ABSTRACT
Obesity has shown a global epidemic trend. The high-lipid state caused by obesity can maintain the heart in a prolonged low-grade inflammatory state and cause ventricular remodeling, leading to a series of pathologies, such as hypertrophy, fibrosis, and apoptosis, which eventually develop into obese cardiomyopathy. Therefore, prolonged low-grade inflammation plays a crucial role in the progression of obese cardiomyopathy, making inflammation regulation an essential strategy for treating this disease. Cyy-272, an indazole derivative, is an anti-inflammatory compound independently synthesized by our laboratory. Our previous studies revealed that Cyy-272 can exert anti-inflammatory effects by inhibiting the phosphorylation and activation of C-Jun N-terminal kinase (JNK), thereby alleviating lipopolysaccharide (LPS)-induced acute lung injury (ALI). The current study aimed to evaluate the potential of Cyy-272 to mitigate the occurrence and progression of obese cardiomyopathy through the inhibition of the JNK signaling pathway. Our results indicate that the compound Cyy-272 has encouraging therapeutic effects on obesity-induced cardiac injury. It significantly inhibits inflammation in cardiomyocytes and heart tissues induced by high lipid concentrations, further alleviating the resulting hypertrophy, fibrosis, and apoptosis. Mechanistically, the protective effect of Cyy-272 on obese cardiomyopathy can be attributed to its direct inhibition of JNK protein phosphorylation. In conclusion, we identified a novel compound, Cyy-272, capable of alleviating obese cardiomyopathy and confirmed that its effect is achieved through direct inhibition of JNK.
ABSTRACT
BACKGROUND: Sulfotransferase family 2B member 1 (SULT2B1) has been reported to play oncogenic role in many types of cancers. Nevertheless, the role that SULT2B1 played in ovarian cancer (OC) and the hidden molecular mechanism is obscure. METHODS: Expression of SULT2B1 in OC was analyzed by GEPIA database. qRT-PCR and western blot (WB) was applied for the appraisement of SULT2B1 and Annexin A9 (ANXA9) in OC cell lines. The capabilities of cells to proliferate, migrate and invade were assessed with CCK-8 assay, wound healing assay, along with transwell assay. Cell apoptotic level was estimated utilizing flow cytometry. WB was employed for the evaluation of migration- and apoptosis-related proteins. Bioinformatic analysis and co-immunoprecipitation were used to predict and verify the combination of SULT2B1 and ANXA9. RESULTS: The data showed that SULT2B1 and ANXA9 were upregulated in OC cells. SULT2B1 depletion suppressed the proliferative, migrative, and invasive capabilities of SKOV3 cells but facilitated the cell apoptosis. SULT2B1-regulated ANXA9 expression and were proved to bind to ANXA9. Additionally, ANXA9 deficiency exhibited the same impacts on cell migrative, invasive capability and apoptotic level as SULT2B1 silencing. Moreover, ANXA9 overexpression reversed the inhibitory impacts of SULT2B1 silencing on the proliferative, migrative, invasive, and apoptotic capabilities of SKOV3 cells. CONCLUSION: In summary, SULT2B1 silencing repressed OC progression by targeting ANXA9.
Subject(s)
Apoptosis , Cell Movement , Ovarian Neoplasms , Sulfotransferases , Humans , Female , Sulfotransferases/metabolism , Sulfotransferases/genetics , Ovarian Neoplasms/metabolism , Ovarian Neoplasms/genetics , Ovarian Neoplasms/pathology , Cell Line, Tumor , Neoplasm Invasiveness , Gene Knockdown Techniques , Annexins/metabolismABSTRACT
ABSTRACT: Chronic kidney disease (CKD) is a significant global health threat that imposes a substantial burden on both individuals and societies. CKD frequently correlates with cardiovascular events, particularly left ventricular hypertrophy (LVH), which contributes to the high mortality rate associated with CKD. Fibroblast growth factor 23 (FGF23), a hormone primarily involved in regulating calcium and phosphorus metabolism, has been identified as a major risk factor for LVH in CKD patients. Elevated serum FGF23 levels are known to induce LVH and myocardial fibrosis by activating the fibroblast growth factor receptor 4 (FGFR4) signal pathway. Therefore, targeting FGFR4 and its downstream signaling pathways holds potential as a treatment strategy for cardiac dysfunction in CKD. In our current study, we have discovered that Hypericin, a key component derived from Hypericum perforatum , has the ability to alleviate CKD-related LVH by targeting the FGFR4/phospholipase C gamma 1 (PLCγ1) signaling pathway. Through in vitro experiments using rat cardiac myocyte H9c2 cells, we observed that Hypericin effectively inhibits FGF23-induced hypertrophy and fibrosis by suppressing the FGFR4/PLCγ1/calcineurin/nuclear factor of activated T-cell (NFAT3) signaling pathway. In addition, our in vivo studies using mice on a high-phosphate diet and rat models of 5/6 nephrectomy demonstrated that Hypericin has therapeutic effects against CKD-induced LVH by modulating the FGFR4/PLCγ1/calcineurin/NFAT3 signaling pathway. In conclusion, our research highlights the potential of Hypericin as a candidate for the treatment of CKD-induced cardiomyopathy. By suppressing the FGFR4/PLCγ1 signaling pathway, Hypericin shows promise in attenuating LVH and myocardial fibrosis associated with CKD.
Subject(s)
Anthracenes , Disease Models, Animal , Fibroblast Growth Factor-23 , Fibroblast Growth Factors , Fibrosis , Hypertrophy, Left Ventricular , Mice, Inbred C57BL , Myocytes, Cardiac , Perylene , Receptor, Fibroblast Growth Factor, Type 4 , Renal Insufficiency, Chronic , Signal Transduction , Animals , Perylene/analogs & derivatives , Perylene/pharmacology , Signal Transduction/drug effects , Fibroblast Growth Factors/metabolism , Renal Insufficiency, Chronic/metabolism , Renal Insufficiency, Chronic/drug therapy , Receptor, Fibroblast Growth Factor, Type 4/metabolism , Hypertrophy, Left Ventricular/physiopathology , Hypertrophy, Left Ventricular/metabolism , Hypertrophy, Left Ventricular/prevention & control , Hypertrophy, Left Ventricular/pathology , Hypertrophy, Left Ventricular/drug therapy , Rats , Male , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , Cell Line , Anthracenes/pharmacology , Ventricular Function, Left/drug effects , Ventricular Remodeling/drug effects , Phospholipase C gamma/metabolism , NFATC Transcription Factors/metabolism , MiceABSTRACT
The inhomogeneous refractive indices of biological tissues blur and distort single-molecule emission patterns generating image artifacts and decreasing the achievable resolution of single-molecule localization microscopy (SMLM). Conventional sensorless adaptive optics methods rely on iterative mirror changes and image-quality metrics. However, these metrics result in inconsistent metric responses and thus fundamentally limit their efficacy for aberration correction in tissues. To bypass iterative trial-then-evaluate processes, we developed deep learning-driven adaptive optics for SMLM to allow direct inference of wavefront distortion and near real-time compensation. Our trained deep neural network monitors the individual emission patterns from single-molecule experiments, infers their shared wavefront distortion, feeds the estimates through a dynamic filter and drives a deformable mirror to compensate sample-induced aberrations. We demonstrated that our method simultaneously estimates and compensates 28 wavefront deformation shapes and improves the resolution and fidelity of three-dimensional SMLM through >130-µm-thick brain tissue specimens.
Subject(s)
Deep Learning , Microscopy , Optics and Photonics , BrainABSTRACT
The capability to image the 3D distribution of melanin in human skin in vivo with absolute quantities and microscopic details will not only enable noninvasive histopathological diagnosis of melanin-related cutaneous disorders, but also make long term treatment assessment possible. In this paper, we demonstrate clinical in vivo imaging of the melanin distribution in human skin with absolute quantities on mass density and with microscopic details by using label-free third-harmonic-generation (THG) enhancement-ratio microscopy. As the dominant absorber in skin, melanin provides the strongest THG nonlinearity in human skin due to resonance enhancement. We show that the THG-enhancement-ratio (erTHG) parameter can be calibrated in vivo and can indicate the melanin mass density. With an unprecedented clinical imaging resolution, our study revealed erTHG-microscopy's unique capability for long-term treatment assessment and direct clinical observation of melanin's micro-distribution to shed light into the unknown pathway and regulation mechanism of melanosome transfer and translocation.
ABSTRACT
BACKGROUND: Extracellular matrix (ECM) secretion and osteogenic differentiation in periodontal ligament fibroblasts (PDLF) facilitate the neogenesis of alveolar bone, which is the cellular basis for alveolar bone repair. Calcitonin (CT) has been reported to play an important role in promoting ECM expression and inducing osteogenic differentiation in osteoblast, but its effects on PDLFs remain obscure. METHODS: The expression of CT, transforming growth factor-beta 1(TGF-ß1) and bone morphogenetic protein (BMP) in gingival crevicular fluid (GCF) was measured by ELISA. The effects of CT on collagen synthesis and osteogenic differentiation in hPDLFs were investigated by using the primarily cultured hPDLFs infected with adenovirus carrying the CT gene. Gene expression was measured by quantitative PCR and western blot. RESULTS: The expression of CT in gingival crevicular fluid (GCF) of patients with periodontitis was significantly higher than that of healthy subjects. In addition, CT expression correlated with the clinical indexes including probing pocket depth (PPD), clinical attachment level (CAL), and gingival index (GI). The in vitro study demonstrated that overexpression of CT by adenovirus infection increased the expression of TGF-ß1, collagen type I and III, and osteoblastic markers including BMP-2/-4, alkaline phosphatase and osteocalcin in human PDLFs. Moreover, CT-enhanced collagen synthesis was abrogated in hPDLFs transfected with TGF-ß1 siRNA, and CT-induced osteoblastic differentiation was blocked in hPDLFs by BMPs inhibitor noggin. CONCLUSIONS: These results suggest that CT promotes collagen synthesis and osteogenic differentiation in hPDLFs via the TGF-ß1 and BMPs signaling pathways, respectively.
Subject(s)
Calcitonin/pharmacology , Cell Differentiation/drug effects , Collagen/biosynthesis , Collagen/drug effects , Fibroblasts/drug effects , Periodontal Ligament/drug effects , Adenoviridae/genetics , Alkaline Phosphatase/metabolism , Bone Morphogenetic Protein 2/metabolism , Bone Morphogenetic Protein 4/metabolism , Bone Morphogenetic Protein 7/metabolism , Bone Morphogenetic Proteins/metabolism , Calcitonin/biosynthesis , Calcitonin/genetics , Cell Culture Techniques , China , Collagen Type I/metabolism , Collagen Type III/metabolism , Disease Progression , Extracellular Matrix/metabolism , Female , Fibroblasts/metabolism , Gene Expression , Gingival Crevicular Fluid/metabolism , Humans , Male , Middle Aged , Osteoblasts/drug effects , Osteocalcin/metabolism , Osteogenesis/drug effects , Periodontal Attachment Loss , Periodontal Index , Periodontal Ligament/metabolism , Periodontal Pocket , Periodontitis/metabolism , Recombinant Proteins , Transforming Growth Factor beta1/metabolism , Up-RegulationABSTRACT
We have conducted a pilot clinical study to not only investigate the sub-THz spectra of ex-vivo fresh human whole blood of 28 patients following 8-hours fasting guideline, but also to find out the critical blood ingredients of which the concentration dominantly affects those sub-THz spectra. A great difference between the sub-THz absorption properties of human blood among different people was observed, while the difference can be up to ~15% of the averaged absorption coefficient of the 28 samples. Our pilot clinical study indicates that triglycerides and the number of red blood cells were two dominant factors to have significant negative correlation to the sub-THz absorption coefficients.
ABSTRACT
OBJECTIVE: To investigate admission patterns of patients with gynecologic cancers over a ten year period, which will provide a basis for further epidemiological studies. METHODS: We reviewed medical records of patients with gynecologic cancers who were admitt d to the West China Second University Hospital of Sichuan University from 2003 to 2012. Their clinicopathological data were extracted and analysed. RESULTS: The number of admitted patients increased over the years, with cervical, uterine and ovary cancers as the top three gynaecological cancers. They accounted for 92.13% of total gynaecological cancers. The peak age of gynaecological cancers was 40-49 years, which accounted for 34.02% (3132/9207) of all patients, followed by 50-59 years (26.64%, 2453/9207). Most (72.46%, 3062/4226) cervical cancer patients aged 30-49 years, compared with 40-59 years for uterine cancers (69.77%, 1768/2534) and 40-59 years for ovarian cancers (58.30%, 1004/1722). Patients in their 20th account for 4.43% (408/9 207) of total cancers, with in which cervical and ovarian cancers as the most common pathological type. Patients under 20 years of age accounted for only 0.98% (90/9207) of total cancers, with ovarian cancers as the most common pathological type. Patients over 60 years accounted for 12.90% (1188/9207) of total cancers, with uterine and ovarian cancers as the most common pathological type. Most patients were at an early stage of cancers when they were admitted to the hospital. CONCLUSION: Hospitalized patients with gynecologic cancers increase over years. Cervical, uterine and ovary cancers remain to be a focus of treatment. Peak age of those cancers varies.
Subject(s)
Genital Neoplasms, Female/epidemiology , Ovarian Neoplasms/epidemiology , Uterine Cervical Neoplasms/epidemiology , Adult , China/epidemiology , Female , Hospitalization/statistics & numerical data , Humans , Middle Aged , Retrospective StudiesABSTRACT
Preterm premature rupture of the membranes (PPROM) remains the leading cause of preterm deliveries and neonatal mortality and morbidity. The current cohort study sought to retrospectively examine perinatal outcomes in cases of PPROM < 34 weeks' gestation that were managed conservatively from 2010 to 2012 and to identify risk factors for short-term neonatal outcomes. Subjects were 510 pregnancies consisting of 114 twin and 396 singleton pregnancies. Clinical chorioamnionitis occurred in 17.8% of the pregnancies. Neonatal mortality was 7.4%, the rate of major neonatal conditions was 40%, and the rate of NICU admission was 72.9%. The latency period exceeded 48 h in 62.5% of the pregnancies and 7 days in 24.3% of the pregnancies. Twin pregnancies had a shorter latency period than singleton pregnancies (median of 2 days versus 4 days, p < 0.001). Pregnancies complicated with early vaginal bleeding had a higher neonatal mortality (13.95% vs. 6.36%, p = 0.013) and morbidity (51.16% vs. 38.32%, p = 0.024), fewer weeks of gestation at PPROM (p = 0.029). Multivariate logistic regression analysis revealed that weeks of gestation at PPROM (OR: 0.953, 95% CI: 0.939-0.966, p < 0.001) and a latency period (OR: 0.948, 95%CI: 0.926-0.970, p < 0.001) were associated with neonatal mortality or morbidity. A twin pregnancy (OR: 0.319, 95% CI: 0.17-0.6, p < 0.001) and weeks of gestation at PPROM (OR: 0.737, 95% CI: 0.66-0.822, p < 0.001) were associated with the latency period. Gestational age at PPROM, a twin pregnancy, and the latency period are associated with neonatal mortality and morbidity.