Ox-LDL-induced CD80+ macrophages expand pro-atherosclerotic NKT cells via CD1d in atherosclerotic mice and hyperlipidemic patients.

Atherosclerosis is an inflammatory disease of blood vessels involving the immune system. Natural killer T (NKT) cells, as crucial components of the innate and acquired immune systems, play critical roles in the development of atherosclerosis. However, the mechanism and clinical relevance of NKT cells in early atherosclerosis are largely unclear. The study investigated the mechanism influencing NKT cell function in apoE deficiency-induced early atherosclerosis. Our findings demonstrated that there were higher populations of NKT cells and interferon-gamma (IFN-γ)-producing NKT cells in the peripheral blood of patients with hyperlipidemia and in the aorta, blood, spleen, and bone marrow of early atherosclerotic mice compared with the control groups. Moreover, we discovered that the infiltration of CD80+ macrophages and CD1d expression on CD80+ macrophages in atherosclerotic mice climbed remarkably. CD1d expression increased in CD80+ macrophages stimulated by oxidized low-density lipoprotein (ox-LDL) ex vivo and in vitro. Ex vivo coculture of macrophages with NKT cells revealed that ox-LDL-induced CD80+ macrophages presented lipid antigen α-Galcer (alpha-galactosylceramide) to NKT cells via CD1d, enabling NKT cells to express more IFN-γ. Furthermore, a greater proportion of CD1d+ monocytes and CD1d+CD80+ monocytes were found in peripheral blood of hyperlipidemic patients compared with that of healthy donors. Positive correlations were found between CD1d+CD80+ monocytes and NKT cells or IFN-γ+ NKT cells in hyperlipidemic patients. Our findings illustrated that CD80+ macrophages stimulated NKT cells to secrete IFN-γ via CD1d-presenting α-Galcer, which may accelerate the progression of early atherosclerosis. Inhibiting lipid antigen presentation by CD80+ macrophages to NKT cells may be a promising immune target for the treatment of early atherosclerosis.NEW & NOTEWORTHY This work proposed the ox-LDL-CD80+ monocyte/macrophage-CD1d-NKT cell-IFN-γ axis in the progression of atherosclerosis. The proinflammatory IFN-γ+ NKT cells are closely related to CD1d+CD80+ monocytes in hyperlipidemic patients. Inhibiting CD80+ macrophages to present lipid antigens to NKT cells through CD1d blocking may be a new therapeutic target for atherosclerosis.

NMAAP1 regulated macrophage polarizion into M1 type through glycolysis stimulated with BCG.

Bacillus Calmette Guerin (BCG) perfusion is widely used as cancer adjuvant therapy, in which macrophages play an important role. Novel macrophage activated associated protein 1 (NMAAP1), upregulated after BCG's activation, was proved to promote macrophage polarization to the M1 type. We found that BCG could stimulate mice BMDM to the M1 type and kill tumor cells. After the deletion of NMAAP1, the tumor volume of mice became larger, and the number of M1 type macrophages in the tumor decreased significantly. When macrophages were induced into the M1 type, aerobic glycolysis, the Warburg effect manifested in the increased uptake of glucose and the conversion of pyruvate to lactic acid. NMAAP1 could bind with IP3R and regulate macrophage polarization to the M1 type. However, the specific mechanism of how NMAAP1 regulates macrophage polarization towards the M1 type and plays an antitumor role must be clarified. NMAAP1 could promote the release of lactic acid and pyruvate, enhance the glycolysis of macrophages, and affect the expression of HIF-1α. After inhibition of glycolysis by 2-DG and lactic acid generation by FX11, the effects of NMAAP1 promoting macrophage polarization to the antitumor M1 type were weakened. Furthermore, NMAAP1 upregulated the expression of HIF-1α, which is associated with glycolysis. Moreover, the Ca2+/NF-κB pathway regulated HIF-1α expression by NMAAP1 in the macrophages. NMAAP1 promotes the polarization of macrophages towards the M1 type by affecting the Warburg effect stimulated by BCG.

PDGFRA exhibits potential as an indicator of angiogenesis within the tumor microenvironment and is up-regulated in BLCA.

Bladder cancer (BLCA) is a common type of urogenital malignancy worldwide. The recurrence and metastasis of bladder cancer are closely related to angiogenesis, but the underlying mechanisms are unclear. In this study, we developed a method to predict survival outcomes among BLCA patients, which could be used to guide immunotherapy and chemotherapy. We obtained patient data from The Cancer Genome Atlas (TCGA) and identified angiogenesis-related genes from the GeneCards database. First, we used differential expression analysis and univariate Cox analysis to identify angiogenesis-related genes and used correlation analysis to generate molecular subtypes based on M2 macrophages. Next, we constructed a prognostic signature consisting of four genes (ECM1, EFEMP1, SLIT2, and PDGFRΑ), which was found to be an independent prognostic factor. Higher risk scores were associated with worse overall survival and higher expression of immune checkpoints. We also evaluated immune cell infiltration using the CIBERSORT and ssGSEA algorithms. Additionally, we performed stratification analyses, constructed a nomogram, and predicted chemotherapeutic responses based on the risk signature. Finally, we validated our findings by using qRT-PCR as well as IHC data to detect the expression levels of the four genes at mRNA and protein levels in BLCA patients and obtained results that were consistent with our predictions. Our study demonstrates the utility of a four-gene prognostic signature for prognostication in bladder cancer patients and designing personalized treatments, which could provide new avenues for personalized management of these patients.

Effects of adsorbate molecular space conformation on the adsorption capacity of porous carbon materials: A case study of propylene glycol methyl ether.

In most investigations of adsorption process, the effects of adsorbate properties on adsorption capacity were often not obtain enough attention, compared with the properties of adsorbent. Apart from the polarity, and the boiling point of adsorbate, the molecular space conformation is also play an important role in its adsorption behavior on porous materials. In this work, two series of orientation-designed activated carbon were used to study the microscopic adsorption behavior of amphiphilic propylene glycol methyl ether (PM) gas. The spatial conformation of the PM molecule was found to have a strong effect on the adsorption of PM on activated carbon and caused two major adsorption behaviors, "propensity" and "directionality". The PM molecule, as well as other oxygenated VOCs, tended to be adsorbed on areas of activated carbon with similar polarity, which caused its adsorption "propensity". However, the cross-sectional area (55.95 Å2) of the hydrophilic hydroxy groups on a PM molecule is much larger than that of the hydrophobic methoxy groups (29.46 Å2), which leads to the adsorption "directionality", such that the amount of PM adsorption on activated carbon was affected by whether PM molecules were adsorbed by their hydrophilic hydroxy groups or hydrophobic methoxy groups over the same adsorption area. Additionally, a predictive model based on the properties of activated carbon and the PM molecule was proposed and further verified.

Eddy-current-induced distortion correction using maximum reconciled mutual information in diffusion MR imaging.

PURPOSE: In diffusion tensor imaging, a large number of diffusion-weighted (DW) images with different diffusion gradient directions are attained during scanning. However, subjects' involuntary head movements and eddy current effect related to large diffusion-sensitizing gradients will cause distortions of DW images. Therefore, for tracking accurately white matter structures and tractography, the distortions have to be realigned before model fitting. Currently, traditional methods use maximum mutual information (MMI) or normalized mutual information (NMI) as similarity measure for DW images registration. These information measures are defined by Shannon entropy. The image entropy is able to embody the global information complexity but ignore the local information complexity caused by heterogeneous intensity contrasts in DW images, making registration algorithm early converge. METHOD: To overcome the above problem, we present maximum reconciled mutual information (MRMI) combining both global information and local information as the similarity measure of the registration algorithm framework. RESULT: (i) In comparison with traditional methods, under our proposed MRMI method, the border of DW image is more anastomotic with the b0 image, and the fitted fractional anisotropy (FA) map after registration is closer to the true brain boundary. (ii) By quantitative analysis of registration results, our method has a significant advantage over others in terms of NMI between b0 image and the aligned DW images. CONCLUSION: The results suggest that there is a high-level matching in space between the b0 image and the DW images aligned by the MRMI method, raising the registration robustness and accuracy compared to the traditional DW registration methods. It may provide a better option for the existing diffusion image registration tools (e.g., FMRIB Software Library) and commonly multimodal medical image registration.

Targeted Aucore-Agshell nanorods as a dual-functional contrast agent for photoacoustic imaging and photothermal therapy.

Optimizing contrast enhancement is essential for producing specific signals in biomedical imaging and therapy. The potential of using Aucore-Agshell nanorods (Au@Ag NRs) as a dual-functional theranostic contrast agent is demonstrated for effective cancer imaging and treatments. Due to its strong NIR absorption and high efficiency of photothermal conversion, effects of both photoacoustic tomography (PAT) and photothermal therapy (PTT) are enhanced significantly. The PAT signal grows by 45.3% and 82% in the phantom and in vivo experiments, respectively, when compared to those using Au NRs. In PTT, The maximum increase of tissue temperature treated with Au@Ag NRs is 22.8 °C, twice that with Au NRs. Results of the current study show the feasibility of using Au@Ag NRs for synergetic PAT with PTT. And it will enhance the potential application on real-time PAT guided PTT, which will greatly benefit the customized PTT treatment of cancer.

Indocyanine Green Derivative Covalently Conjugated with Gold Nanorods for Multimodal Phototherapy of Fibrosarcoma Cells.

A hydrophilic indocyanine green derivative (ICG-Der-02) was covalently doped into mesoporous silica-coated gold nanorods (AuNRs/mSiO2). The self-synthesized derivative offers one carboxyl functional group on a side chain, which enables ICG-Der-02 to be covalently linked to nanomaterials and reduces the probability of leakage/desorption of the dye. The detection of infrared luminescence around 1270 nm confirmed that 102 is efficiently generated by the nanocomposite (AuNRs/mSiO2-ICG-Der-02). Furthermore, a second layer of silica was coated onto the nanocomposite, which then was conjugated with the α(v) integrin-targeting cyclic peptide (RGD-4C). The cell tests showed that the resulting nanoconjugate (AuNRs/mSiO2-ICG-Der-02/RGD-4C) was able to bind preferentially to HT-1080 human fibrosarcoma cells. Due to the synergistic effect of the produced nanoconjugates, a dual-modality photothermal and photochemical therapy was successfully achieved by 808 nm irradiation. Compared to using photothermal or photochemical therapy alone, the dual-modality photothermal/photochemical therapeutic strategy proved to be more damaging to HT-1080 cells and enhanced the effectiveness of photodestruction. Our work presents a novel approach to the multimodal treatment of fibrosarcoma and shows promise for future use in cancer theranostics.

Ex vivo determination of glucose permeability and optical attenuation coefficient in normal and adenomatous human colon tissues using spectral domain optical coherence tomography.

Recent reports have suggested that spectral domain optical coherence tomography (SD-OCT) is a useful tool for quantifying the permeability of hyperosmotic agents in various tissues. We report our preliminary results on quantification of glucose diffusion and assessment of the optical attenuation change due to the diffusion of glucose in normal and adenomatous human colon tissues in vitro by using a SD-OCT and then calculated the permeability coefficients (PC) and optical attenuation coefficients (AC). The PC of a 30% aqueous solution of glucose was 3.37±0.23×10⁻6 cm/s in normal tissue and 5.65±0.16×10⁻6 cm/s in cancerous colon tissue. Optical AC in a normal colon ranged from 3.48±0.37 to 2.68±0.82 mm⁻¹ and was significantly lower than those seen in the cancerous tissue (8.48±0.95 to 3.16±0.69 mm⁻¹, p<0.05). The results suggest that quantitative measurements of using PC and AC from OCT images could be a potentially powerful method for colon cancer detection.

The role of vascular endothelial growth factor in fractional laser resurfacing with the carbon dioxide laser.

The aim of this study was to analyze the role of vascular endothelial growth factor (VEGF) in mechanisms of cutaneous remodeling induced by fractional CO(2) laser treatment. The dorsal skin of Kunming mice was exposed to a single-pass fractional CO(2) laser treatment. Biopsies were taken 1 h, and 1, 3, 7, 14, 28 and 56 days after treatment. Skin samples VEGF expression was evaluated by immunohistochemistry and ELISA, fibroblasts by hematoxylin-eosin staining, and types I and III collagen by ELISA. Staining for VEGF was found in many types of cell including fibroblasts. The amount of VEGF in the skin of laser-treated areas had increased significantly compared to that in the control areas on days 1 and 3 (P < 0.05, P < 0.01, respectively), then decreased by day 7 after treatment and returned to the baseline level. The number of fibroblasts in the skin of the laser-treated areas had increased significantly compared to that in control areas on days 3, 7, 14, 28 and 56 after irradiation (P < 0.05, P < 0.01, P < 0.01, P < 0.01, P < 0.01, respectively). The amount of type I collagen was significantly higher in the skin of the laser-treated areas compared to that in control areas from day 28 to day 56 (P < 0.05, respectively), and type III collagen was significantly higher from day 3 to day 56 (P < 0.05, P < 0.05, P < 0.05, P < 0.05, P < 0.01, respectively). There was a positive correlation between the level of VEGF and fibroblast proliferation early stage after laser treatment (r = 0.853, P < 0.01), but there was no correlation after the first week (r = -0.124, P > 0.05). The amounts of type I and III collagen showed no significant correlations with the expression of VEGF in the late stages after laser treatment (r = 0.417, P > 0.05 and r = 0.340, P > 0.05, respectively). The results suggest that VEGF might be mainly involved in the early stages of wound healing, including the stages of acute inflammation, fibroblast proliferation and vessel formation induced by fractional CO(2) laser resurfacing.

Corneal nerve morphology and sensitivity changes after ultraviolet A/riboflavin treatment.

Collagen crosslinking induced by riboflavin and ultraviolet A irradiation (UVAR) has recently been introduced as a clinical treatment to halt or reverse the progression of keratoconus. We investigated changes in corneal sensitivity and nerve morphology as part of a comprehensive safety evaluation of this treatment. Fifty-four New Zealand white rabbits were divided into three experimental groups: UVAR with deepithelialization, UVAR without deepithelialization, and deepithelialization alone. Corneal sensitivity was measured with a Cochet-Bonnet esthesiometer before treatment and 3, 7, 14, 30, 90, and 180 days after treatment. Corneal nerve morphology was evaluated using acetylcholinesterase histochemistry staining. We found that corneal sensitivity in the center of the treated area was significantly reduced 3 days after UVAR with deepithelialization treatment compared with the corneal sensitivity of the control eye but gradually recovered to normal levels at 90 days. Corneal sensitivity after deepithelialization treatment was significantly lower than control corneal sensitivity at 3 days but was significantly higher after 30 days of recovery compared with the corneal sensitivity after UVAR with deepithelialization. Corneal sensitivity after UVAR without deepithelialization treatment had significantly decreased at 7 days compared with control corneal sensitivity but was not significantly different from control values at other measurement times. In parallel with these functional alterations, corneal nerve degeneration was visible in the treatment area by 3 days; by 7 days there was a significant decrease in nerve density. Corneal nerve sprouts were identified from neighboring non-injured nerve fibers 7 days after treatment; by 90 days, excessively regenerating nerves were observed throughout the anterior stroma. The density of corneal nerve fibers appeared normal by 180 days. Ultraviolet A/riboflavin with deepithelialization treatment resulted in corneal nerve fiber damage and subsequent regeneration in the treatment area, simultaneously accompanied by the reduction and recovery of corneal sensitivity.

Spatiotemporal properties of multipeaked electrically evoked potentials elicited by penetrative optic nerve stimulation in rabbits.

PURPOSE: To investigate the spatiotemporal properties of the cortical responses elicited by intraorbital optic nerve (ON) stimulation with penetrating electrodes as means of designing optimal stimulation strategies for an ON visual prosthesis. METHODS: The ON of rabbits was exposed by orbital surgery for electrical stimulation. Craniotomy was performed to expose the visual cortex contralateral to the operated eye. Electrically evoked potentials (EEPs) were recorded by an electrode array positioned on the visual cortex. RESULTS: There were primarily four components (N1, P1, P2, P3) in EEPs with implicit times of 8.0 ± 0.6, 11.3 ± 1.3, 20.5 ± 1.4, and 26.9 ± 1.5 ms, respectively, when the ON was stimulated by penetrating electrodes. The thresholds to elicit these components were different, and the higher thresholds were seen with slower cortical components. The corresponding thresholds were 13.8 ± 3.1 µA for N1, 21.8 ± 4.7 µA for P1, 36.4 ± 11.4 µA for P2, and 68.4 ± 17.2 µA for P3. The time courses of the EEP components were also distinct. The locations of EEPs with the maximum P1 amplitude showed a spatial correspondence to the ON stimulation sites. Different profiles of cortical responses could be discriminated when the ON stimulation sites were separated by 150 µm. CONCLUSIONS: Multiple components with different properties were elicited in EEPs when the ON was stimulated by penetrating electrodes. Retinotopic and localized stimulation could be achieved with this stimulating approach.

Multi-channel visual evoked potential as an ancillary tool to diagnose intraorbital optic nerve lesions.

Multi-channel visual evoked potential (MVEP) recording method was used to assist in diagnosing a 4-month-old Chinese Albino rabbit with an intraorbital mass. Subcutaneous MVEP of its both eyes were recorded simultaneously using 16 electrodes (4 x 4) multi-channel array. Analysis of the cortical potential landscapes (CPL) showed that the conduction function of right eye was remarkably impaired in terms of decreased amplitudes and prolonged latencies. Specific side-dominant distribution asymmetry of the decreased MVEP amplitudes indicated that the temporal side of the optic nerve (ON) was severely involved. Overall prolonged latencies of the CPL without side differences suggested that the functional impairment could have been caused by the mechanical compression exerted by an intraorbital mass. Surgical removal procedures confirmed that the mass was located temporally to the ON. Pathological examination provided a final diagnosis of a giant polycystic mucocele. Beyond its significance as a standard tool to assess functional changes of the visual pathway, MVEP recordings might assist locating intraorbital lesions that involve the ON by careful analysis of abnormal CPLs.

Low-hemorrhage-risk surgical approach to expose the optic nerve in rabbits without bony removal and rectus resection.

OBJECTIVE: A low-hemorrhage-risk surgical approach to expose the optic nerve (ON) in rabbits through the orbital process of the frontal bone without removal of the bony orbit and resection of the rectus muscle was explored and assessed in this study. This approach will be used to investigate a new visual prosthesis that requires intraorbital ON stimulation with penetrating electrodes. Animals Chinese Albino rabbits (n = 10). METHODS: Rabbits were classified into a surgery and a control group (five in each). In the surgery group, the ON exposure was explored by the newly proposed surgical approach. Surgical time, blood loss, visually evoked potentials (VEP) at four different scheduled time points, and H&E-stained histology of the ON at one month after surgery were recorded and analyzed to assess the ease and safety of the approach. RESULTS: The average surgical time for the ON exposure was 16.40 +/- 1.14 min with average blood loss of 0.52 +/- 0.08 mL. Within the one-month follow-up, the ON exhibited a naturally reversible conduction change in terms of VEP amplitude. Histological examination of the ON was unremarkable. A postoperative mild ptosis of the surgical eye resolved within one month after surgery. CONCLUSION: The ease and safety of this new surgical approach allowed it to be easily used by non-expert operators and widely applied in rabbit experiments for various research purposes requiring exposure of the ON.

Laser induced collagen remodeling: a comparative study in vivo on mouse model.

BACKGROUND AND OBJECTIVE: Many lasers have claimed the clinical efficacy on skin rejuvenation. In this study, the mechanisms of laser induced collagen remodeling were explored systematically on a Kunming (KM) mouse model in vivo by comparing the different non-ablative laser effects using four different laser treatment modalities. MATERIALS AND METHODS: The dorsal skin of KM mice was exposed by depilation before the laser treatments. Four laser treatment modalities were used: the 595-nm pulsed dye laser (PDL) (10 ms), 1,320-nm neodymium-yttrium-aluminum garnet (Nd:YAG) laser (0.35 ms), 1,064-nm Nd:YAG laser with Q-switched (5 ns), and long-pulsed (0.3 ms) mode. Each modality exposed one side of the mouse dorsal skin leaving the other side as the contralateral control. Then skin histology, fibroblast number, and the genesis of collagen type I and III were studied by comparing the treatment site and control site at 1 hour, 1 day, 1 week, 3 weeks, 4 weeks, and 8 weeks after laser treatment. Hydroxyproline content of the skin tissue was measured 4 weeks and 8 weeks after laser exposure. RESULTS: All laser treatments led to marked improvements in dermal layer thickness and collagen fiber density, and the increase in fibroblast number and hydroxyproline content compared with their own controls. Collagen synthesis and remodeling induced by the Q-switched 1,064-nm laser was most effective 4 weeks after treatment, while there was no significant difference among the other three modalities. Among the new collagen genesis after the different laser treatments, collagen type III increased sharply after the Q-switched 1,064-nm laser treatment whereas more collagen type I was elicited by the other laser treatment modalities. CONCLUSIONS: The efficacy of photo-mechanical effects in promoting more effectively the synthesis of collagen type III, whereas the photo-thermal effect favored more the formation of collagen type I.