Effects of naringenin on the pharmacokinetics of tofacitinib in rats.

Context: Naringenin and tofacitinib are often used together for treatment of rheumatoid arthritis in Chinese clinics.Objective: This experiment investigates the effect of naringenin on the pharmacokinetics of tofacitinib in rats.Materials and methods: Twelve Sprague-Dawley rats were randomly divided into two groups (experimental group and control group). The experimental group was pre-treated with naringenin (150 mg/kg/day) for two weeks before dosing tofacitinib, and equal amounts of CMC-Na solution in the control group. After a single oral administration of 5 mg/kg of tofacitinib, 50 µL blood samples were directly collected into 1.5 mL heparinized tubes via the caudal vein at 0.083, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 h. The plasma concentration of tofacitinib was quantified by UPLC/MS-MS.Results: Results indicated that naringenin could significantly affect the pharmacokinetics of tofacitinib. The AUC0-24 of tofacitinib was increased from 1222.81 ± 222.07 to 2016.27 ± 481.62 ng/mL/h, and the difference was significant (p < 0.05). Compared with the control group, the Tmax was increased from 0.75 ± 0.29 to 3.00 ± 0.00 h (p < 0.05), and the MRT(0-24) was increased from 4.90 ± 0.51 to 6.57 ± 0.66 h (p < 0.05), but the clearance was obviously decreased from 4.10 ± 0.72 to 2.42 ± 0.70 L/h/kg (p < 0.05) in experimental group. Although the Cmax and t1/2 of tofacitinib were increased, there were no significant differences (p > 0.05).Conclusions: This research demonstrated a drug-drug interaction between naringenin and tofacitinib possibly when preadministered with naringenin; thus, we should pay attention to this possibility in the clinic.

Hybrid Structure Multichannel All-Fiber Current Sensor.

We have experimentally developed a hybrid-structure multi-channel all-fiber current sensor with ordinary silica fiber using fiber loop architecture. According to the rationale of time division multiplexing, the sensor combines parallel and serial structures. The purpose of the hybrid-structure multi-channel all-fiber current sensor is to get more information from the different measured points simultaneously. In addition, the hybrid-structure fiber current sensor exhibited a good linear response for each channel. A three-channel experiment was performed in the study and showed that the system could detect different current positions. Each channel could individually detect the current and needed a separate calibration system. Furthermore, the three channels will not affect each other.

Identification of a novel lncRNA prognostic signature and analysis of functional lncRNA AC115619.1 in hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) is the deadliest malignancy. Long non-coding RNAs (lncRNAs) are involved in the development of multiple human malignancies. This study aimed to establish a reliable signature and identify novel biomarkers for HCC patients. Methods: Differentially expressed lncRNAs (DElncRNAs) were identified from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Univariate, LASSO, and multivariate Cox regression analyses were applied to screen the prognostic lncRNAs and establish a prognostic model. Receiver operating characteristic (ROC) curves and Kaplan-Meier analyses were conducted to validate the prognostic value of this model. The association between lncRNAs and differential m6A genes was analyzed by Spearman's analysis. A series of bioinformatic and in vitro experiments were applied to explore the function of hub lncRNA. Results: A total of 32 DElncRNAs were identified, and 12 DElncRNAs were associated with the prognosis of HCC patients. A prognostic signature comprising six prognostic lncRNAs (LINC02428, LINC02163, AC008549.1, AC115619.1, CASC9, and LINC02362) was constructed, and the model exhibited an excellent capacity for prognosis prediction. Furthermore, 12 differential m6A regulators were identified, and RBMX was found to be correlated negatively with the hub lncRNA AC115619.1. The expression level of AC115619.1 was lower in HCC tissues than that in normal tissues and was significantly related to clinicopathologic features, survival rate, and drug sensitivity. Overexpression of AC115619.1 notably inhibited the proliferation, migration, and invasion of HCC cells. Conclusion: This study provided a promising prognostic signature for HCC patients and identified AC115619.1 as a novel biomarker, which plays an essential role in regulating the progression of HCC.

Polarization coherency matrix tomography.

In this paper, a polarization-sensitive optical coherence tomography (PS-OCT) based polarization coherency matrix tomography (PCMT) combining polarization coherency matrix with Mueller matrix is proposed for the determination of complete polarization properties of tissue. PCMT measures the Jones matrix of biological sample based on similar transformation, in which four elements have initial random phase from different polarization states based on traditional PS-OCT. The results indicate that PCMT can eliminate the phase difference of incident lights with different polarization states. In addition, the polarization coherency matrix using three polarization states has complete information of the sample Jones matrix. Finally, the 16 elements of the sample Mueller matrix are applied for deriving fully polarized optical properties of the sample based on the elliptical diattenuator and the elliptical retarder. Thus, the method based on the PCM and Mueller matrix has the advantage over the traditional PS-OCT.

Cuproptosis-associated genes and immune microenvironment characterization in breast cancer.

Excess Cu can cause cell death as a cofactor for essential enzymes. The relationship between cuproptosis-associated genes (CAGs) and breast cancer (BR) is not completely investigated. Here, the transcriptome expression and mutation profile data of BR samples from the Cancer Genome Atlas database were retrieved to identify CAGs. Patients with BR were clustered using consensus clustering. A least absolute shrinkage and selection operator analysis was then performed to construct a CAGs risk signature. As a result, all 13 cuproptosis regulators were significantly differentially expressed between BR and normal samples; among them, 9 cuproptosis genes were correlated with prognoses. Patients with BR were separated into 2 clusters that were associated with patient survival, clinical phenotypes, and immune infiltration, Based on the components of cuproptosis. Subsequently, genes differentially expressed between clusters were obtained, and 11 CAGs were ultimately incorporated into the risk signature. Functional analyses revealed that the risk signature correlated with patient outcomes, ER, PR, HER2 expression, and BR IHC subtypes. Additionally, immune microenvironment analyses showed that CAGs-high-risk patients exhibited lower immune cell infiltration and immune functions. Furthermore, high-risk BR patients had higher TMB, lower immune checkpoint expression, higher m6A gene expression, and higher tumor stemness. Finally, the immunophenoscore analysis revealed that the risk signature could potentially predict the immune response in BR and help guide the application of various immunotherapeutic drugs. Overall, the newly constructed CAGs risk signature presented a predictive value for the prognosis and tumor microenvironment of BR patients and can be further used in the guidance of immunotherapy for BR.

Influence of Hashimoto thyroiditis on diagnosis and treatment of thyroid nodules.

Background: As the prevalence of Hashimoto's thyroiditis (HT) and thyroid cancer (TC) has been increasing dramatically in recent years, the association between the two diseases has been widely debated and studied. However, no consistent findings are available and the relationship remains controversial. In this study, we analyzed the influence of HT on the diagnosis and treatment of thyroid nodules and investigated the relationship between HT and TC. Methods: From Jan 2017 to Apr 2021, 4678 patients underwent thyroid surgery were collected. Of these patients, 440 were diagnosed with HT (242 nodular goiter (NG) with HT, 198 TC with HT). These patients were grouped when appropriate and the data from these patients were statistically analyzed by using SPSS and GraphPad Prism 6. Results: HT occurred in 198 of 1089 (18.2%) TC patients and 242 of 3589 (6.74%) patients without TC (p=0.000). In terms of the ultrasonography features, in the NG with HT group, 33.1% (80/242) of patients had fine calcification and 45.9% (111/242) of patients whose TI-RADS classification were > Level 3. In the isolated PTC group, 32.3% (2343/7260) LN were metastasis-positive while in the NG with HT group, only 26.0% (504/1939) LN were metastasis-positive (P=0.000). The proportion of PTMC was significantly higher (P=0.000), while the proportion of multifocal carcinoma was significantly lower when coexisting with HT (P=0.029). When comparing the data from the two groups diagnosed as PTMC coexisting with HT or not, there was no significant difference in the composition ratio of tumor number, LN metastasis, LN dissection area, regional LN metastasis and number of negative/positive LN (P=0.614, P=0.051, P=0.139, P=0.350, P=1.000 and P=0.333 respectively). In the MPTC group, 42.2% (872/2065) LN were metastasis-positive while in the MPTC with HT group, only 23.6% (50/212) LN were metastasis-positive (P=0.000). Conclusions: Our data suggested that HT is associated with an increased risk of developing TC but may be a protective factor against PTC progression and metastasis. The coexistence of HT affects the judgment of thyroid nodules by ultrasonography.

Identification of an endoplasmic reticulum stress-associated gene signature to predict the immune status and prognosis of cutaneous melanoma.

Besides protecting normal cells from various internal and external perturbations, endoplasmic reticulum (ER) stress is also directly related to the pathogenesis of cutaneous melanoma (CM). However, due to the lack of specific molecular biomarkers, ER stress has not been considered a novel treatment target for CM. Here, we identified ER stress-related genes involved in the prognosis of CM patients and constructed an effective model for the prognostic prediction of these patients. First, gene expression data of CM and normal skin tissues from the Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) databases were retrieved to identify differentially expressed ER stress-related genes in CM. Meanwhile, an independent cohort obtained from the Gene Expression Omnibus (GEO) database was used for validation. The ER stress genes (ZBP1, DIABLO, GNLY, FASLG, AURKA, TNFRSF21, and CD40LG) that were associated with CM prognosis were incorporated into our prognostic model. The functional analyses indicated that the prognostic model was correlated with patient survival, gender, and cancer growth. Multivariate and univariate Cox regressions revealed that the constructed model could serve as an independent prognostic factor for CM patients. The pathway enrichment analysis showed that the risk model was enriched in different immunity and cancer progression-associated pathways. Moreover, the signature model was significantly connected with the immune subtypes, infiltration of immune cells, immune microenvironment, as well as tumor stem cells. The gene function analysis revealed that 7 ER stress genes were differentially expressed in CM patients and were significantly associated with prognosis and several antitumor drugs. Overall, our current model presented predictive value for the prognosis of CM patients and can be further used in the development of novel therapeutic strategies for CM.

Morphological characteristics of zebrafish's yolk sac for malformation based on orthogonal-polarization-gating optical coherence tomography.

In this study, an automatic algorithm combining an ellipsoid approximation and U-net has been presented for the characterization of a zebrafish's yolk sac. The polarization-difference-balanced-detection image of zebrafish was obtained based on orthogonal-polarization-gating optical coherence tomography and used to segment the yolk sac region. And ellipsoid can approximate the shape of the three-dimensional yolk sac, and the multiple parameters of volume and the three principal axes (k, l and m) can be used to quantify the yolk sac. In addition, the multiple parameters of two principal axes (l and m) and volume can distinguish the malformation from the normal controlled group. Finally, the volume malformation of the yolk sac calculated by the proposed algorithm ranges from 16.55% to 46.05%. Thus, the degree of malformation can be applied for toxicity analysis. And this method provides a potential application for an accurate judgment index for biotoxicological testing.

Micro-Raman Analysis of Sperm Cells on Glass Slide: Potential Label-Free Assessment of Sperm DNA toward Clinical Applications.

Routine assessment of sperm DNA integrity involves the time-consuming and complex process of staining sperm chromatin. Here, we report a Raman spectroscopy method combined with extended multiplicative signal correction (EMSC) for the extraction of characteristic fingerprints of DNA-intact and DNA-damaged sperm cells directly on glass slides. Raman results of sperm cell DNA integrity on glass substrates were validated one-to-one with clinical sperm cell staining. Although the overall Raman spectral pattern showed considerable similarity between DNA-damaged and DNA-intact sperm cells, differences in specific Raman spectral responses were observed. We then employed and compared multivariate statistical analysis based on principal component analysis-linear discriminant analysis (PCA-LDA) and partial least-squares-discriminant analysis (PLS-DA), and the classifications were validated by leave-one-out-cross-validation (LOOCV) and k-fold cross-validation methods. In comparison, the PLS-DA model showed relatively better results in terms of diagnostic sensitivity, specificity, and the classification rate between the sperm DNA damaged group and the DNA intact group. Our results demonstrate the potential of Raman based label-free DNA assessment of sperm cell on glass substrates as a simple method toward clinical applications.

Orthogonal-polarization-gating optical coherence tomography for human sweat ducts in vivo.

We propose an orthogonal-polarization-gating optical coherence tomography (OPG-OCT) for human sweat ducts in vivo. OPG-OCT is composed of the orthogonal linearly polarized light of a sample arm individually interfering with orthogonal linearly polarized lights of the reference arms, where OPG-OCT induces two images, one reflecting the projection intensity and the other the horizontal linear diattenuation (HLD). The results demonstrate that OPG-OCT projection intensity could improve the image quality of sweat ducts. HLD also clearly illustrates the spiral shape of the sweat ducts. Finally, sweat ducts in intensity image are segmented by employing convolutional neural networks (CNN). The proportions of left-handed and right-handed ducts are extracted to characterize the sweat ducts based on HLD. Therefore, the OPG-OCT technique employing CNN for the human sweat glands has the potential to automatically identify the human sweat ducts in vivo.

Label-free Raman spectroscopy: A potential tool for early diagnosis of diabetic keratopathy.

Diabetes has become a major public health problem worldwide, and the incidence of diabetes has been increasing progressively. Diabetes is prone to cause various complications, among which diabetic keratopathy (DK) emphasizes the significant impact on the cornea. The current diagnosis of DK lacks biochemical markers that can be used for early and non-invasive screening and detection. In contrast, in this study, Raman spectroscopy, which demonstrates non-destructive, label-free features, especially the unique advantage of providing molecular fingerprint information for target substances, were utilized to interrogate the intrinsic information of the corneal tissues from normal and diabetic mouse models, respectively. Visually, the Raman spectral response derived from the biochemical components and biochemical differences between the two groups were compared. Moreover, multivariate analysis methods such as principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) were carried out for advanced statistical analysis. PCA yields a diagnostic results of 57.4% sensitivity, 89.2% specificity, 74.8% accuracy between the diabetic group and control group; Moreover, PLS-DA was employed to enhance the diagnostic ability, showing 76.1% sensitivity, 86.1% specificity, and 87.6% accuracy between the diabetic group and control group. Our proof-of-concept results show the potential of Raman spectroscopy-based techniques to help explore the underlying pathogenesis of DK disease and thus be further expanded for potential applications in the early screening of diabetic diseases.

Dl-3-n-Butylphthalide Ameliorates Diabetic Nephropathy by Ameliorating Excessive Fibrosis and Podocyte Apoptosis.

Diabetic nephropathy (DN) is a common diabetes associated complication. Thus, it is important to understand the pathological mechanism of DN and find the appropriate therapeutic strategy for it. Dl-3-n-Butylphthalide (DL-NBP) has anti-inflammatory and antioxidant effects, and been widely used for the treatment of stroke and cardiovascular diseases. In this study, we selected three different doses (20, 60, and 120 mg⋅kg-1 d-1) of DL-NBP and attempted to elucidate its role and molecular mechanism underlying DN. We found that DL-NBP, especially at the dose of 60 or 120 mg⋅kg-1 d-1, could significantly ameliorate diabetes-induced elevated blood urea nitrogen (BUN) and creatinine level, and alleviate renal fibrosis. Additionally, the elevated expressions of collagen and α-smooth muscle actin (α-SMA) in the kidney from db/db mice were found to be significantly suppressed after DL-NBP treatment. Furthermore, mechanistic studies revealed that DL-NBP inhibits pro-inflammatory cytokine levels, thereby ameliorating the development of renal fibrosis. Moreover, we found that DL-NBP could not only reduce the endoplasmic reticulum stress (ERS), but also suppress activation of the renin-angiotensin system to inhibit vascular endothelial growth factor (VEGF) level, which subsequently reduces the podocyte apoptosis in kidney of db/db mice. In a word, our findings suggest that DL-NBP may be a potential therapeutic drug in the treatment of DN.

Rapid prediction of drug inhibition under heat stress: single-photon imaging combined with a convolutional neural network.

A method of predicting cellular drug inhibition due to heat stress is presented. Black phosphorus nanosheets are used as photothermal agents to induce stress granule formation in tumor cells. The addition of different drugs induces different thermal stress responses. The features of single-photon images are automatically extracted and analyzed by a convolutional neural network algorithm for classification and recognition, with a maximum accuracy rate of 94.52%. Unlike traditional visual discrimination, this method realizes intelligent recognition without human intervention, providing a new model for computer-aided diagnosis with greater objectivity.

A model of speckle contrast in optical coherence tomography for characterizing the scattering coefficient of homogenous tissues.

We present a theoretical model for analyzing the speckle contrast of optical coherence tomography (OCT). This model is based on the addition of noise and an OCT signal in the logarithmic scale. The theoretical model reveals that, for the superficial layer of homogenous tissue, the contrast ratio is a linear function of the location of the coherence gate in the sample and the slope of this linear dependence is proportional to the scattering coefficient. The theoretical model is consistent with the experimental results, suggesting that the slope can be useful to characterize the scattering coefficient of the homogenous samples.

Chemosensitizing indomethacin-conjugated dextran-based micelles for effective delivery of paclitaxel in resistant breast cancer therapy.

Multidrug resistance (MDR) against chemotherapeutic agents has become the major obstacle to successful cancer therapy and multidrug resistance-associated proteins (MRPs) mediated drug efflux is the key factor for MDR. Indomethacin (IND), one of the non-steroidal anti-inflammatory agents, has been demonstrated to increase cytotoxic effects of anti-tumor agents as MRP substrates. In this study, dextran-g-indomethacin (DEX-IND) polymeric micelles were designed to delivery paclitaxel (PTX) for the treatment of MDR tumors. The DEX-IND polymer could effectively encapsulate PTX with high loading content and DEX-IND/PTX micelles present a small size distribution. Compared with free PTX, the release of PTX from DEX-IND/PTX micelles could be prolonged to 48 h. Cellular uptake test showed that the internalization of DEX-IND/PTX micelles by drug-sensitive MCF-7/ADR cells was significantly higher than free PTX benefiting from the inhibitory effect of IND on MRPs. In vitro cytotoxicity test further demonstrated that DEX-IND/PTX micelles could enhance the cytotoxicity of PTX against MCF-7/ADR tumor cells. In vivo pharmacokinetic results showed that DEX-IND/PTX micelles had longer systemic circulation time and slower plasma elimination rate in comparison to PTX. The anti-tumor efficacy test showed that DEX-IND/PTX micelles exhibited greater tumor growth-inhibition effects on MDR tumor-bearing mice, with good correlation between in vitro and in vivo. Overall, the cumulative evidence indicates that DEX-IND/PTX micelles hold significant promise for the treatment of MDR tumors.