DNA Methylation of KLRC1 and KLRC3 in Autoimmune Thyroiditis: Perspective of Different Water Iodine Exposure.

Objective: This study aimed to identify differentially methylated genes (DMGs) associated with natural killer cells in patients with autoimmune thyroiditis (AIT), focusing on the influence of varying water iodine exposure levels. Methods: Participants were divided into categories based on median water iodine (MWI) concentrations: iodine-fortified areas (IFA, MWI < 10 µg/L), iodine-adequate areas (IAA, 40 ≤ MWI ≤ 100 µg/L), and iodine-excessive areas (IEA, MWI > 300 µg/L). A total of 176 matched AIT cases and controls were recruited and divided into 89, 40, and 47 pairs for IFA, IAA, and IEA, respectively. DMGs were identified using 850K BeadChip analysis for 10/10 paired samples. Validation of DNA methylation and mRNA expression levels of the DMGs was conducted using MethylTarget™ and QRT-PCR for 176/176 paired samples. Results: KLRC1, KLRC3, and SH2D1B were identified as significant DMGs. Validation revealed that KLRC1 was hypomethylated and highly expressed, whereas KLRC3 was hypermethylated and highly expressed in individuals with AIT. Furthermore, KLRC1 was hypomethylated and highly expressed in both IFA and IEA. Conclusion: The DNA methylation status of KLRC1 and KLRC3 may play crucial roles in AIT pathogenesis. Additionally, DNA methylation of KLRC1seems to be influenced by different iodine concentrations in water.

Hericium erinaceus ß-glucan/tannic acid hydrogels based on physical cross-linking and hydrogen bonding strategies for accelerating wound healing.

The majority of natural fungal ß-glucans exhibit diverse biological functionalities, such as immunomodulation and anti-inflammatory effects, attributed to their distinctive helix or highly branched conformation This study utilized ß-glucan with helix conformation and high-viscosity extracted from Hericium erinaceus, employing freeze-thaw and solvent exchange strategies to induce multiple hydrogen bonding between molecules, thereby initiating the self-assembly process of ß-glucan from random coil to stable helix conformation without chemical modifications. Subsequently, the natural bioactive compound tannic acid was introduced through physical entanglement, imparting exceptional antioxidant properties to the hydrogel. The HEBG/TA hydrogel exhibited injectable properties, appropriate mechanical characteristics, degradability, temperature-responsive tannic acid release, antioxidant activity, and hemostatic potential. In vivo experiments using skin full-thickness defect and deep second-degree burn wound models demonstrated significant therapeutic efficacy, including neovascularization, and tissue regeneration. Moreover, the HEBG/TA hydrogel demonstrated its ability to regulate cytokines by effectively inhibiting the production of inflammatory mediators (TNF-α, IL-6), while simultaneously enhancing the expression of cell proliferation factor KI-67 and markers associated with angiogenesis such as CD31 and α-SMA. This study highlights the potential of combining natural ß-glucan with bioactive molecules for skin repair.

Insights into dynamic evolution of glucuronofucogalactoglucan from water extract of Agrocybe cylindracea during maturation.

This study explored the physicochemical properties and structural characteristics of Agrocybe cylindracea polysaccharides at four developmental stages, as well as their dynamic evolution during maturation. Results showed that the polysaccharides from A. cylindracea water extract exhibited similar structural characteristics across all four maturity stages, despite a significant reduction in yields. Four water-soluble heteroglycans, including one high molecular weight (ACPM-Et50-I) and three low molecular weight (ACPM-Et50-II, ACPM-Et60, ACPM-Et80), were isolated from A. cylindracea at each maturity stage. ACPM-Et50-I was identified as branched heterogalactans, while ACPM-Et60 and ACPM-Et80 were branched heteroglucans. However, ACPM-Et50-II was characterized as a branched glucuronofucogalactoglucan at the tide-turning stage but a glucuronofucoglucogalactan at the pileus expansion stage due to the increase of its α-(1 â†’ 6)-D-Galp. In general, although the structural skeletons of most A. cylindracea heteroglycans were similar during maturation as shown by their highly consistent glycosyl linkages, there were still differences in the distribution of some heteroglucans. This work has for the first time reported a glucuronofucogalactoglucan in A. cylindracea and its dynamic evolution during maturation, which may facilitate the potential application of A. cylindracea in food and biomedicine industries.

Changes of the Physicochemical Properties and Structural Characteristics of Alkali-Extracted Polysaccharides from Agrocybe cylindracea Across the Growth Process.

Polysaccharides derived from Agrocybe cylindracea have been demonstrated to exhibit various bioactivities. However, studies on their structural characteristics during the growth process are limited. This study aimed to compare the physicochemical properties and structural characteristics of alkali-extracted polysaccharides from A. cylindracea fruiting bodies (JACP) across four growth stages. Results showed that the extraction yields and protein levels of JACP declined along with the growth of A. cylindracea, while the contents of neutral sugar and glucose increased significantly. However, JACP exhibited structural characteristics similar to those across the four stages. Four polysaccharide subfractions were isolated from each growth stage, including JACP-Et30, JACP-Et50, JACP-Et60, and JACP-Et70. JACP-Et30 from the four stages and JACP-Et50 from the initial three stages were identified as heteroglucans with ß-1,3-d-Glcp and ß-1,6-d-Glcp residues as main chains, respectively. However, other subfractions were considered as ß-1,6-d-glucans containing minor glucuronic acid. These subfractions were predominantly replaced by Glcp residues at the O-3 and O-6 positions. Overall, while JACP exhibited variable physicochemical properties, its structural characteristics remained stable during the growth process, offering new insights into its potential applications in the food and medicinal industries.

Dynamics of α-glucan from Agrocybe cylindracea water extract at different developmental stages and its structure characteristics.

Polysaccharides are the important bioactive macromolecules in Agrocybe cylindracea, but their changes are as yet elusive during developmental process. This study investigated the dynamic changes of polysaccharides from A. cylindracea fruiting body water extract at four developmental stages and its structure characteristics. Results revealed that the polysaccharides from A. cylindracea water extract significantly increased at the pileus expansion stage and the increased fraction could be α-glucan. The further purification and identification indicated that this α-glucan was a glycogen. It had typical morphology of ß particles with a molecular weight of 1375 kDa. Its backbone comprised α-D-(1 â†’ 4)-Glcp and α-D-(1 â†’ 4,6)-Glcp residues at a ratio of 5:1, terminated by α-D-Glcp residue. Rheological behavior suggested that it was a Newtonian fluid at the concentration of 1 %. In addition, despite both the glycogen and natural starch were composed of D-glucose, they exhibited the entirely distinct Maltese cross characteristic and unique crystalline structure. This study is the first to demonstrate the presence of abundant glycogen in the pileus expansion stage of A. cylindracea, which provides new insights on the change patterns of fungal polysaccharides.

Recent advances in the biosynthesis of fungal glucan structural diversity.

Glucans are the most abundant class of macromolecule polymers in fungi, which are commonly found in Ascomycota and Basidiomycota. Fungal glucans are not only essential for cell integrity and function but also crucial for the immense industrial interest in high value applications. They present a variety of structural characteristics at the nanoscale due to the high regulation of genes and the involvement of stochastic processes in synthesis. However, although recent findings have demonstrated the genes of glucans synthesis are relatively conserved across diverse fungi, the formation and organization of diverse glucan structures is still unclear in fungi. Here, we summarize the structural features of fungal glucans and the recent developments in the mechanisms of glucans biosynthesis. Furthermore, we propose the engineering strategies of targeted glucan synthesis and point out the remaining challenges in the synthetic process. Understanding the synthesis process of diverse glucans is necessary for tailoring high value glucan towards specific applications. This engineering strategy contributes to enable the sustainable and efficient production of glucan diversity.

The BRAFV600E mutation maintains the aggressiveness of papillary thyroid cancers requiring downregulation of primary cilia.

Although disorders of primary cilia (PCs) were first reported in human papillary thyroid cancer (PTC) tissues in 1987, their precise role in PTC remains unclear. PCs sense the thyroid follicle colloid environment and act as a cell signaling hub. The present study investigated whether PCs are needed for BRAFV600E-driven PTC. We assessed whether BRAFV600E protein expression correlates with papillary histological architecture and clinicopathological features of PTC. We found that expression of ciliary intraflagellar transport 88 (IFT88) and PC formation were reduced in BRAFV600E-driven PTCs and that loss of cilia may be associated with lymph node metastasis. In PTC cells, the BRAFV600E mutation maintained the aggressiveness of PTC, which was partially related to loss of PCs. Our work confirms that BRAFV600E mutation-driven PC downregulation contributes to maintaining the aggressiveness of PTCs and that manipulating PC can potentially reduce the adverse incidence of PTC in a range of conditions.

Sinusoidal-amplitude binary phase mask and its application in achieving an ultra-long optical needle.

Optical needle has become a hot research topic in recent years, due to the excellent properties and potential applications. To achieve a sub-diffraction optical needle, there are three common methods including planar diffractive lenses, reflective mirrors or axicons, and high-NA objective lenses with the designed phase or amplitude elements. Here, we propose a new kind of designed phase and amplitude element called the sinusoidal-amplitude binary phase mask (SA-BPM), which modulates the amplitude and phase distributions of the incident vector optical fields (VOFs) simultaneously. Based on Richards-Wolf vector diffraction integral, the corresponding parameters of SA-BPM and the optimal optical needle length are calculated by exhaustive method and genetic algorithm. We further upgrade the SA-BPM by adding a Gaussian function in the amplitude modulation, and design the Gaussian SA-BPM (GSA-BPM). We find that the ultra-long optical needles are achieved with the SA-BPM and GSA-BPM, and the depth of focus of the optical needles are improved by 30%-70% compared with the case of binary phase mask. Such SA-BPM and GSA-BPM we proposed have great potential for manipulation and utilization of the ultra-long optical needles.

Value of contrast-enhanced ultrasound area ratio in identifying benign and malignant small breast masses.

BACKGROUND: Tumor size affects clinical staging and is closely related to prognosis. Therefore, early diagnosis of breast cancer is one of the most important methods to reduce mortality and improve prognosis. However, minimal breast cancer is difficult to differentiate from small benign breast masses due to insufficient typical malignant signs. The significantly increased range of enhancement can be an important indication for the prediction of malignancy; however, quantitative studies on the extent of enhancement are rarely reported. The purpose of this study was to investigate the value of contrast-enhanced ultrasound (CEUS) area ratio in finding benign and malignant small breast masses. METHODS: A retrospective analysis was conducted on 88 patients with breast masses confirmed by surgery or needle biopsy (the maximal diameter not over 1 cm). 88 breast masses were divided into the younger age group (not over 40 years old) and older age group (over 40 years old) according to the patient's age. The receiver operating characteristic (ROC) curve was used to determine the cutoff values of CEUS area ratio in diagnosing benign or malignant small breast masses in each group. The efficiency of different cutoff values in finding benign and malignant small breast masses of the distinct groups was analyzed. RESULTS: The CEUS area ratio of malignant mass was larger than benign masses (P<0.05). The CEUS area ratio of malignant masses in the younger age group was larger than that in the older age group (P<0.05). The results of the ROC curve analysis showed that the area under the curve (AUC) and the cutoff values of the entire group, the younger age group, and the older age group were 0.887, 1.65; 0.909, 1.95; and 0.908, 1.22, respectively. When the cutoff value of the older age group was reduced from 1.65 to 1.22, its diagnostic sensitivity was improved significantly (P<0.05). CONCLUSIONS: CEUS area ratio has specific application value in finding benign and malignant small breast masses. Proper reduction of the cutoff value of elderly patients can further improve its diagnostic sensitivity without significantly reducing the specificity.

[Effect of Alkaline Sludge Fermentation Products on the Nitrification Process and Performance].

The aim of the present study was to investigate the effect of alkaline sludge fermentation products as a carbon source on the nitrification process and performance. During the operation of a biological nitrogen removal (BNR) system with sludge fermentation mixture as the carbon source, the activities of ammonia-oxidizing bacteria (AOB) and nitrite-oxidizing bacteria (NOB) were inhibited at the beginning. After 16 days, the activity of AOB began to recover rapidly, but the activity of NOB was still inhibited. The specific nitrate production rate (SNaPR, N/VSS) decreased from 0.1791 g·(g·d)-1 to 0.0078 g·(g·d)-1. At the same time, the nitrite accumulation rate increased from 8.12% to 91.42% and remained stable. The sludge fermentation mixture was separated into sludge fermentation liquid and sludge fermentation sediment. The changes in nitrification activity by adding different types of fermentation products were investigated. The results showed that the activity of NOB decreased in the experimental group fed with the sludge fermentation mixture and the fermentation liquid. The SNaPR decreased from an initial 0.1793 g·(g·d)-1 to 0.1510 g·(g·d)-1 and 0.1617 g·(g·d)-1, respectively. In the experimental group fed with fermentation sediment, the activity of NOB increased. SNaPR rose from 0.1793 g·(g·d)-1 to 0.1864 g·(g·d)-1. Therefore, the activity of the NOB can be inhibited when the sludge fermentation mixture and the fermentation liquid are used as a carbon source in the nitrification process. In addition, the short-range nitrification process can be realized, which is beneficial to accelerating the reaction speed and saving investment in this type of carbon source.

Emerging Roles of p53 Related lncRNAs in Cancer Progression: A Systematic Review.

p53 is the major mediator of the tumor suppressor response. It participates in apoptosis and senescence and can respond to DNA damage. As a crucial sequence-specific transcription factor, p53 regulates the expression of many genes, such as small noncoding RNAs (ncRNAs), microRNAs, and long ncRNAs (lncRNAs). Given the emergence of novel and high-throughput sequencing technologies, many lncRNAs have been discovered. LncRNAs may function as vital gene regulators in a variety of biological processes through extensive mechanisms. Recently, lncRNAs have been demonstrated to be associated with the p53 regulatory pathway. In this review, we discuss the current and fast growing knowledge about the influence of lncRNAs to the p53 signaling pathway, the different mechanisms by which they affect gene expression in cancer. Our findings show that p53-associated lncRNAs may be used as biomarkers for cancer diagnosis or targets for disease therapy.

Identification of new fusion genes and their clinical significance in endometrial cancer.

BACKGROUND: Fusion genes may play an important role in tumorigenesis, prognosis, and drug resistance; however, studies on fusion genes in endometrial cancer (EC) are rare. This study aimed to identify new fusion genes and to explore their clinical significance in EC. METHODS: A total of 28 patients diagnosed with EC were enrolled in this study. RNA sequencing was used to obtain entire genomes and transcriptomes. STAR-comparison and STAR-fusion prediction were applied to predict the fusion genes. Chi-square tests and Student t tests were used to verify the clinical significance with SPSS 13.0 software. RESULTS: New fusion genes were found, and the number of fusion genes varied from 3 to 110 among all patients with EC. The type of fusion genes varied and included messenger RNA (mRNA)-mRNA, long non-coding RNA (lncRNA)-lncRNA, and lncRNA-mRNA. There were six fusion genes with high fusion rates, namely, RP11-123O10.4-GRIP1, RP11-444D3.1-SOX5, RP11-680G10.1-GSE1, NRIP1-AF127936.7, RP11-96H19.1-RP11-446N19.1, and DPH7-PTP4A3. Further studies showed that these fusion genes are related to stage, grade, and recurrence, in which NRIP1-AF127936.7 and DPH7-PTP4A3 were found only in stage III patients with EC. DPH7-PTP4A3 was found in grades 2 and 3, and recurrent patients with EC. CONCLUSION: Fusion genes play an essential role in EC. Six genes that are overexpressed with high fusion rates are identified. NRIP1-AF127936.7 and DPH7-PTP4A3 might be related to stage, and DPH7-PTP4A3 be related to grade and recurrence.

The roles of Wnt/ß-catenin signaling pathway related lncRNAs in cancer.

Long noncoding RNAs (lncRNAs), with length of more than 200 nucleotides, are not translated into proteins but involved in multiple diverse diseases, especially tumorigenesis. The dysregulation of lncRNAs greatly contributes to the progression of various tumors through specific signaling pathways, including Wnt/ß-catenin signaling pathway, which is associated with malignant features of tumors. The interactions between lncRNAs, which have specific expression characteristics in diverse cancer tissues, and Wnt/ß-catenin signaling pathway, exhibit potential as novel biomarkers and therapeutic targets. In this review, we aim to present research findings on the roles of Wnt pathway-related lncRNAs and their effects on Wnt/ß-catenin signaling to regulate tumorigenesis in different cancer types. Results may be used as basis to develop or improve strategies for treatment of different carcinomas.

RNAi­mediated downregulation of asparaginase­like protein 1 inhibits growth and promotes apoptosis of human cervical cancer line SiHa.

Asparaginase like 1 (ASRGL1) protein belongs to the N­terminal nucleophile group, cleaving the isoaspartyl­dipeptides and L­asparagine by adding water. It tends to be overexpressed in cancerous tumors including ovarian cancer and breast tumors. The present study assessed the potential ability of ASRGL1 as a molecular target in gene­based cervical cancer treatment. The protein expression level of ASRGL1 was determined in paraffin­embedded tumor specimen by immunohistochemistry. Additionally, in order to assess the activity of ASRGL1 during the process of cervical cancer cell multiplication, ASRGL1­short hairpin (sh) RNA­expressing lentivirus was established, which was used to infect SiHa cells. The Cellomics ArrayScan VT1 Reader identified the influence of downregulation on SiHa caused by RNA interference­intervened ASRGL1. Flow cytometric analysis was also performed to evaluate the influence. The cyclin dependent kinase (CDK2), cyclin A2, B­cell lymphoma 2 (Bcl­2) and Bcl­2­associated X protein (Bax) expression levels were assessed by western blot analysis. ASRGL1 was observed to be overexpressed in cervical cancer tissues when compared with the adjacent normal tissues. The knockdown of ASRGL1 in SiHa by ASRGL1­shRNA lentivirus infection significantly inhibited cell growth and enhanced cellular apoptosis; the cells were also captured during the S phase. The knockdown of ASRGL1 expression led to the increased expression of Bax and decreased expression of Bcl­2, CDK2 and cyclin A2. In conclusion, ASRGL1 was closely associated with growth and apoptosis in cervical cancer. Therefore, ASRGL1 may be a novel, potentially effective anti­cervical cancer therapy.

Tchebichef image moment approach to the prediction of protein secondary structures based on circular dichroism.

Circular dichroism (CD) spectroscopy is a widely used technique for the evaluation of protein secondary structures that has a significant impact for the understanding of molecular biology. However, the quantitative analysis of protein secondary structures based on CD spectra is still a hard work due to the serious overlap of the spectra corresponding to different structural motifs. Here, Tchebichef image moment (TM) approach is introduced for the first time, which can effectively extract the chemical features in CD spectra for the quantitative analysis of protein secondary structures. The proposed approach was applied to analyze reference set and the obtained results were evaluated by the strict statistical parameters such as correlation coefficient, cross-validation correlation coefficient and root mean squared error. Compared with several specialized prediction methods, TM approach provided satisfactory results, especially for turns and unordered structures. Our study indicates that TM approach can be regarded as a feasible tool for the analysis of the secondary structures of proteins based on CD spectra. An available TMs package is provided and can be used directly for secondary structures prediction.

Ultra-bright γ-ray emission and dense positron production from two laser-driven colliding foils.

Matter can be transferred into energy and the opposite transformation is also possible by use of high-power lasers. A laser pulse in plasma can convert its energy into γ-rays and then e - e + pairs via the multi-photon Breit-Wheeler process. Production of dense positrons at GeV energies is very challenging since extremely high laser intensity ~1024 Wcm-2 is required. Here we propose an all-optical scheme for ultra-bright γ-ray emission and dense positron production with lasers at intensity of 1022-23 Wcm-2. By irradiating two colliding elliptically-polarized lasers onto two diamondlike carbon foils, electrons in the focal region of one foil are rapidly accelerated by the laser radiation pressure and interact with the other intense laser pulse which penetrates through the second foil due to relativistically induced foil transparency. This symmetric configuration enables efficient Compton back-scattering and results in ultra-bright γ-photon emission with brightness of ~1025 photons/s/mm2/mrad2/0.1%BW at 15 MeV and intensity of 5 × 1023 Wcm-2. Our first three-dimensional simulation with quantum-electrodynamics incorporated shows that a GeV positron beam with density of 2.5 × 1022 cm-3 and flux of 1.6 × 1010/shot is achieved. Collective effects of the pair plasma may be also triggered, offering a window on investigating laboratory astrophysics at PW laser facilities.

The multi-resolution capability of Tchebichef moments and its applications to the analysis of fluorescence excitation-emission spectra.

Fluorescence spectroscopy with an excitation-emission matrix (EEM) is a fast and inexpensive technique and has been applied to the detection of a very wide range of analytes. However, serious scattering and overlapping signals hinder the applications of EEM spectra. In this contribution, the multi-resolution capability of Tchebichef moments was investigated in depth and applied to the analysis of two EEM data sets (data set 1 consisted of valine-tyrosine-valine, tryptophan-glycine and phenylalanine, and data set 2 included vitamin B1, vitamin B2 and vitamin B6) for the first time. By means of the Tchebichef moments with different orders, the different information in the EEM spectra can be represented. It is owing to this multi-resolution capability that the overlapping problem was solved, and the information of chemicals and scatterings were separated. The obtained results demonstrated that the Tchebichef moment method is very effective, which provides a promising tool for the analysis of EEM spectra. It is expected that the applications of Tchebichef moment method could be developed and extended in complex systems such as biological fluids, food, environment and others to deal with the practical problems (overlapped peaks, unknown interferences, baseline drifts, and so on) with other spectra.

Prediction of phosphorylation sites based on Krawtchouk image moments.

Protein phosphorylation is one of the most pervasive post-translational modifications and regulates diverse cellular processes in organisms. Under the catalysis of protein kinases, protein phosphorylation usually occurred in the residues serine (S), threonine (T), or tyrosine (Y). In this contribution, we proposed a novel scheme (named KMPhos) for the theoretical prediction of protein phosphorylation sites. First, the numerical matrix was obtained from a protein sequence fragment by replacing the characters of the residues with the chemical descriptors of amino acid molecules to approximately describe the chemical environment of the protein fragment, which was turned to the grayscale image. Then the Krawtchouk image moments were calculated and used to establish the support vector machine models. The accuracies of 10-fold cross validation for the obtained models on the training set are up to 89.7%, 88.6%, and 90.1% for the residues S, Y, and T, respectively. For the independent test set, the prediction accuracies are up to 90.7% (S), 87.8% (T), and 89.3% (Y). The results of ROC and other evaluations are also satisfactory. Compared with several specialized prediction tools, KMPhos provided the higher accuracy and reliability. An available KMPhos package is provided and can be used directly for phosphorylation sites prediction.

Metabolite changes in the ipsilateral and contralateral cerebral hemispheres in rats with middle cerebral artery occlusion.

Cerebral ischemia not only causes pathological changes in the ischemic areas but also induces a series of secondary changes in more distal brain regions (such as the contralateral cerebral hemisphere). The impact of supratentorial lesions, which are the most common type of lesion, on the contralateral cerebellum has been studied in patients by positron emission tomography, single photon emission computed tomography, magnetic resonance imaging and diffusion tensor imaging. In the present study, we investigated metabolite changes in the contralateral cerebral hemisphere after supratentorial unilateral ischemia using nuclear magnetic resonance spectroscopy-based metabonomics. The permanent middle cerebral artery occlusion model of ischemic stroke was established in rats. Rats were randomly divided into the middle cerebral artery occlusion 1-, 3-, 9- and 24-hour groups and the sham group. 1H nuclear magnetic resonance spectroscopy was used to detect metabolites in the left and right cerebral hemispheres. Compared with the sham group, the concentrations of lactate, alanine, γ-aminobutyric acid, choline and glycine in the ischemic cerebral hemisphere were increased in the acute stage, while the concentrations of N-acetyl aspartate, creatinine, glutamate and aspartate were decreased. This demonstrates that there is an upregulation of anaerobic glycolysis (shown by the increase in lactate), a perturbation of choline metabolism (suggested by the increase in choline), neuronal cell damage (shown by the decrease in N-acetyl aspartate) and neurotransmitter imbalance (evidenced by the increase in γ-aminobutyric acid and glycine and by the decrease in glutamate and aspartate) in the acute stage of cerebral ischemia. In the contralateral hemisphere, the concentrations of lactate, alanine, glycine, choline and aspartate were increased, while the concentrations of γ-aminobutyric acid, glutamate and creatinine were decreased. This suggests that there is a difference in the metabolite changes induced by ischemic injury in the contralateral and ipsilateral cerebral hemispheres. Our findings demonstrate the presence of characteristic changes in metabolites in the contralateral hemisphere and suggest that they are most likely caused by metabolic changes in the ischemic hemisphere.

Combination of coenzyme Q10-loaded liposomes with ultrasound targeted microbubbles destruction (UTMD) for early theranostics of diabetic nephropathy.

Diabetic nephropathy (DN) is one of the most common and lethal microvascular complications of diabetes. This study aimed to explore whether coenzymeQ10 (CoQ10) as an antioxidant combined with ultrasound-targeted microbubble destruction (UTMD) could reverse the progress of early diabetic nephropathy (DN). CoQ10 has great potential to treat early DN. However, the clinical application of CoQ10 has been limited because of its low aqueous solubility and non-specific distribution. Therefore, CoQ10-loaded liposomes (CoQ10-lip) were prepared and combined with ultrasound microbubbles for the early theranostics of DN. CoQ10-lip exhibited a good round morphology with a diameter of 183±1.7nm and a negative zeta potential of -25.3mV, which was capable of prolonging the release of the encapsulated CoQ10. The early DN rat models were induced by streptozotocin (STZ) and confirmed by contrast-enhanced ultrasound (CEUS) and 24-h urinary albumin. After the administration of CoQ10-lip combined with the UTMD technique to rats with early DN, the morphology and function of the kidney were evaluated by ultrasonography, histological and molecular analyses. The renal hemodynamics were significantly improved, moreover, 24-h urinary protein, and oxidative stress indexes were modulated after treatment with CoQ10-lip+UTMD indicating recovery of renal function. An elevated level of Nphs2 protein and reduced caspase 3 level indicated the preservation of podocytes and inhibition of cell apoptosis after CoQ10-lip+UTMD treatment. The molecular mechanism was associated with the upregulation of Bcl-2 and the downregulation of Bax. Moreover, the combination of CoQ10-lip and ultrasound microbubbles demonstrated a better protective effect on the damaged kidney than the other groups (free CoQ10 or CoQ10-lip+/- UTMD). Conclusively, CoQ10-lip in combination with ultrasound microbubbles might be a potential strategy to reverse the progress of early DN.