Chronic Exposure to Cigarette Smoke Affects the Ileum and Colon of Guinea Pigs Differently. Relaxin (RLX-2, Serelaxin) Prevents Most Local Damage

Cigarette smoking (CS) is the cause of several organ and apparatus diseases. The effects of smoke in the gut are partially known. Accumulating evidence has shown a relationship between smoking and inflammatory bowel disease, prompting us to investigate the mechanisms of action of smoking in animal models. Despite the role played by neuropeptides in gut inflammation, there are no reports on their role in animal models of smoking exposure. The hormone relaxin has shown anti-inflammatory properties in the intestine, and it might represent a putative therapy to prevent gut damage caused by smoking. Presently, we investigate the effects of chronic smoke exposure on inflammation, mucosal secretion, and vasoactive intestinal peptide (VIP) and substance P (SP) expressions in the ileum and colon of guinea pigs. We also verify the ability of relaxin to counter the smoke-induced effects. Smoke impacted plasma carbon monoxide (CO). In the ileum, it induced inflammatory infiltrates, fibrosis, and acidic mucin production; reduced the blood vessel area; decreased c-kit-positive mast cells and VIP-positive neurons; and increased the SP-positive nerve fibers. In the colon, it reduced the blood vessel area and the goblet cell area and decreased c-kit-positive mast cells, VIP-positive neurons, and SP-positive nerve fibers. Relaxin prevented most of the smoking-induced changes in the ileum, while it was less effective in the colon. This study shows the diverse sensitivity to CS between the ileum and the colon and demonstrates that both VIP and SP are affected by smoking. The efficacy of relaxin proposes this hormone as a potential anti-inflammatory therapeutic to counteract gut damage in humans affected by inflammatory bowel diseases.

Vascular Response after Directional Coronary Atherectomy for Left Main Bifurcation Lesion

Aims. To evaluate the vascular response after directional coronary atherectomy (DCA) for left main (LM) bifurcation lesion. Methods. This study was a retrospective, single-center study enrolling 31 patients who underwent stentless therapy using DCA followed by drug-coated balloon (DCB) angioplasty for LM bifurcation lesion. We compared intravascular ultrasound (IVUS) findings before and after DCA. Results. After DCA, the lumen and vessel areas significantly increased, whereas the plaque area (PA) and %PA were significantly reduced. When the lesions were divided into small vessel and large vessel groups using the median value of the vessel area, the maximum balloon pressure of the DCA catheter was greater in the large vessel group. Changes in the lumen and vessel areas were also significantly greater in the large vessel group. On the other hand, the changes in PA and %PA were similar between groups. Conclusions. The main vascular responses associated with lumen enlargement after DCA were plaque reduction and vessel expansion. Contribution of vessel expansion to lumen enlargement was larger than the effect of plaque reduction in large vessel lesions.

Quantifying the pattern of retinal vascular orientation in diabetic retinopathy using optical coherence tomography angiography

Quantitative imaging using optical coherence tomography angiography (OCTA) could provide objective tools for the detection and characterization of diabetic retinopathy (DR). In this study, an operator combining the second derivative and Gaussian multiscale convolution is applied to identify the retinal orientation at each pixel in the OCTA image. We quantified the pattern of retinal vascular orientation and developed three novel quantitative metrics including vessel preferred orientation, vessel anisotropy, and vessel area. Each of eight 45º sectors of the circular disk centered at the macular region was defined as the region of interest. Significant sectoral differences were observed in the preferred orientation (p < 0.0001) and vessel area (p < 0.0001) in the 34 healthy subjects, whereas vessel anisotropy did not demonstrate a significant difference among the eight sectors (p = 0.054). Differential retinal microvascular orientation patterns were observed between healthy controls (n = 34) and the DR subjects (n = 7). The vessel area characterized from the vascular orientation pattern was shown to be strongly correlated with the traditionally reported vessel density (Pearson R > 0.97, p < 0.0001). With three metrics calculated from the vascular orientation pattern simultaneously and sectorally, our quantitative assessment for retinal microvasculature provides more information than vessel density alone and thereby may enhance the detection of DR. These preliminary results suggest the feasibility and advantage of our vessel orientation-based quantitative approach using OCTA to characterize DR-associated changes in retinal microvasculature.

Different Wood Anatomical and Growth Responses in European Beech (Fagus sylvatica L.) at Three Forest Sites in Slovenia

European beech (Fagus sylvatica L.) adapts to local growing conditions to enhance its performance. In response to variations in climatic conditions, beech trees adjust leaf phenology, cambial phenology, and wood formation patterns, which result in different tree-ring widths (TRWs) and wood anatomy. Chronologies of tree ring width and vessel features [i.e., mean vessel area (MVA), vessel density (VD), and relative conductive area (RCTA)] were produced for the 1960–2016 period for three sites that differ in climatic regimes and spring leaf phenology (two early- and one late-flushing populations). These data were used to investigate long-term relationships between climatic conditions and anatomical features of four quarters of tree-rings at annual and intra-annual scales. In addition, we investigated how TRW and vessel features adjust in response to extreme weather events (i.e., summer drought). We found significant differences in TRW, VD, and RCTA among the selected sites. Precipitation and maximum temperature before and during the growing season were the most important climatic factors affecting TRW and vessel characteristics. We confirmed differences in climate-growth relationships between the selected sites, late flushing beech population at Idrija showing the least pronounced response to climate. MVA was the only vessel trait that showed no relationship with TRW or other vessel features. The relationship between MVA and climatic factors evaluated at intra-annual scale indicated that vessel area in the first quarter of tree-ring were mainly influenced by climatic conditions in the previous growing season, while vessel area in the second to fourth quarters of tree ring width was mainly influenced by maximum temperature and precipitation in the current growing season. When comparing wet and dry years, beech from all sites showed a similar response, with reduced TRW and changes in intra-annual variation in vessel area. Our findings suggest that changes in temperature and precipitation regimes as predicted by most climate change scenarios will affect tree-ring increments and wood structure in beech, yet the response between sites or populations may differ.

Vascular Response after Directional Coronary Atherectomy for Left Main Bifurcation Lesion

Purpose: To evaluate the vascular response after directional coronary atherectomy (DCA) for left main (LM) bifurcation lesion.Methods: This study was a retrospective, single-center study enrolling 31 patients who underwent stent-less therapy using DCA followed by drug-coated balloon angioplasty for LM bifurcation lesion. We compared the intravascular ultrasound (IVUS) findings pre- and post DCA. Results: After DCA, the lumen and vessel areas significantly increased whereas the plaque area (PA) and %PA significantly decreased. When the lesions were divided into small and large vessel groups using the median vessel area value, the maximum balloon pressure of the DCA catheter was greater in the large than in the small vessel group. Changes in the lumen and vessel areas were also significantly greater in the large than in the small vessel group. Conversely, the PA and %PA changes were similar between the groups. Conclusion: The main vascular responses associated with lumen enlargement after DCA were plaque reduction and vessel expansion. Contribution of vessel expansion to lumen enlargement was larger than the effect of plaque reduction in large than in small-vessel lesions.

Conversion of cancer-associated fibroblasts from pro- to antitumor improves the sensitivity of pancreatic cancer to chemotherapeutics

Previous therapeutic attempts to deplete cancer-associated fibroblasts (CAFs) or inhibit their proliferation in pancreatic ductal adenocarcinoma (PDAC) were not successful in mice or patients. Thus, CAFs may be tumor suppressive or heterogeneous, with distinct cancer-restraining and -promoting CAFs (rCAFs and pCAFs, respectively). Here, we show that induced expression of the glycosylphosphatidylinositol-anchored protein Meflin, a rCAF-specific marker, in CAFs by genetic and pharmacological approaches improved the chemosensitivity of mouse PDAC. A chemical library screen identified Am80, a synthetic, non-natural retinoid, as a reagent that effectively induced Meflin expression in CAFs. Am80 administration improved the sensitivity of PDAC to chemotherapeutics, accompanied by increases in tumor vessel area and intratumoral drug delivery. Mechanistically, Meflin was involved in the suppression of tissue stiffening by interacting with lysyl oxidase to inhibit its collagen crosslinking activity. These data suggested that modulation of CAF heterogeneity may represent a strategy for PDAC treatment.

Lung Damage among Individuals with Biomass Smoke Exposure Characterized by CT Features and Changes in Pulmonary Function

BackgroundBiomass smoke exposure (BSE) is an important etiological factor in chronic obstructive pulmonary disease (COPD). However, few studies have focused on the effects of BSE in the respiratory muscles or lungs.MethodsUsing a cohort, we selected 98 participants in underdeveloped rural areas: 16 healthy individuals with BSE (“BSE normal”), 19 patients with BSE and COPD (“BSE+COPD”), 13 healthy individuals with cigarette smoke exposure (“CSE normal”), 25 patients with cigarette smoke exposure and COPD (“CSE+COPD”), and 25 healthy controls. Patients with GOLD stage I and II COPD were included. Baseline data (demographic data, BSE or CSE, lung function, and CT findings) and follow-up lung function data were collected. CT parameters of emphysema, pulmonary small vessels, airway remodeling, pectoralis muscles, and erector spinae muscle were measured.ResultsIndividuals with BSE were mainly women (32/35, 91.43%). Compared with the CSE+COPD group, the BSE+COPD group demonstrated slow lung function decline, increased lower lung emphysema, and narrower airway lumen and airway wall thickening in moderate and small airways (all P<.05). Compared with healthy controls, the CSE normal and BSE normal groups exhibited significant reduction of pulmonary small vessel area and obvious airway remodeling in small airways (P<.05). Compared with the BSE normal group, the BSE+COPD group showed significantly more severe emphysema and airway remodeling, as well as reduced left pectoralis major muscle area (all P<.05).ConclusionsHealthy individuals with BSE had reduced pulmonary small vessel area and obvious airway remodeling; patients with BSE and COPD showed more severe emphysema, airway remodeling, and pectoralis major muscle change. More investigations are needed regarding interventions for BSE.Trial registration: ChiCTR, ChiCTR-OO-14004264 . Registered 12 February 2014, http://www.chictr.org.cn/showproj.aspx?proj=5304

Optical Coherence Tomography Angiography-Based Quantitative Assessment of Morphologic Changes in Active Myopic Choroidal Neovascularization During Anti-vascular Endothelial Growth Factor Therapy

Purpose: To establish quantitative profile of the morphologic changes among patients with active myopic choroidal neovascularization (mCNV) before and after anti-vascular endothelial growth factor (VEGF) therapy using optical coherence tomography angiography (OCTA) to assess the therapeutic response.Methods: Patients with active mCNV who received anti-VEGF injections between February 2017 to October 2020 and fit the study criteria were retrospectively reviewed. Quantitative analysis of their OCTA images were carried out to evaluate the morphologic features and vascular changes of mCNV lesions in response to anti-VEGF therapy. For further quantitative profiling, mCNV area, fractal dimension, vessel area, vessel density, vessel diameter, vessel length, vessel junction, junction density, and vessel tortuosity were obtained by means of advanced skeletonization postprocessing analyses.Results: Thirty-one eyes of 29 consecutive patients with OCTA-positive mCNV lesions (mean spherical equivalent: −12.55 ± 3.24 diopters) were included. The 31 cases were divided into two phenotypes at baseline: organized interlacing pattern (83.87%) and disorganized vascular loops pattern (16.13%). The values of mCNV area, fractal dimension, vessel area, vessel length, vessel junction, and junction density decreased remarkably 1 month after the initial anti-VEGF injection (p &lt; 0.001). Although, vessel density, vessel diameter, and vessel tortuosity increased meanwhile, only vessel diameter displayed statistical significance (p = 0.027). Of note, relative ratio analysis showed that vessel junction was the most sensitive biomarker in response to anti-VEGF therapy, reflecting a mean decrease of 50.36%. Sensitivity lowered successively in biomarkers of vessel length, vessel area, junction density, mCNV area, and fractal dimension. In addition, percent change of mCNV area (r = 0.552, p = 0.002), fractal dimension (r = 0.446, p = 0.017), vessel area (r = 0.518, p = 0.005), and vessel length (r = 0.440, p = 0.019) were moderately associated with that of central retinal thickness.Conclusions: The study showed morphological as well as quantitative changes on OCTA responding to anti-VEGF treatment in mCNV patients, among which vessel junctions might be the most predictive biomarker. OCTA-based analysis, providing intuitive images and a large spectrum of quantitative data at the same time, could promote new insights into the therapeutic response assessment in mCNV patients.

SpARF4 reduces cadmium accumulation by negatively regulating SpABCG14 and SpACO4 in the cadmium/zinc hyperaccumulator Sedum plumbizincicola

Root development and apoplastic transport are respectively important for cadmium (Cd) absorption and transportation, which profoundly influence Cd bioremediation. However, molecular mechanisms underlying the two processes are not completely understood. In this study, we demonstrated that auxin response factor 4 (SpARF4) from a Cd hyperaccumulator Sedum plumbizincicola was a negative regulator for these processes. SpARF4 positively regulated by auxin was highly expressed in xylem. Overexpression of SpARF4 significantly decreased vessel area and declined lignin content of S. plumbizincicola. Meanwhile, less adventitious roots were found, and lateral root development was delayed in transgenic plants. Furthermore, ethylene production and auxin transportation were impaired. More importantly, SpARF4 negatively regulated Cd content of xylem saps and aerial tissues. Combining dual-LUC reporter, Y1H and qRT-PCR assays, SpARF4 was a repressor for two downstream genes (SpABCG14 and SpACO4) which influenced vascular bundle development and ethylene production, respectively. PIN1, 2, 3, 7 were downregulated and slowed down local auxin accumulation rate, which suspended root development. These results indicate that SpARF4 can decelerate Cd transportation rate from roots to aerial parts and reduce Cd content of aboveground tissues by delaying the root development and decreasing vessel area.