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Although approximately 70% of bladder cancers are noninvasive and have high recurrence rates, early-stage disease is understudied. The lack of models to validate the contribution of molecular drivers of bladder tumorigenesis is a significant issue. Although mutations in PIK3CA are frequent in human bladder cancer, an in vivo model for understanding their contribution to bladder tumorigenesis is unavailable. Therefore, a Upk2-Cre/Pik3caH1047R mouse model expressing one or two R26-Pik3caH1047R alleles in a urothelium-specific manner was generated. Pik3caH1047R functionality was confirmed by quantifying Akt phosphorylation, and mice were characterized by assessing urothelial thickness, nuclear atypia, and expression of luminal and basal markers at 6 and 12 months of age. While at 6 months, Pik3caH1047R mice developed increased urothelial thickness and nuclear atypia, progressive disease was not observed at 12 months. Immunohistochemistry showed urothelium maintained luminal differentiation characterized by high forkhead box A1 (Foxa1) and peroxisome proliferator-activated receptor γ expression. Surprisingly, Pik3caH1047R mice subjected to low-dose carcinogen exposure [N-butyl-N-(4-hydroxybutyl)nitrosamine] exhibited no significant differences after exposure relative to mice without exposure. Furthermore, single-sample gene set enrichment analysis of invasive human tumors showed those with mutant PIK3CA did not exhibit significantly increased phosphatidylinositol 3-kinase/AKT pathway activity compared with wild-type PIK3CA tumors. Overall, these data suggest that Pik3caH1047R can elicit early tumorigenic changes in the urothelium, but progression to invasion may require additional genetic alterations.
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Proteínas Proto-Oncogênicas c-akt , Neoplasias da Bexiga Urinária , Animais , Humanos , Camundongos , Carcinogênese/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Mutação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , Urotélio/metabolismoRESUMO
Purpose: To investigate morphological and hemodynamic characteristics of the ophthalmic artery (OA) in patients with white matter hyperintensity (WMH), and the association of the presence and severity of WMH with OA characteristics. Methods: This cross-sectional study included 44 eyes of 25 patients with WMH and 38 eyes of 19 controls. The Fazekas scale was adopted as criteria for evaluating the severity of white matter hyperintensities. The morphological characteristics of the OA were measured on the basis of three-dimensional reconstruction. The hemodynamic parameters of the OA were calculated using computational fluid dynamics simulations. Results: Compared with the control group, the diameter (16.0±0.27 mm vs. 1.71±0.18 mm, P=0.029), median blood flow velocity (0.12 m/s vs. 0.22 m/s, P<0.001), mass flow ratio (2.16% vs. 3.94%, P=0.012) and wall shear stress (2.65 Pa vs. 9.31 Pa, P<0.001) of the OA in patients with WMH were significantly decreased. After adjusting for confounding factors, the diameter, blood flow velocity, wall shear stress, and mass flow ratio of the OA were significantly associated with the presence of WMH. Male sex and high low-density protein level were associated with moderate-to-severe total WMH, and smoking was associated with the moderate-to-severe periventricular WMH. Conclusions: The diameter, blood flow velocity, mass flow ratio, and wall shear stress of the OA were independently associated with the presence of WMH. Atherosclerosis might be involved in the common mechanism of the occurrence of WMH and the OA changes.
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Hemodinâmica , Artéria Oftálmica , Substância Branca , Humanos , Masculino , Feminino , Artéria Oftálmica/diagnóstico por imagem , Artéria Oftálmica/fisiopatologia , Substância Branca/diagnóstico por imagem , Substância Branca/fisiopatologia , Substância Branca/irrigação sanguínea , Substância Branca/patologia , Estudos Transversais , Hemodinâmica/fisiologia , Pessoa de Meia-Idade , Idoso , Velocidade do Fluxo Sanguíneo , Imageamento por Ressonância Magnética , AdultoRESUMO
Hypericum beanii N. Robson, a perennial upright herb, predominantly inhabits temperate regions. This species has been utilized for the treatment of various inflammation-related diseases. One new xanthone 3,7-dihydroxy-1,6-dimethoxyxanthone (1) and twenty-three known xanthones (2-24) were isolated from the aerial parts of H. beanii. The structure of the new compound was determined based on high-resolution electrospray ionization mass spectroscopy (HR-ESIMS), nuclear magnetic resonance (NMR), Infrared Spectroscopy (IR), ultraviolet spectrophotometry (UV) spectroscopic data. The anti-inflammatory effects of all the isolates were assessed by measuring the inhibitory effect on nitric oxide (NO) production in LPS-stimulated RAW 264.7 macrophages. Compounds 3,4-dihydroxy-2-methoxyxanthone (15), 1,3,5,6-tetrahydroxyxanthone (19), and 1,3,6,7-tetrahydroxyxanthone (22) exhibited significant anti-inflammatory effects at a concentration of 10 µM with higher potency compared to the positive control quercetin. Furthermore, compounds 15, 19, and 22 reduced inducible NO synthase (iNOS), tumor necrosis factor alpha (TNF-α), interleukin-1ß (IL-1ß), IL-6, and cyclooxygenase 2 (COX-2) mRNA expression in the LPS-stimulated RAW 264.7 macrophages, suggesting that these compounds may mitigate the synthesis of the aforementioned molecules at the transcriptional level, provisionally confirming their anti-inflammatory efficacy.
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Anti-Inflamatórios , Ciclo-Oxigenase 2 , Hypericum , Interleucina-1beta , Interleucina-6 , Macrófagos , Óxido Nítrico , Fator de Necrose Tumoral alfa , Xantonas , Camundongos , Xantonas/farmacologia , Xantonas/química , Xantonas/isolamento & purificação , Animais , Células RAW 264.7 , Óxido Nítrico/metabolismo , Óxido Nítrico/biossíntese , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Ciclo-Oxigenase 2/metabolismo , Ciclo-Oxigenase 2/genética , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Interleucina-6/metabolismo , Interleucina-6/genética , Interleucina-6/biossíntese , Fator de Necrose Tumoral alfa/metabolismo , Interleucina-1beta/metabolismo , Interleucina-1beta/genética , Hypericum/química , Lipopolissacarídeos/farmacologia , Extratos Vegetais/farmacologia , Extratos Vegetais/químicaRESUMO
BACKGROUND: Cerebral small vessel disease (CSVD) is a systemic disease, affecting not only the brain, but also eyes and other organs. The total CSVD score is a tool for comprehensive evaluation of brain lesions in patients with CSVD. The ophthalmic artery (OA) is a direct response to ocular blood flow. However, little is known about the correlation between CSVD and characteristics of OA. We investigated the OA morphologies and hemodynamics in patients with CSVD and the correlation between these changes and the total CSVD score. METHODS: This cross-sectional observational study included 34 eyes from 22 patients with CSVD and 10 eyes from 5 healthy controls. The total CSVD score was rated according to the CSVD signs on magnetic resonance imaging. OA morphological characteristics were measured on the basis of 3D OA model reconstruction. OA hemodynamic information was calculated using computational fluid dynamics simulations. RESULTS: The total CSVD score negatively correlated with the OA diameter, blood flow velocity, and mass flow ratio (all P < 0.05). After adjusting for potential confounding factors, the total CSVD score was still independently correlated with the OA blood velocity (ß = - 0.202, P = 0.005). The total CSVD score was not correlated with OA angle (P > 0.05). The presence of cerebral microbleeds and enlarged perivascular spaces was correlated with the OA diameter (both P < 0.01), while the lacunar infarcts and white matter hyperintensities were correlated with the OA blood velocity (both P < 0.001). CONCLUSIONS: The decrease of the blood velocity in the OA was associated with the increase in the total CSVD score. The changes of the OA diameter and velocity were associated with the presence of various CSVD signs. The findings suggest that more studies are needed in the future to evaluate CSVD by observing the morphologies and hemodynamics of OA.
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Doenças de Pequenos Vasos Cerebrais , Acidente Vascular Cerebral Lacunar , Humanos , Estudos Transversais , Artéria Oftálmica/diagnóstico por imagem , Doenças de Pequenos Vasos Cerebrais/diagnóstico por imagem , Doenças de Pequenos Vasos Cerebrais/complicações , Acidente Vascular Cerebral Lacunar/complicações , Imageamento por Ressonância Magnética , HemodinâmicaRESUMO
BACKGROUND: Abnormal miRNA and mRNA expression and dysregulated immune microenvironment have been found to frequently induce the progression of hepatocellular carcinoma (HCC) in recent reports. In particular, the immune-related competing endogenous RNAs (ceRNA) mechanism plays a crucial role in HCC progression. However, the underlying mechanisms remain unclear. METHODS: Differentially expressed immune-related genes were obtained from the Immport, GEO, and TCGA databases. The mRNA and protein expression levels in HCC tissues and adjacent normal tissues were confirmed, and we further investigated the methylation levels of these biomarkers to explore their function. Then, the TIMER and TISCH databases were used to assess the relationship between immune infiltration and hub genes. Survival analysis and univariate and multivariate Cox models were used to evaluate the association between hub genes and HCC diagnosis. Hub gene expression was experimentally validated in six HCC cell lines and 15 HCC samples using qRT-PCR and immunohistochemistry. The hub genes were uploaded to DSigDB for drug prediction enrichment analysis. RESULTS: We identified that patients with abnormal miRNAs (hsa-miR-125b-5p and hsa-miR-21-5p) and their targeted genes (NTF3, PSMD14, CD320, and SORT1) had a worse prognosis. Methylation analysis of miRNA-targeted genes suggested that alteration of methylation levels is also a factor in the induction of tumorigenesis. We also found that the development of HCC progression caused by miRNA-mRNA interactions may be closely correlated with the infiltration of immunocytes. Moreover, the GSEA, GO, and KEGG analysis suggested that several common immune-related biological processes and pathways were related to miRNA-targeted genes. The results of qRT-PCR, immunohistochemistry, and western blotting were consistent with our bioinformatics results, suggesting that abnormal miRNAs and their targeted genes may affect HCC progression. CONCLUSIONS: Briefly, our study systematically describes the mechanisms of miRNA-mRNA interactions in HCC and predicts promising biomarkers that are associated with immune filtration for HCC progression.
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This study used the tert-butylcalix[6]arene (TBC[6]) as the ligand and successfully synthesized six TBC[6]-stabilized titanium-oxo clusters (TOCs) by the one-step solvothermal reaction. These six compounds were [Ti4O2(TBC[6])2] (Ti4), {Ti2(TBC[6])(EtO)2(SaH2)2} (Ti2-SA, H2Sa = squaric acid), {Ti2(TBC[6])2(EtO)2(Oa)} (Ti2-OA, H2Oa = oxalic acid), [H2Ti4(TBC[6])(BA)2(EtO)10] (Ti4-BA, HBA = benzoic acid), [Ti6O2(TBC[6])(BA)4(OiPr)10] (Ti6-BA), and [Ti8(TBC[6])2(Sal)4(EtO)16] (Ti8-Sal, H2Sal = salicylic acid). These clusters contain one or two TBC[6] ligands, with the biconical or monoconical configuration, greatly increasing the variety of TOCs it could support. The introduction of auxiliary carboxylic ligands can further stimulate the growth of structures, with the cluster core gradually increased from {Ti-TBC[6]-Ti} to {Ti2-TBC[6]-Ti2}, to {Ti3-TBC[6]-Ti3}, and finally to {Ti3-TBC[6]-Ti2-TBC[6]-Ti3} with 3.1 nm length. Structural regulation may affect their solution stability, absorption spectra, and photocurrent response. The study of catalytic activities shows that these clusters can be used as recyclable heterogeneous photocatalysts for the oxidation of sulfide to sulfoxide. The catalytic efficiency of the TBC[6]-Tix system is closely related to the cluster structure, and the exposure of the Ti site on the catalyst surface can significantly enhance the catalytic activity of the clusters.
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Riparian buffers benefit both natural and man-made ecosystems by preventing soil erosion, retaining soil nutrients, and filtering pollutants. Nevertheless, the relationship between vertical methane fluxes, soil carbon, and methane microbial communities in riparian buffers remains unclear. This study examined vertical methane fluxes, soil carbon, and methane microbial communities in three different soil depths (0-5 cm, 5-10 cm, and 10-15 cm) within a riparian buffer of a Sponge City Park for one year. Structural equation model (SEM) results demonstrated that vertical methane fluxes varied with soil depths (λ = -0.37) and were primarily regulated by methanogenic community structure (λ = 0.78). Notably, mathematical regression results proposed that mcrA/pmoA ratio (R2 = 0.8) and methanogenic alpha diversity/methanotrophic alpha diversity ratio (R2 = 0.8) could serve as valid predictors of vertical variation in methane fluxes in the riparian buffer of urban river. These findings suggest that vertical variation of methane fluxes in riparian buffer soils is mainly influenced by carbon inputs and methane microbial abundance and community diversity. The study's results quantitatively the relationship between methane fluxes in riparian buffer soils and abiotic and biotic factors in the vertical direction, therefore contributing to the further development of mathematical models of soil methane emissions.
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Euryarchaeota , Microbiota , Humanos , Solo/química , Metano , Carbono , Microbiologia do SoloRESUMO
UPII-mutant Ha-ras transgenic mice develop urothelial hyperplasia and low-grade papillary carcinoma, which mimics human non-muscle invasive bladder cancer (NMIBC). We investigated the effects and mechanisms of kawain, a main kavalactone in the kava plant, on oncogenic Ha-ras-driven urothelial carcinoma in these mice. The mice were fed at six weeks of age with vehicle control or kawain (6 g/kg) formulated food for approximately five months. Seventy-eight percent of the mice or more fed with kawain food survived more than six months of age, whereas only 32% control food-fed male mice survived, (p = 0.0082). The mean wet bladder weights (a surrogate for tumor burden) of UPII-mutant Ha-ras transgenic mice with kawain diet was decreased by approximately 56% compared to those fed with the control diet (p = 0.035). The kawain diet also significantly reduced the occurrence of hydronephrosis and hematuria in UPII-mutant Ha-ras transgenic mice. Histological examination and immunohistochemistry analysis revealed that vehicle control-treated mice displayed more urothelial carcinoma and Ki67-positive cells in the bladder compared to kawain treated mice. Global metabolic profiling of bladder tumor samples from mice fed with kawain food showed significantly more enrichment of serotonin and less abundance of xylulose, prostaglandin A2, D2 and E2 compared to those from control diet-fed mice, suggesting decreased shunting of glucose to the pentose phosphate pathway (PPP) and reduced inflammation. In addition, kawain selectively inhibited the growth of human bladder cancer cell lines with a significant suppression of 4E-BP1 expression and rpS6 phosphorylation. These observations indicate a potential impact of kawain consumption on bladder cancer prevention by rewiring the metabolic programs of the tumor cells.
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Carcinoma de Células de Transição , Neoplasias da Bexiga Urinária , Animais , Camundongos , Transformação Celular Neoplásica , Camundongos Transgênicos , Serina-Treonina Quinases TOR , Neoplasias da Bexiga Urinária/patologiaRESUMO
In conjunction with pandemics, medical image data are growing exponentially. In some countries, hospitals collect biometric data from patients, such as fingerprints, iris, or faces. This data can be used for things like identity verification and security management. However, this medical data can be easily compromised by hackers. In order to prevent illegal tampering with medical images and invasion of privacy, a new texture fusion medical image encryption (TFMIE) algorithm derived from biometric images is proposed, which can encrypt the image using biometric information for storage or transmission. First, the medical image is decomposed into n-bit-planes by bit-plane decomposition. Secondly, a fusion image is generated by a biometric image with a circular local binary pattern and pixel-weighted average method. The fused image is further decomposed into n bit-planes through bit-plane decomposition and performs XOR operation with the original medical image in reverse order. Following the execution of the XOR operation, a new scrambling and diffusion algorithm based on a one-dimensional fractional trigonometric function (1DFTF) chaotic map is employed to form the cipher image. The experimental results show that compared with the existing methods, the average information entropy value of TFMIE is 7.99, and the average values of NPCR and UACI reach 0.9958 and 0.3346, respectively, which have strong key sensitivity, good robustness, and anti-attack ability. The method is lossless and has high transmission efficiency, which can meet the needs of medical big data encryption.
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Algoritmos , Biometria , Humanos , Entropia , Hospitais , IrisRESUMO
Diabetic peripheral neuropathy(DPN) is a chronic complication resulted from peripheral nerve injury in the late stage of diabetes. It involves a variety of pathological changes such as oxidative stress, endoplasmic reticulum stress, neuroinflammation, and apoptosis of Schwann cells(SCs). DPN is the main factor leading to lower limb disability or amputation in diabetic patients, with high incidence, long disease course, and poor prognosis. The modern medicine treatment of DPN mainly focuses on controlling blood glucose and improving microcirculation and nerve nutrition, which can only mitigate the clinical symptoms and not fundamentally reverse the pathological changes of peripheral nerves. Autophagy is a self-clearing mechanism that maintains cellular homeostasis by removing excess metabolites. Traditional Chinese medicine(TCM), featuring the holistic concept and syndrome differentiation, can treat chronic diseases in a multi-target, multi-pathway, and wide-range manner. Modern studies have shown that the occurrence and development of DPN are related to a variety of pathological changes, and autophagy is a key mechanism associated with DPN. The environment with persistent high glucose can lead to the inhibition or over-activation of peripheral nerve cells, which causes irreversible damage of nerve cells and the occurrence and development of DPN. Therefore, restoring autophagy balance and reducing nerve damage is one of the key ways to treat DPN. The recent studies have confirmed that some active ingredients in traditional Chinese medicines and TCM compound prescriptions can inhibit the oxidative stress, endoplasmic reticulum stress, mitochondrial damage, inflammation, and apoptosis of SCs in DPN by regulating the autophagy pathway, thus playing a role in the prevention and treatment of DPN. However, the systematic induction in this field remains to be carried out. This paper reviewed the relevant literature, explained the mechanism of TCM in the prevention and treatment of DPN by regulating autophagy, and summarized the potential targets of TCM in the treatment of DPN, with a view to providing new ideas for clinical research and drug development.
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Diabetes Mellitus , Neuropatias Diabéticas , Humanos , Autofagia , Neuropatias Diabéticas/tratamento farmacológico , Neuropatias Diabéticas/prevenção & controle , Neuropatias Diabéticas/complicações , Medicina Tradicional Chinesa , Estresse Oxidativo , Células de Schwann/metabolismo , Células de Schwann/patologiaRESUMO
Sepsis is a significant cause of mortality in hospitalized patients. Concomitant development of acute kidney injury (AKI) increases sepsis mortality through unclear mechanisms. Although electrolyte disturbances and toxic metabolite buildup during AKI could be important, it is possible that the kidney produces a protective molecule lost during sepsis with AKI. We have previously demonstrated that systemic Tamm-Horsfall protein (THP; uromodulin), a kidney-derived protein with immunomodulatory properties, falls in AKI. Using a mouse sepsis model without severe kidney injury, we showed that the kidney increases circulating THP by enhancing the basolateral release of THP from medullary thick ascending limb cells. In patients with sepsis, changes in circulating THP were positively associated with a critical illness. THP was also found de novo in injured lungs. Genetic ablation of THP in mice led to increased mortality and bacterial burden during sepsis. Consistent with the increased bacterial burden, the presence of THP in vitro and in vivo led macrophages and monocytes to upregulate a transcriptional program promoting cell migration, phagocytosis, and chemotaxis, and treatment of macrophages with purified THP increases phagocytosis. Rescue of septic THP-/- mice with exogenous systemic THP improved survival. Together, these findings suggest that through releasing THP, the kidney modulates the immune response in sepsis by enhancing mononuclear phagocyte function, and systemic THP has therapeutic potential in sepsis.NEW & NOTEWORTHY Specific therapies to improve outcomes in sepsis with kidney injury have been limited by an unclear understanding of how kidney injury increases sepsis mortality. Here, we identified Tamm-Horsfall protein, known to protect in ischemic acute kidney injury, as protective in preclinical sepsis models. Tamm-Horsfall protein also increased in clinical sepsis without severe kidney injury and concentrated in injured organs. Further study could lead to novel sepsis therapeutics.
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Injúria Renal Aguda , Sepse , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/prevenção & controle , Animais , Modelos Animais de Doenças , Rim/metabolismo , Sepse/complicações , Sepse/metabolismo , Uromodulina/genética , Uromodulina/metabolismoRESUMO
Rational selection of metal ions and organic ligands to synthesize metal-organic complexes (MOCs) is necessary for constructing multifunctional materials. Herein, we have obtained a novel heterotrimetallic Zn2Dy2Ir pentanuclear MOC by the assembly of DyIII, luminescent ZnII(valpn), and [IrIII(H2L)(ppy)2]Cl metalloligands (Hppy = 2-phenylpyridine, H2L = 2,2'-bipyridine-5,5'-di-p-benzoic acid). Single-crystal structural analysis shows that the central [IrIII(L)(ppy)2]- bridges two ZnDy moieties using two carboxylates of L2-. Measurements of organic light-emitting diodes (OLEDs) show that the maximum luminance is 284.2 cd/m2 and the turn-on voltage is 6 V. Magnetic studies reveal that Zn2Dy2Ir is a field-induced single-molecule magnet (SMM) with an energy barrier of 19.1(2) K under a 2 kOe dc field. Zn2Dy2Ir shows luminescence sensing with a quenching efficiency of up to 99.0% for 2,4,6-trinitrophenol (TNP).
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Integrating magnetic and optical properties into a metal-organic framework (MOF) remains a great challenge. Herein, we have reasonably constructed two 3D magnetooptical MOFs by incorporating a [IrIII(ppy)2(bpy)]+-based fluorescent metalloligand and magnetic LnIII centers. The alternating arrangements of Δ- or Λ-[IrIII(ppy)2(bpy)]+ endow these MOFs with enhanced optical properties. Moreover, the use of DyIII leads to field-induced slow magnetic relaxation. This work provides an effective strategy for the preparation of magnetooptical bifunctional MOFs.
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Telomerase is a promising diagnostic and prognostic biomarker for cancers. Sensitive, simple, and reliable telomerase activity detection is vital for cancer diagnosis. Herein, we developed an ultrasensitive visualized assay for telomerase activity that combined the exponential amplification reaction (EXPAR) and lateral flow assay for easy and quick signal readout, which we termed as a lateral flow readout-EXPAR (LFR-EXPAR) assay. In the LFR-EXPAR assay, telomerase elongation products initiate the exponential amplification reaction, the generated trigger hybridizes with the reporter to form the recognition site of the nicking enzyme, and the nicking enzyme cuts the reporter strand. The degradation of the reporter can be detected with a universal lateral flow dipstick and read out with the naked eye. After conducting a series of proof-of-concept investigations, the LFR-EXPAR assay was found to achieve a sensitivity comparable to that of a TRAP (telomere repeat amplification protocol) assay. The LFR-EXPAR assay can be used to realize ultrasensitive and point-of-care detection of telomerase without requiring specialized instruments, holding great promise for early cancer diagnosis.
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Neoplasias , Telomerase , Humanos , Neoplasias/diagnóstico , Técnicas de Amplificação de Ácido Nucleico/métodos , Sistemas Automatizados de Assistência Junto ao Leito , TelômeroRESUMO
Diabetic kidney disease (DKD) is one of the microvascular complications of diabetes mellitus and a major cause of end-stage renal disease with limited treatment options. Wogonin is a flavonoid derived from the root of Scutellaria baicalensis Georgi, which has shown a potent renoprotective effect. But the mechanisms of action in DKD are not fully elucidated. In this study, we investigated the effects of wogonin on glomerular podocytes in DKD using mouse podocyte clone 5 (MPC5) cells and diabetic mice model. MPC5 cells were treated with high glucose (30 mM). We showed that wogonin (4, 8, 16 µM) dose-dependently alleviated high glucose (HG)-induced MPC5 cell damage, accompanied by increased expression of WT-1, nephrin, and podocin proteins, and decreased expression of TNF-α, MCP-1, IL-1ß as well as phosphorylated p65. Furthermore, wogonin treatment significantly inhibited HG-induced apoptosis in MPC5 cells. Wogonin reversed HG-suppressed autophagy in MPC5 cells, evidenced by increased ATG7, LC3-II, and Beclin-1 protein, and decreased p62 protein. We demonstrated that wogonin directly bound to Bcl-2 in MPC5 cells. In HG-treated MPC5 cells, knockdown of Bcl-2 abolished the beneficial effects of wogonin, whereas overexpression of Bcl-2 mimicked the protective effects of wogonin. Interestingly, we found that the expression of Bcl-2 was significantly decreased in biopsy renal tissue of diabetic nephropathy patients. In vivo experiments were conducted in STZ-induced diabetic mice, which were administered wogonin (10, 20, 40 mg · kg-1 · d-1, i.g.) every other day for 12 weeks. We showed that wogonin administration significantly alleviated albuminuria, histopathological lesions, and p65 NF-κB-mediated renal inflammatory response. Wogonin administration dose-dependently inhibited podocyte apoptosis and promoted podocyte autophagy in STZ-induced diabetic mice. This study for the first time demonstrates a novel action of wogonin in mitigating glomerulopathy and podocytes injury by regulating Bcl-2-mediated crosstalk between autophagy and apoptosis. Wogonin may be a potential therapeutic drug against DKD.
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Nefropatias Diabéticas/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Flavanonas/farmacologia , Glomérulos Renais/efeitos dos fármacos , Podócitos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/administração & dosagem , Flavanonas/administração & dosagem , Injeções Intraperitoneais , Glomérulos Renais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Podócitos/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Relação Estrutura-AtividadeRESUMO
Rationale: Cross-sectional human data suggest that enrichment of oral anaerobic bacteria in the lung is associated with an increased T-helper cell type 17 (Th17) inflammatory phenotype.Objectives: In this study, we evaluated the microbial and host immune-response dynamics after aspiration with oral commensals using a preclinical mouse model.Methods: Aspiration with a mixture of human oral commensals (MOC; Prevotella melaninogenica, Veillonella parvula, and Streptococcus mitis) was modeled in mice followed by variable time of killing. The genetic backgrounds of mice included wild-type, MyD88-knockout, and STAT3C backgrounds.Measurements and Main Results: 16S-rRNA gene sequencing characterized changes in microbiota. Flow cytometry, cytokine measurement via Luminex and RNA host-transcriptome sequencing was used to characterize the host immune phenotype. Although MOC aspiration correlated with lower-airway dysbiosis that resolved within 5 days, it induced an extended inflammatory response associated with IL-17-producing T cells lasting at least 14 days. MyD88 expression was required for the IL-17 response to MOC aspiration, but not for T-cell activation or IFN-γ expression. MOC aspiration before a respiratory challenge with S. pneumoniae led to a decrease in hosts' susceptibility to this pathogen.Conclusions: Thus, in otherwise healthy mice, a single aspiration event with oral commensals is rapidly cleared from the lower airways but induces a prolonged Th17 response that secondarily decreases susceptibility to S. pneumoniae. Translationally, these data implicate an immunoprotective role of episodic microaspiration of oral microbes in the regulation of the lung immune phenotype and mitigation of host susceptibility to infection with lower-airway pathogens.
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Infecções Pneumocócicas/prevenção & controle , Streptococcus pneumoniae , Células Th17/fisiologia , Animais , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Fator 88 de Diferenciação Mieloide/fisiologia , Infecções Pneumocócicas/etiologia , Prevotella melaninogenica , Streptococcus mitis , VeillonellaRESUMO
Electronic-cigarettes (E-cigs) are marketed as a safe alternative to tobacco to deliver the stimulant nicotine, and their use is gaining in popularity, particularly among the younger population. We recently showed that mice exposed to short-term (12 wk) E-cig smoke (ECS) sustained extensive DNA damage in lungs, heart, and bladder mucosa and diminished DNA repair in lungs. Nicotine and its nitrosation product, nicotine-derived nitrosamine ketone, cause the same deleterious effects in human lung epithelial and bladder urothelial cells. These findings raise the possibility that ECS is a lung and bladder carcinogen in addition to nicotine. Given the fact that E-cig use has become popular in the past decade, epidemiological data on the relationship between ECS and human cancer may not be known for a decade to come. In this study, the carcinogenicity of ECS was tested in mice. We found that mice exposed to ECS for 54 wk developed lung adenocarcinomas (9 of 40 mice, 22.5%) and bladder urothelial hyperplasia (23 of 40 mice, 57.5%). These lesions were extremely rare in mice exposed to vehicle control or filtered air. Current observations that ECS induces lung adenocarcinomas and bladder urothelial hyperplasia, combined with our previous findings that ECS induces DNA damage in the lungs and bladder and inhibits DNA repair in lung tissues, implicate ECS as a lung and potential bladder carcinogen in mice. While it is well established that tobacco smoke poses a huge threat to human health, whether ECS poses any threat to humans is not yet known and warrants careful investigation.
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Adenocarcinoma de Pulmão/induzido quimicamente , Sistemas Eletrônicos de Liberação de Nicotina , Hiperplasia/induzido quimicamente , Neoplasias Pulmonares/induzido quimicamente , Fumaça/efeitos adversos , Fumar/efeitos adversos , Adenocarcinoma de Pulmão/patologia , Animais , Dano ao DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Hiperplasia/patologia , Pulmão/patologia , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Nicotina/administração & dosagem , Bexiga Urinária/patologia , Urotélio/patologiaRESUMO
Increased agricultural surface runoff in rural watersheds is a leading cause of nonpoint source pollution. In this study, a new biomass concentrator reactor (BCR) is conducted to degrade simulated agricultural surface runoff for both start-up process and treatment process. The results show that both in the start-up phase and in the stable phase, BCR had a good degradation effect on simulated agricultural surface runoff. Within 13 days-15 days of completed start-up of BCR, degradation of COD can be considered to the first-order kinetics: lnCt=lnC0-0.1377t (R2 = 0.78). During the stabilization phase, the average removal rate of COD, NH4+-N, NO3--N, TN and TP from the effluents through the BCR membrane was 94.58%, 85.79%, 53.58%, 37.87%, and 60.62%, respectively, which was increased by 7.4%, 2.5%, 5.1%, 0.18% and 11.4%, respectively, compared to control experiment which the effluents without membrane. The pollutants degradation by BCR in stable phase show a partly relative model of Lawrence-McCarty equation, which the nitrogen and phosphorus degradation is vN=(4.1+S)/(2.53×S) (R2 = 0.69) and vP=(8.78+S)/(3.0×S) (R2 = 0.67), respectively. In the stable phase, the operation cost of BCR is about $0.08/(Lâ¢d). Future research on improved BCR maybe focus on the membrane pollution and cleaning, optimized operation conditions, new materials of membrane.
Assuntos
Movimentos da Água , Poluentes Químicos da Água , Biomassa , Monitoramento Ambiental , Nitrogênio/análise , Fósforo/análise , Poluentes Químicos da Água/análise , Poluição da ÁguaRESUMO
Treatment of PtMe3I in tetrahydrofuran with either in situ prepared [R-PNP]Li ([R-PNP]- = [(R2P-o-C6H4)2N]-; R = Ph, iPr) or H[R-PNP] in the presence of triethylamine at room temperature affords quantitatively fac-[R-PNP]PtMe3. Thermolysis of fac-[R-PNP]PtMe3 in benzene solutions generates mer-[R-PNP]PtMe3 and ultimately [R-PNP]PtMe and ethane. Complexes mer-[R-PNP]PtMe3 represent the first meridional trialkylplatinum(IV) derivatives to date.
RESUMO
Incorporating heterometal and chromogenic groups into the titanium oxo cluster (TOC) nanomaterials is one of the effective strategies for the development of new high-performance photoelectrically active materials. In this Article, we report the structures and photoelectrochemical (PEC) performances of a family of TOCs, including pure [Ti12O8(OEt)16L8] ({Me-Ti12}) and six Cd-doped clusters formulated as [H4Cd2Ti10O8(OEt)16(L)8(H2O)2] ({Cd2Ti10}; L = salicylic acid and their derivatives). The six Cd-doped clusters are isostructural, containing the same {Cd2Ti10O8} core, but are protected by salicylic ligands modified with different functional groups. The compositions, structures, and solution stability of these clusters have been studied in detail by single-crystal X-ray diffraction and electrospray ionization mass spectrometry measurements. The embedding of heterometallic Cd(II) and chemical modification of organic protective shells can effectively regulate the PEC water oxidation activity of those clusters, with {F-Cd2Ti10} having the highest turnover number of 518.55 and the highest turnover frequency of 172.85 h-1. Our work highlights the potential of using TOCs that do not contain noble metals as water oxidation catalysts, and their catalytic activity can be regulated by structural modification.