistically significant difference in operation duration ( P =0.286), blood loss ( P =0.06), length of stay ( P =0.821), and time to drainage tube removal ( P =0.096) between the 2 groups. CONCLUSION: Microincision of the cystic duct confluence, followed by a primary suture, is a safe and effective treatment for CBD stones in patients with a normal CBD diameter, as determined by preoperative imaging.
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Conducto Colédoco , Conducto Cístico , Cálculos Biliares , Técnicas de Sutura , Humanos , Masculino , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Conducto Cístico/cirugía , Anciano , Cálculos Biliares/cirugía , Cálculos Biliares/complicaciones , Conducto Colédoco/cirugía , Adulto , Resultado del Tratamiento , Microcirugia/métodos , Colecistectomía Laparoscópica/métodos , Tempo OperativoRESUMEN
Energy transfer between atoms and molecules is fundamental to many physical and chemical processes, and understanding the mechanisms and outcomes of energy transfer is crucial for various applications in physics and chemistry. Here, the rovibrational excitation of YO(X 2Σ+) molecules with the collision of Kr and Ne has been studied in the laser-ablation crossed beam and time-sliced ion velocity map imaging setup in combination with the resonance enhanced multiphoton ionization scheme. Significant changes in the angular distribution for different rovibrational excitations of YO molecules are observed with the collision of Kr. The sharp forward distribution for low rovibrational excitation of YO(v' = 0, 1) molecules suggest that the weak attractive potential between Kr and YO is dominant at large impact parameters. Comparatively, the strong sideway distribution for highly rovibrationally excited YO(v' = 1, 2, 3, and 5) is due to rainbow scattering from the stronger attractive potential of Kr···YO at relatively small impact parameters. The more isotropic angular distribution in the highly rovibrationally excited YO(v' = 11) indicates the formation of a short-lived complex. A change in the angular distribution of scattered YO with different rovibrational excitations was also observed in the collisions of Ne. For YO as a heteronuclear diatomic molecule, collisions of the Y- and the O-end of YO with rare gases would affect the contribution of inelastic processes at different impact parameters.
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Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, and the development of non-alcoholic steatohepatitis (NASH) might cause irreversible hepatic damage. Hyperlipidemia (HLP) is the leading risk factor for NAFLD. This study aims to illuminate the causative contributor and potential mechanism of Kallistatin (KAL) mediating HLP to NAFLD. 221 healthy control and 253 HLP subjects, 62 healthy control and 44 NAFLD subjects were enrolled. The plasma KAL was significantly elevated in HLP subjects, especially in hypertriglyceridemia (HTG) subjects, and positively correlated with liver injury. Further, KAL levels of NAFLD patients were significantly up-regulated. KAL transgenic mice induced hepatic steatosis, inflammation, and fibrosis with time and accelerated inflammation development in high-fat diet (HFD) mice. In contrast, KAL knockout ameliorated steatosis and inflammation in high-fructose diet (HFruD) and methionine and choline-deficient (MCD) diet-induced NAFLD rats. Mechanistically, KAL induced hepatic steatosis and NASH by down-regulating adipose triglyceride lipase (ATGL) and comparative gene identification 58 (CGI-58) by LRP6/GÉs/PKA/GSK3ß pathway through down-regulating peroxisome proliferator-activated receptor γ (PPARγ) and up-regulating kruppel-like factor four (KLF4), respectively. CGI-58 is bound to NF-κB p65 in the cytoplasm, and diminishing CGI-58 facilitated p65 nuclear translocation and TNFα induction. Meanwhile, hepatic CGI-58-overexpress reverses NASH in KAL transgenic mice. Further, free fatty acids up-regulated KAL against thyroid hormone in hepatocytes. Moreover, Fenofibrate, one triglyceride-lowering drug, could reverse hepatic steatosis by down-regulating KAL. These results demonstrate that elevated KAL plays a crucial role in the development of HLP to NAFLD and may be served as a potential preventive and therapeutic target.
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Enfermedad del Hígado Graso no Alcohólico , Serpinas , Humanos , Ratones , Ratas , Animales , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Inflamación/metabolismo , Ratones TransgénicosRESUMEN
Cancer metabolism mainly includes carbohydrate, amino acid and lipid metabolism, each of which can be reprogrammed. These processes interact with each other to adapt to the complicated microenvironment. Ferroptosis is a regulated cell death induced by iron-dependent lipid peroxidation, which is morphologically different from apoptosis, necrosis, necroptosis, pyroptosis, autophagy-dependent cell death and cuprotosis. Cancer metabolism plays opposite roles in ferroptosis. On the one hand, carbohydrate metabolism can produce NADPH to maintain GPX4 and FSP1 function, and amino acid metabolism can provide substrates for synthesizing GPX4; on the other hand, lipid metabolism might synthesize PUFAs to trigger ferroptosis. The mechanisms through which cancer metabolism affects ferroptosis have been investigated extensively for a long time; however, some mechanisms have not yet been elucidated. In this review, we summarize the interaction between cancer metabolism and ferroptosis. Importantly, we were most concerned with how these targets can be utilized in cancer therapy.
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Ferroptosis , Neoplasias , Humanos , Neoplasias/genética , Apoptosis , Necrosis , Peroxidación de Lípido , Aminoácidos , Microambiente TumoralRESUMEN
BACKGROUND: The progression of tumors from less aggressive subtypes to more aggressive states during metastasis poses challenges for treatment strategies. Previous studies have revealed the molecular subtype conversion between primary and metastatic tumors in breast cancer (BC). However, the subtype conversion during lymph node metastasis (LNM) and the underlying mechanism remains unclear. METHODS: We compared clinical subtypes in paired primary tumors and positive lymph nodes (PLNs) in BC patients and further validated them in the mouse model. Bioinformatics analysis and macrophage-conditioned medium treatment were performed to investigate the role of macrophages in subtype conversion. RESULTS: During LNM, hormone receptors (HRs) were down-regulated, while HER2 was up-regulated, leading to the transformation of luminal A tumors towards luminal B tumors and from luminal B subtype towards HER2-enriched (HER2-E) subtype. The mouse model demonstrated the elevated levels of HER2 in PLN while retaining luminal characteristics. Among the various cells in the tumor microenvironment (TME), macrophages were the most clinically relevant in terms of prognosis. The treatment of a macrophage-conditioned medium further confirmed the downregulation of HR expression and upregulation of HER2 expression, inducing tamoxifen resistance. Through bioinformatics analysis, MNX1 was identified as a potential transcription factor governing the expression of HR and HER2. CONCLUSION: Our study revealed the HER2-E subtype conversion during LNM in BC. Macrophages were the crucial cell type in TME, inducing the downregulation of HR and upregulation of HER2, probably via MNX1. Targeting macrophages or MNX1 may provide new avenues for endocrine therapy and targeted treatment of BC patients with LNM.
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Background/purpose: The guided protocols always yield a higher accuracy than freehand surgery. However, the accuracy of digital guides for crown lengthening surgery (CLS) is unknown. The purpose of this study was to evaluate the trueness of 3 types of digital guides for CLS. Materials and methods: Twenty individually designed maxillary models were divided into 4 groups according to surgical guides: type I (T1), type II (T2), type III (T3), and free-hand. T1 comprised a planed gingival margin at the tissue level. T2 included both the planed gingival margin and alveolar crest at the tissue level. T3 consisted of a planed gingival margin at the tissue level and an alveolar crest at the bone level. CLS was performed under the indication of the guides. Trueness of the guides was evaluated through the deviation of the gingival zenith and alveolar crest height. Results: The control group had higher vertical and horizontal distance deviations of gingival zenith compared to the 3 digital guide groups (P < 0.001). There were no significant differences among the 3 test groups in terms of gingival zenith deviations (P > 0.05). With regard to height deviation of alveolar crest, the control and T1 groups were higher than T2 group (P < 0.001), while T3 group had the lowest deviations among the 4 groups (P < 0.001). Conclusion: The digital guides assisted CLS procedures are more accurate than free-hand method. The trueness of type III guide was better than type I and type II.
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BACKGROUND: The function of kallistatin in airway inflammation, particularly chronic rhinosinusitis with nasal polyps (CRSwNP), has not been elucidated. OBJECTIVE: We sought to investigate the role of kallistatin in airway inflammation. METHODS: Kallistatin and proinflammatory cytokine expression levels were detected in nasal polyps. For the in vivo studies, we constructed the kallistatin-overexpressing transgenic mice to elucidate the role of kallistatin in airway inflammation. Furthermore, the levels of plasma IgE and proinflammatory cytokines in the airways were evaluated in the kallistatin-/- rat in vivo model under a type 2 inflammatory background. Finally, the Notch signaling pathway was explored to understand the role of kallistatin in CRSwNP. RESULTS: We showed that the expression of kallistatin was significantly higher in nasal polyps than in the normal nasal mucosa and correlated with IL-4 expression. We also discovered that the nasal mucosa of kallistatin-overexpressing transgenic mice expressed higher levels of IL-4 expression, associating to TH2-type inflammation. Interestingly, we observed lower IL-4 levels in the nasal mucosa and lower total plasma IgE of the kallistatin-/- group treated with house dust mite allergen compared with the wild-type house dust mite group. Finally, we observed a significant increase in the expression of Jagged2 in the nasal epithelium cells transduced with adenovirus-kallistatin. This heightened expression correlated with increased secretion of IL-4, attributed to the augmented population of CD4+CD45+Notch1+ T cells. These findings collectively may contribute to the induction of TH2-type inflammation. CONCLUSIONS: Kallistatin was demonstrated to be involved in the CRSwNP pathogenesis by enhancing the TH2 inflammation, which was found to be associated with more expression of IL-4, potentially facilitated through Jagged2-Notch1 signaling in CD4+ T cells.
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Linfocitos T CD4-Positivos , Mucosa Nasal , Rinosinusitis , Serpinas , Células Th2 , Animales , Femenino , Humanos , Masculino , Ratones , Ratas , Linfocitos T CD4-Positivos/inmunología , Quimiotaxis de Leucocito/inmunología , Enfermedad Crónica , Citocinas/metabolismo , Inmunoglobulina E/inmunología , Inmunoglobulina E/sangre , Inflamación/inmunología , Interleucina-4/inmunología , Interleucina-4/metabolismo , Ratones Transgénicos , Mucosa Nasal/inmunología , Mucosa Nasal/metabolismo , Pólipos Nasales/inmunología , Rinosinusitis/inmunología , Serpinas/inmunología , Serpinas/genética , Serpinas/metabolismo , Transducción de Señal , Células Th2/inmunologíaRESUMEN
BACKGROUND: Renal fibrosis significantly contributes to the progressive loss of kidney function in chronic kidney disease (CKD), with alternatively activated M2 macrophages playing a crucial role in this progression. The serum succinate level is consistently elevated in individuals with diabetes and obesity, both of which are critical factors contributing to CKD. However, it remains unclear whether elevated succinate levels can mediate M2 polarization of macrophages and contribute to renal interstitial fibrosis. METHODS: Male C57/BL6 mice were administered water supplemented with 4% succinate for 12 weeks to assess its impact on renal interstitial fibrosis. Additionally, the significance of macrophages was confirmed in vivo by using clodronate liposomes to deplete them. Furthermore, we employed RAW 264.7 and NRK-49F cells to investigate the underlying molecular mechanisms. RESULTS: Succinate caused renal interstitial macrophage infiltration, activation of profibrotic M2 phenotype, upregulation of profibrotic factors, and interstitial fibrosis. Treatment of clodronate liposomes markedly depleted macrophages and prevented the succinate-induced increase in profibrotic factors and fibrosis. Mechanically, succinate promoted CTGF transcription via triggering SUCNR1-p-Akt/p-GSK3ß/ß-catenin signaling, which was inhibited by SUCNR1 siRNA. The knockdown of succinate receptor (SUCNR1) or pretreatment of anti-CTGF(connective tissue growth factor) antibody suppressed the stimulating effects of succinate on RAW 264.7 and NRK-49F cells. CONCLUSIONS: The causative effects of succinate on renal interstitial fibrosis were mediated by the activation of profibrotic M2 macrophages. Succinate-SUCNR1 played a role in activating p-Akt/p-GSK3ß/ß-catenin, CTGF expression, and facilitating crosstalk between macrophages and fibroblasts. Our findings suggest a promising strategy to prevent the progression of metabolic CKD by promoting the excretion of succinate in urine and/or using selective antagonists for SUCNR1.
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Insuficiencia Renal Crónica , beta Catenina , Masculino , Ratones , Animales , beta Catenina/metabolismo , Ácido Succínico/metabolismo , Liposomas/metabolismo , Ácido Clodrónico/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Insuficiencia Renal Crónica/metabolismo , Fibrosis , Macrófagos/metabolismoRESUMEN
Non-alcoholic fatty liver disease (NAFLD), characterized by hepatic steatosis, is one of the commonest causes of liver dysfunction. Adipose triglyceride lipase (ATGL) is closely related to lipid turnover and hepatic steatosis as the speed-limited triacylglycerol lipase in liver lipolysis. However, the expression and regulation of ATGL in NAFLD remain unclear. Herein, our results showed that ATGL protein levels were decreased in the liver tissues of high-fat diet (HFD)-fed mice, naturally obese mice, and cholangioma/hepatic carcinoma patients with hepatic steatosis, as well as in the oleic acid-induced hepatic steatosis cell model, while ATGL mRNA levels were not changed. ATGL protein was mainly degraded through the proteasome pathway in hepatocytes. Beta-transducin repeat containing (BTRC) was upregulated and negatively correlated with the decreased ATGL level in these hepatic steatosis models. Consequently, BTRC was identified as the E3 ligase for ATGL through predominant ubiquitination at the lysine 135 residue. Moreover, adenovirus-mediated knockdown of BTRC ameliorated steatosis in HFD-fed mouse livers and oleic acid-treated liver cells via upregulating the ATGL level. Taken together, BTRC plays a crucial role in hepatic steatosis as a new ATGL E3 ligase and may serve as a potential therapeutic target for treating NAFLD.
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Neoplasias Hepáticas , Enfermedad del Hígado Graso no Alcohólico , Humanos , Ratones , Animales , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Ácido Oléico/farmacología , Ácido Oléico/metabolismo , Repeticiones WD40 , Hígado/metabolismo , Neoplasias Hepáticas/patología , Dieta Alta en Grasa/efectos adversos , Ratones Endogámicos C57BLRESUMEN
Spin-orbit coupling plays an important role in chemical reactivity, especially in reactions that require the change of electron spin states. However, it is difficult to measure and analyze the reaction dynamics between spin-orbit splitting states, particularly for splitting states with a small energy difference. In this study, we find that nonreactive scattering of spin-orbit splitting states can provide complementary information that is overlooked in chemical reaction studies. Here, the oxidation reactivities of spin-orbit Al(2P1/2,3/2) states with small energy difference of 112 cm-1 are clearly distinguished in the high rotational AlO(v = 0 and 1, N) products at low collision energy of 507 cm-1 using a laser ablation crossed-beam and time-sliced ion velocity mapping technique, in conjunction with state-selected nonreactive scattering studies. For both the AlO(v = 0 and 1) channels, the spin-orbit relative reactivity σ3/2/σ1/2 increases with the increase of rotational level N of AlO products. However, for AlO(v = 0), the reactivity of the Al(2P3/2) excited state is consistently lower than that of the Al(2P1/2) ground state, whereas for AlO(v = 1), the reactivity of Al(2P3/2) is higher than that of Al(2P1/2) at a higher rotational state. The relative reactivity of spin-orbit split Al(2P) states at different scattering angles shows a more pronounced enhancement of forward scattering relative to side and backward scattering for Al(2P3/2) when a higher rotationally excited AlO is produced. Nonreactive scattering studies of Al(2P) suggest that the Al(2P3/2) state is deexcited to the ground Al(2P1/2) state at the sideways and backward scattering directions, and the deexcitation is supposed to reduce the reactivity of the excited Al(2P3/2) at the corresponding direction.
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Purpose: Retinal pigment epithelium (RPE) dysfunction induced by oxidative stress-related epithelial-mesenchymal transition (EMT) of RPE is the primary underlying mechanism of age-related macular degeneration (AMD). Kallistatin (KAL) is a secreted protein with an antioxidative stress effect. However, the relationship between KAL and EMT in RPE has not been determined. Therefore we aimed to explore the impact and mechanism of KAL in oxidative stress-induced EMT of RPE. Methods: Sodium iodate (SI) was injected intraperitoneally to construct the AMD rat model and investigate the changes in RPE morphology and KAL expression. KAL knockout rats and KAL transgenic mice were used to explain the effects of KAL on EMT and oxidative stress. In addition, Snail overexpressed adenovirus and si-RNA transfected ARPE19 cells to verify the involvement of Snail in mediating KAL-suppressed EMT of RPE. Results: AMD rats induced by SI expressed less KAL in the retina, and KAL knockout rats showed RPE dysfunction spontaneously where EMT and reactive oxygen species (ROS) production increased in RPE. In contrast, KAL overexpression attenuated EMT and ROS levels in RPE, even in TGF-ß treatment. Mechanistically, Snail reversed the beneficial effect of KAL on EMT and ROS reduction. Moreover, KAL ameliorated SI-induced AMD-like pathological changes. Conclusions: Our findings demonstrated that KAL inhibits oxidative stress-induced EMT by downregulating the transcription factor Snail. Herein, KAL knockout rats may be an appropriate animal model for observing spontaneous RPE dysfunction for AMD-like retinopathy, and KAL may represent a novel therapeutic target for treating dry AMD.
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Atrofia Geográfica , Degeneración Macular , Serpinas , Animales , Ratones , Ratas , Células Epiteliales , Transición Epitelial-Mesenquimal , Degeneración Macular/genética , Ratones Transgénicos , Estrés Oxidativo , Especies Reactivas de Oxígeno , Pigmentos Retinianos , Serpinas/genéticaRESUMEN
Phytochemical investigation of 70% EtOH extract of the seeds of Capsella bursa-pastoris led to the isolation of a new cyclobutane organic acid (1), and fourteen known compounds, including two organosulfur compounds (2, 3), two quinonoids (4, 5), five flavonoids (6-10), three sterols (11-13) and two other types (14, 15). The structures of the compounds were elucidated by extensive spectroscopic analyses as well as comparison of their spectroscopic data with those reported in the literature. The antioxidant capacities of all compounds and extractive fractions were evaluated by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical-scavenging test and ferric reducing antioxidant power (FRAP) assay. Then the antioxidative substances were evaluated for their neuroprotective effects against H2O2-induced HT22 cell injury. The results indicated the strong scavenging ability to free radical of the extractive fractions and compounds 1-3, 8-10 and 13, and the ferric reducing antioxidant power of the extractive fractions and compounds 1-3, 8 and 10, which were close to or higher than that of the positive control trolox. The EtOAc fraction, n-BuOH fraction, and compounds 1, 3 and 8 can protect HT-22 cells from oxidative damage.
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Antioxidantes , Capsella , Antioxidantes/análisis , Peróxido de Hidrógeno , Extractos Vegetales/química , Fitoquímicos/farmacología , Semillas/químicaRESUMEN
STATEMENT OF PROBLEM: An accurate digital workflow for transferring the interocclusal relationship from complete arch diagnostic interim restorations to complete arch tooth preparations is essential in complete mouth rehabilitation. However, research on the accuracy of digital cross-mounting methods is lacking. PURPOSE: The purpose of this in vitro study was to compare the trueness of 4 sectional-cast digital cross-mounting methods in transferring the interocclusal relationship for complete mouth rehabilitation. MATERIAL AND METHODS: Maxillary and mandibular anatomic typodonts were used to build complete arch tooth preparations and diagnostic interim restorations for complete mouth rehabilitation in vitro. Four sectional casts were designed: an anterior cast (AR), a posterior cast (PO), a unilateral cast (UL), and a tripod cast (TR). Both extraoral scanning (EOS) and intraoral scanning (IOS) were used to obtain intermediate digital sectional casts, which were cross-registered with diagnostic interim restorations and definitive casts to transfer the interocclusal relationship. Trueness was determined by assessing tooth distance deviation and mandibular 3-dimensional (3D) deviation. Differences among the 4 sectional-cast methods were analyzed with the Kruskal-Wallis test, and differences between the 2 scanning methods were analyzed with the Mann-Whitney U test (α=.05). RESULTS: Significant differences in the trueness of interocclusal relationship transfer were observed among the 4 sectional-cast methods (P<.05). Regarding tooth overall distance deviation, TR-EOS found no statistically significant difference compared with PO-EOS (P>.05), but TR-EOS had half the overall distance deviation of PO-EOS. Both TR-EOS and PO-EOS had smaller deviations than the AR-EOS and UL-EOS groups (P<.05). TR-IOS had a smaller distance deviation than the AR-IOS, PO-IOS, and UL-IOS groups (P<.05). The overall distance deviation of EOS was significantly smaller than that of IOS in the TR and PO groups (P<.05). Regarding mandibular 3D deviation, TR-EOS found no statistically significant difference but had half the root mean square (RMS) of 3D deviation compared with the PO-EOS groups (P>.05). Both TR-EOS and PO-EOS groups had a smaller RMS than the AR-EOS and groups (P<.05). The TR-IOS group had a smaller RMS than the AR-IOS, PO-IOS, and UL-IOS groups (P<.05). The 3D deviation of EOS was significantly smaller than that of IOS in the PO group (P<.05). CONCLUSIONS: Both EOS and IOS with the tripod sectional-cast digital method accurately transferred the interocclusal relationship for complete mouth rehabilitation.
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INTRODUCTION: Hepatocellular carcinoma (HCC) is one of the common malignant tumors. Although surgical resection is the best treatment for HCC, many patients with HCC are found to have metastases at the time of initial diagnosis and lose the opportunity for radical treatment. Therefore, the study of the invasion and metastasis of HCC has always been the focus of HCC research. This study aimed to assess the influence of LAIR-1 on HCC cell proliferation and invasion and the relevant mechanisms involved in this process. METHODS: Immunocytochemical staining assay, quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting (WB) were used to detect the expression of LAIR-1mRNA and protein in healthy human hepatocyte LO2 and the HCC cell lines HepG2, Bel-7402, MHCC97-H, and Huh-7. Then, we evaluated the cell viability, colony formation, and invasion of MHCC97-H and Huh-7 cells in each group by silencing or overexpressing LAIR-1 expression in MHCC97-H and Huh-7 cells, respectively. WB was used to detect the expression levels of PI3K-AKT-mTOR pathway related proteins. RESULTS: Our findings showed that LAIR-1 can inhibit cell viability, colony formation and invasion in vitro. Meanwhile, LAIR-1 significantly downregulated the expression of PI3K, p-AKT and p-mTOR, which were abolished by the PI3K inhibitor, LY294002. CONCLUSIONS: Our study revealed that LAIR-1 inhibited cell proliferation and invasion, probably via suppressing the PI3K-AKT-mTOR pathway.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Neoplasias Hepáticas/genética , Línea Celular , Proliferación CelularRESUMEN
CONTEXT: Excessive insulin resistance, inadequate insulin compensation, or both could result in gestational diabetes mellitus (GDM). Levels of pigment epithelium-derived factor (PEDF), a novel adipokine that could induce insulin resistance, are high in patients with obesity and diabetes. However, the impact of PEDF in pregnancy remains unknown. OBJECTIVE: This study aimed to elucidate the role of PEDF on insulin resistance and compensatory elevation of insulin levels during normal pregnancy and in patients with GDM. METHODS: In this population-based and cohort study, logistic regression analysis was performed to determine the association of PEDF/adiponectin/leptin levels with the risk of developing GDM and to predict postpartum prediabetes. PEDF protein, PEDF transgenic mice, PEDF knockout mice, and PEDF-neutralized antibodies were used to observe changes in insulin resistance and insulin levels with pregnancy. RESULTS: Plasma PEDF levels were increased in normal pregnancy and higher in GDM women. Higher PEDF levels were associated with the increased risk of developing GDM and emerged as a significant independent determinant of postpartum prediabetes in GDM women. Mechanistically, in vivo and in vitro experiments revealed that PEDF induced insulin resistance by inhibiting the insulin signaling pathway. CONCLUSION: In addition to insulin resistance and upregulated insulin levels in normal pregnancy and GDM, aberrant PEDF levels can serve as a "fingerprint" of metabolic abnormalities during pregnancy. Thus, PEDF is a valuable biomarker but could interfere with the time course for early diagnosis and prognosis of GDM.
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Diabetes Gestacional , Resistencia a la Insulina , Estado Prediabético , Embarazo , Animales , Ratones , Humanos , Femenino , Adipoquinas , Estudios de Cohortes , InsulinaRESUMEN
Extranodal NK/T-cell lymphoma (NKTL) is a rare and aggressive form of extranodal lymphoma with a poor prognosis. Currently, there are very limited treatment options for patients with advanced-stage disease or those with relapsed/recurrent disease. Here we show that Chiauranib, an orally small molecule inhibitor of select serine-threonine kinases (aurora B, VEGFRs, PDGFR, CSF1R, c-Kit), inhibited NKTL cell proliferation, induced cell cycle arrest, as well as suppressed the microvessel density in vitro and in vivo similar as in other types of cancer cells. Surprisingly, Chiauranib unfolded a new effect to induce apoptosis of NKTL cells by triggering AIF-dependent apoptosis other than the traditional cyt-c/caspase mitochondrial apoptosis pathway. The knockdown of AIF in vitro and in vivo dramatically blocked the efficacy of Chiauranib on NKTL. Mechanistically, the release of AIF from mitochondria is due to the upregulation of VDAC1 by the AKT-GSK3ß pathway and activation of calcium-dependent m-calpain, which promotes the cleavage of VDAC1 and therefore permits the release of AIF. Notably, the low expression of Bax in both NKTL cells and patient tissues restrained the cyt-c release. It resulted in the inhibition of cyt-c/caspase mitochondrial pathway, suggesting that drugs targeting this traditional pathway may not be effective in NKTL. Furthermore, we found that L-asparaginase triggered CD95 (Fas/Apo-1)-caspase 8-caspase 3 apoptotic pathway in NKTL cells, and combination of Chiauranib and L-asparaginase exhibited a synergistic effect, suggesting a feasibility to combine these two drugs for effective treatment of NKTL. This study demonstrates Chiauranib's positive efficacy toward NKTL through the activation of the AIF-dependent apoptosis pathway for the first time. The novel and multi-targets of Chiauranib and the synergistic effect with L-asparaginase may provide a promising therapy for NKTL patients.
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Linfoma de Células T , Quinolinas , Humanos , Asparaginasa/farmacología , Asparaginasa/uso terapéutico , NaftalenosRESUMEN
Retinal fibrosis is a severe pathological change in the late stage of diabetic retinopathy and is also the leading cause of blindness. We have previously revealed that N-cadherin was significantly increased in type 1 and type 2 diabetic mice retinas and the fibrovascular membranes from proliferative diabetic retinopathy (PDR) patients. However, whether N-cadherin directly induces retinal fibrosis in DR and the related mechanism is unknown. Here, we investigated the pathogenic role of N-cadherin in mediating retinal fibrosis and further explored the relevant therapeutic targets. We found that the level of N-cadherin was significantly increased in PDR patients and STZ-induced diabetic mice and positively correlated with the fibrotic molecules Connective Tissue Growth Factor (CTGF) and fibronectin (FN). Moreover, intravitreal injection of N-cadherin adenovirus significantly increased the expression of FN and CTGF in normal mice retinas. Mechanistically, overexpression of N-cadherin promotes N-cadherin cleavage, and N-cadherin cleavage can further induce translocation of non-p-ß-catenin in the nucleus and upregulation of fibrotic molecules. Furthermore, we found a novel N-cadherin cleavage inhibitor, pigment epithelial-derived factor (PEDF), which ameliorated the N-cadherin cleavage and subsequent retinal fibrosis in diabetic mice. Thus, our findings provide novel evidence that elevated N-cadherin level not only acts as a classic EMT maker but also plays a causative role in diabetic retinal fibrosis, and targeting N-cadherin cleavage may provide a strategy to inhibit retinal fibrosis in DR patients.
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Cadherinas , Diabetes Mellitus Experimental , Retinopatía Diabética , Animales , Humanos , Ratones , beta Catenina/metabolismo , Cadherinas/metabolismo , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/metabolismo , Retinopatía Diabética/metabolismo , FibrosisRESUMEN
One new pentacyclic triterpenoid glycoside, ardisiapunine E (1), along with two known compounds were isolated from the root of Ardisia lindleyana D.Dietr. Their structures were elucidated by 1H and 13C NMR, DEPT, HMBC, HSQC, 1H-1H COSY and NOESY spectroscopic analyses, ESI-MS, and literature. Compounds 1-3 exhibited obvious anti-proliferative activities against the HeLa cell line in a dose- and time-dependent manner by inducing G2/M phase arrest and apoptosis in vitro, both consisting of pentacyclic triterpenes and sugar. Hence, this study identified a new and two known pentacyclic triterpenoid glycosides promoting apoptosis as a potential anti-proliferative agent.