STING1-accelerated vascular smooth muscle cell senescence-associated vascular calcification in diabetes is ameliorated by oleoylethanolamide via improved mitochondrial DNA oxidative damage.

Vascular calcification is a prevalent hallmark of cardiovascular risk in elderly and diabetic individuals. Senescent vascular smooth muscle cells (VSMCs) participate in calcification; however, the associated underlying mechanisms remain unknown. Aberrant activation of the cytosolic DNA sensing adaptor stimulator of interferon gene 1 (STING1) caused by cytosolic DNA, particularly that leaked from damaged mitochondria, is a catalyst for aging-related diseases. Although oleoylethanolamide (OEA) is an endogenous bioactive lipid mediator with lipid overload-associated vasoprotective effects, its benefit in diabetic vascular calcification remains uncharacterized. This study focused on the role of STING1 in mitochondrial dysfunction-mediated calcification and premature VMSC senescence in diabetes and the effects of OEA on these pathological processes. In diabetic in vivo rat/mouse aorta calcification models and an in vitro VSMC calcification model induced by Nε-carboxymethyl-lysine (CML), senescence levels, STING1 signaling activation, and mitochondrial damage markers were significantly augmented; however, these alterations were markedly alleviated by OEA, partially in a nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent manner, and similar anti-calcification and senescence effects were observed in STING1-knockout mice and STING1-knockdown VSMCs. Mechanistically, mitochondrial DNA (mtDNA) damage was aggravated by CML in a reactive oxygen species-dependent manner, followed by mtDNA leakage into the cytosol, contributing to VSMC senescence-associated calcification via STING1 pathway activation. OEA treatment significantly attenuated the aforementioned cytotoxic effects of CML by enhancing cellular antioxidant capacity through the maintenance of Nrf2 translocation to the nucleus. Collectively, targeting STING1, a newly defined VSMC senescence regulator, contributes to anti-vascular calcification effects.

Causal relationship between iron deficiency anemia and asthma: a Mendelian randomization study.

Background: Observational studies have suggested an association between iron deficiency anemia (IDA) and asthma, which may affect the occurrence of asthma. However, whether IDA is a new management goal for asthma remains to be determined. Objective: We conducted a two-sample Mendelian randomization(MR)analysis to assess the association between IDA and asthma. Methods: We performed a two-sample MR study to assess a causal relationship between IDA (ncase = 12,434, ncontrol = 59,827) and asthma (ncase = 20,629, ncontrol = 135,449). Inverse variance weighted (IVW) was used as the primary method for the analyses. Furthermore, we used weighted medians and MR-Egger to enhance robustness. Data linking genetic variation to IDA and asthma were combined to assess the impact of IDA on asthma risk. Results: There are five single nucleotide polymorphisms (SNPs) were used as genetic tool variables for exposure factors. Genetically determined IDA was significantly associated with an increased risk of asthma (OR = 1.37, 95% CI: 1.09-1.72, p = 0.007). There was little heterogeneity in the MR studies and no evidence of level pleiotropy was found. Conclusions: In our MR study, our findings emphasize that IDA may be associated with a high risk of asthma, indicating a potential role for IDA in the development of asthma. Future research needs to elucidate its potential mechanisms to pave the way for the prevention and treatment of asthma.

Empagliflozin ameliorates vascular calcification in diabetic mice through inhibiting Bhlhe40-dependent NLRP3 inflammasome activation.

Type 2 diabetes mellitus (T2DM) patients exhibit greater susceptibility to vascular calcification (VC), which has a higher risk of death and disability. However, there is no specific drug for VC therapy. NLRP3 inflammasome activation as a hallmark event of medial calcification leads to arterial stiffness, causing vasoconstrictive dysfunction in T2DM. Empagliflozin (EMPA), a sodium-glucose co-transporter 2 inhibitor (SGLT2i), restrains hyperglycemia with definite cardiovascular benefits. Given the anti-inflammatory activity of EMPA, herein we investigated whether EMPA protected against VC in the aorta of T2DM mice by inhibiting NLRP3 inflammasome activation. Since db/db mice receiving a normal diet developed VC at the age of about 20 weeks, we administered EMPA (5, 10, 20 mg·kg-1·d-1, i.g) to 8 week-old db/db mice for 12 weeks. We showed that EMPA intervention dose-dependently ameliorated the calcium deposition, accompanied by reduced expression of RUNX2 and BMP2 proteins in the aortas. We found that EMPA (10 mg·kg-1·d-1 for 6 weeks) also protected against VC in vitamin D3-overloaded mice, suggesting the protective effects independent of metabolism. We showed that EMPA (10 mg·kg-1·d-1) inhibited the abnormal activation of NLRP3 inflammasome in aortic smooth muscle layer of db/db mice. Knockout (KO) of NLRP3 significantly alleviated VC in STZ-induced diabetic mice. The protective effects of EMPA were verified in high glucose (HG)-treated mouse aortic smooth muscle cells (MOVASs). In HG-treated NLRP3 KO MOVASs, EMPA (1 µM) did not cause further improvement. Bioinformatics and Western blot analysis revealed that EMPA significantly increased the expression levels of basic helix-loop-helix family transcription factor e40 (Bhlhe40) in HG-treated MOVASs, which served as a negative transcription factor directly binding to the promotor of Nlrp3. We conclude that EMPA ameliorates VC by inhibiting Bhlhe40-dpendent NLRP3 inflammasome activation. These results might provide potential significance for EMPA in VC therapy of T2DM patients.

Risk factors for peripheral artery disease and diabetic peripheral neuropathy among patients with type 2 diabetes.

AIMS: To investigate the prevalence of peripheral artery disease (PAD) and diabetic peripheral neuropathy (DPN) and the associated risk factors among Chinese patients with type 2 diabetes mellitus. METHODS: A cross-sectional study was conducted using data between November 1, 2018, and December 31, 2022. PAD was defined as ABI ≤ 0.9. DPN diagnosis involved specialized physician assessments using questionnaires and vibration perception threshold tests. Logistic regression analysis was used to identify related factors. We also evaluated the association between the clustering of risk factors and disease incidence. RESULTS: The study population comprised 13,315 patients (mean age: 63.3 years). 4.9 % of the patients had PAD and 43.9 % had DPN. Multivariate regression analysis revealed advanced age, smoking, hypertension, coronary heart disease, dyslipidemia, elevated HbA1c, and uric acid levels as independent risk factors for PAD. For DPN, independent risk factors included advanced age, female gender, hypertension, coronary heart disease, elevated total cholesterol, triglycerides, lipoprotein(a), fasting plasma glucose, HbA1c, alkaline phosphatase, cystatin C, albumin-to-creatinine ratio, and elevated homocysteine levels, whereas apolipoprotein A was a protective factor. The clustering of risk factors was prevalent and associated with higher disease risk. CONCLUSIONS: Our study contributed to identifying high-risk individuals and improving lower limb health among diabetic individuals.

Multi-dimensional information sensing of complex surfaces based on fringe projection profilometry.

Multi-dimensional and high-resolution information sensing of complex surface profiles is critical for investigating various structures and analyzing their mechanical properties. This information is currently accessed separately through different technologies and devices. Fringe projection profilometry (FPP) has been widely applied in shape measurement of complex surfaces. Since structured light information is projected instead of being attached onto the surface, it holds back accurately tracking corresponding points and fails to further analyze deformation and strain. To address this issue, we propose a multi-dimensional information sensing method based on digital image correction (DIC)-assisted FPP. Firstly, colorful fluorescent markers are introduced to produce modulated information with both high-intensity reflectivity and color difference. And then, the general information separation method is presented to simultaneously acquire speckle-free texture, fringe patterns and high-contrast speckle patterns for multi-dimensional information sensing. To the best of our knowledge, this proposed method, for the first time, simultaneously realizes accurate and high-resolution 2D texture (T), 4D shape (x, y, z, t) and analytical dimensional mechanical parameters (deformation (d), strain (s)) information sensing based on the FPP system. Experimental results demonstrate the proposed method can measure and analyze 3D geometry and mechanical state of complex surfaces, expanding the measuring dimension of the off-the-shelf FPP system without any extra hardware cost.

Oleoylethanolamide alleviates hyperlipidaemia-mediated vascular calcification via attenuating mitochondrial DNA stress triggered autophagy-dependent ferroptosis by activating PPARα.

Vascular calcification, a prevalent pathological alteration in metabolic syndromes, is tightly related with cardiometabolic risk events. Ferroptosis, a newly iron-dependent programmed cell death, induced by palmitic acid (PA), the major saturated free fatty acid in hyperlipidemia, is a vital mechanism of vascular calcification. Recent studies reported that ferroptosis is a distinctive type of cell death dependent on autophagy, with the lipotoxicity of PA on cell viability being closely linked with autophagy. Oleoylethanolamide (OEA), an endogenous bioactive mediator of lipid homeostasis, exerts vascular protection against intimal calcification, atherosclerosis; however, its beneficial effect on vascular smooth muscle cell (VSMC)-associated medial calcification has not been investigated. Our aim was to characterize the effect of OEA on vascular calcification and ferroptosis of VSMCs under hyperlipidaemia/PA exposure. In vivo, vascular calcification model was induced in rats by high-fat diet and vitamin D3 plus nicotine; in vitro, VSMCs ferroptosis was induced by PA or plus ß-glycerophosphate mimicking vascular calcification. The calcium deposition in hyperlipidaemia-mediated rat thoracic aortas, the PA-induced ferroptosis and subsequent calcium deposition in VSMCs, were suppressed by OEA treatment. Additionally, CGAS-STING1-induced ferritinophagy, the main molecular mechanism of PA-triggered ferroptosis of VSMCs, was activated by mitochondrial DNA damage; however, early administration of OEA alleviated these phenomena. Intriguingly, overexpression of peroxisome proliferator activated receptor alpha (PPARα) contributed to a decrease in PA-induced ferroptosis, whereas PPARɑ knockdown inhibited the OEA-mediated anti-ferroptotic effects. Collectively, our study demonstrated that OEA serves as a prospective candidate for the prevention and treatment of vascular calcification in metabolic abnormality syndromes.

Time-overlapping structured-light projection: high performance on 3D shape measurement for complex dynamic scenes.

High-speed three-dimensional (3D) shape measurement has been continuously researched due to the demand for analyzing dynamic behavior in transient scenes. In this work, a time-overlapping structured-light 3D shape measuring technique is proposed to realize high-speed and high-performance measurement on complex dynamic scenes. Time-overlapping structured-light projection is presented to maximumly reduce the information redundancy in temporal sequences and improve the measuring efficiency; generalized tripartite phase unwrapping (Tri-PU) is used to ensure the measuring robustness; fringe period extension is achieved by improving overlapping rate to further double the encoding fringe periods for higher measuring accuracy. Based on the proposed measuring technique, one new pixel-to-pixel and unambiguous 3D reconstruction result can be updated with three newly required patterns at a reconstruction rate of 3174 fps. Three transient scenes including collapsing wood blocks struck by a flying arrow, free-falling foam snowflakes and flying water balloon towards metal grids were measured to verify the high performance of the proposed method in various complex dynamic scenes.

Three-dimensional shape and deformation measurement on complex structure parts.

Stereo digital image correlation technique (stereo-DIC or 3D-DIC) has been widely used in three-dimensional (3D) shape and deformation measurement due to its high accuracy and flexibility. But it is a tough task for it to deal with complex structure components because of the severe perspective distortion in two views. This paper seeks to resolve this issue using a single-camera system based on DIC-assisted fringe projection profilometry (FPP). A pixel-wise and complete 3D geometry of complex structures can be reconstructed using the robust and efficient Gray-coded method based on a FPP system. And then, DIC is just used to perform the temporal matching and complete full-field pixel-to-pixel tracking. The in- and out-of-plane deformation are obtained at the same time by directly comparing the accurate and complete 3D data of each corresponding pixel. Speckle pattern design and fringe denoising methods are carefully compared and chosen to simultaneously guarantee the measuring accuracy of 3D shape and deformation. Experimental results demonstrate the proposed method is an effective means to achieve full-field 3D shape and deformation measurement on complex parts, such as honeycomb structure and braided composite tube, which are challenging and even impossible for the traditional stereo-DIC method.

Loss-of-function variants in FSIP1 identified by targeted sequencing are associated with one particular subtype of mucosal melanoma.

BACKGROUND: Mucosal melanoma is a tumor caused by the malignant transformation of pigment-producing cells and can arise from any mucosal tissue where melanocytes are present. Due to its rarity, the mucosal melanoma subtype is poorly described, and its genetic characteristics are infrequently studied. The discovery or confirmation of new mucosal melanoma susceptibility genes will provide important insights for the study of its pathogenesis. MATERIALS AND METHODS: We performed deep targeted sequencing of 100 previously reported melanoma-related genes in 39 mucosal melanoma samples and a gene-level loss-of-function (LOF) variant enrichment analysis for mucosal melanoma from different incidence sites. RESULTS: We detected 7,589 variants in these samples, and 484 were LOF variants (gain or loss of a stop codon, missense, and splice site). Four different gene-level enrichment analyses revealed that FSIP1 (fibrous sheath interacting protein 1) is a susceptibility gene for oral mucosal melanoma (OR = 0.33, PChi = 4.05 × 10-2, Pburden = 3.06 × 10-2, Pskat = 3.01 × 10-2, Pskato = 3.01 × 10-2), whereas the different methods did not detect a significant susceptibility gene for the other subtypes. CONCLUSIONS: In our study, a susceptibility gene for oral mucosal melanoma was confirmed in a Chinese Han population, and these findings contribute to a better genetic understanding of mucosal melanoma of different subtypes.

Oleoylethanolamide stabilizes atherosclerotic plaque through regulating macrophage polarization via AMPK-PPARα pathway.

BACKGROUND: Atherosclerotic plaque rupture is the major trigger of acute cardiovascular risk events, and manipulation of M1/M2 macrophage homeostasis is an effective strategy for regulating atherosclerotic plaque stability. This study was aimed to illuminate the effects of oleoylethanolamide (OEA) on macrophage polarization and plaque stability. METHODS: Macrophages derived from THP-1 were treated with OEA followed by LPS/IFN-γ, and the markers of M1, M2 macrophages were monitored by western blot, real-time PCR and immunofluorescence staining. The effect of OEA on macrophage polarization in the arch of aortic arteries was tested by immunofluorescence staining and western blot, and the plaque stability was completed by Masson's trichrome and hematoxylin and eosin (HE) in apolipoprotein E (ApoE)-/- mice. RESULTS: OEA treatment enhanced the expression of two classic M2 macrophage markers, macrophage mannose receptor (CD206) and transforming growth factor (TGF-ß), while the expression of iNOS (M1 macrophages) was decreased in THP-1-derived macrophages. Blocking of PPARα using siRNA and inhibition of AMP-activated protein kinase (AMPK) by its inhibitor compound C attenuated the OEA-induced expression of M2 macrophage markers. In addition, OEA significantly suppressed M1, promoted M2 macrophage polarization, increased collagen content and decreased necrotic core size in atherosclerotic plaques in ApoE-/- mice, which were linked with the expression of PPARα. CONCLUSIONS: OEA improved atherosclerotic plaque stability through regulating macrophage polarization via AMPK-PPARα pathway.

Breathable Nanowood Biofilms as Guiding Layer for Green On-Skin Electronics.

Thin-film electronics are urged to be directly laminated onto human skin for reliable, sensitive biosensing together with feedback transdermal therapy, their self-power supply using the thermoelectric and moisture-induced-electric effects also has gained great attention (skin and on-skin electronics (On-skinE) themselves are energy storehouses). However, "thin-film" On-skinE 1) cannot install "bulky" heatsinks or sweat transport channels, but the output power of thermoelectric generator and moisture-induced-electric generator relies on the temperature difference (∆T ) across generator and the ambient humidity (AH), respectively; 2) lack a routing and accumulation of sweat for biosensing, lack targeted delivery of drugs for precise transdermal therapy; and 3) need insulation between the heat-generating unit and heat-sensitive unit. Here, two breathable nanowood biofilms are demonstrated, which can help insulate between units and guide the heat and sweat to another in-plane direction. The transparent biofilms achieve record-high transport// /transport⊥ (//: along cellulose nanofiber alignment direction, ⊥: perpendicular direction) of heat (925%) and sweat (338%), winning applications emphasizing on ∆T/AH-dependent output power and "reliable" biosensing. The porous biofilms are competent in applications where "sensitive" biosensing (transporting// sweat up to 11.25 mm s-1 at the 1st second), "insulating" between units, and "targeted" delivery of saline-soluble drugs are of uppermost priority.

DT-13 ameliorates TNF-α-induced nitric oxide production in the endothelium in vivo and in vitro.

The steroidal saponin DT-13 (25(R,S)-ruscogenin-1-O-[ß-d-glucopyranosyl-(1 â†’ 2)][ß-d-xylopyranosyl-(1 â†’ 3)]-ß-d-fucopyranoside), one of the major active compounds of the herb Liriope muscari (Decne.), exhibits significant anti-inflammatory, anti-tumor and cardioprotective effects. This study aimed to explore the protective effect of DT-13 on endothelium through regulating of nitric oxide production induced by Tumor necrosis factor-α (TNF-α). The results demonstrated that DT-13 inhibited inflammatory cell infiltration and thus played a protective effect on endothelial cells in vivo, as shown by hematoxylin-eosin (H&E) staining and immunohistochemical staining. Enzyme-linked immunosorbent assay (ELISA) results demonstrated that DT-13 could suppress the TNF-α-induced upregulation of reactive oxygen species (ROS), tumor necrosis factor receptor (TNFR), interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1) and nitric oxide in vivo dose-dependently and suppressed production of nitric oxide in vitro as shown by DAF-FMDA. Western blotting results indicated that DT-13 could down-regulate phosphorylation of endothelial nitric oxide synthase (eNOS) significantly in TNF-α-induced human umbilical vein endothelial cells (HUVECs). Taken together, we speculate that DT-13 inhibits endothelium vascular inflammation through regulating nitric oxide production and the expression of ROS, TNFR, IL-8, MCP-1, which are associated with inflammation.

Safety and efficacy of first-line bevacizumab combined with taxane therapy in Chinese patients with HER2-negative locally recurrent or metastatic breast cancer: findings from the ATHENA study.

BACKGROUND: Three randomised trials have demonstrated that combining bevacizumab with first-line chemotherapy significantly improves progression-free survival versus chemotherapy alone in HER2-negative locally recurrent/metastatic breast cancer (LR/mBC). However, data from Chinese populations are limited and possible differences between ethnic and geographic populations are unknown. This study was conducted to determine whether there are differences in safety and efficacy in patients with HER2-negative LR/mRC between Chinese and Western populations after they receive first-line bevacizumab combined with taxane-based therapy. METHODS: In the single-arm, open-label, Avastin Therapy for Advanced Breast Cancer (ATHENA) study (NCT00448591), patients with HER2-negative LR/mBC received first-line bevacizumab (investigator's choice of 10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks) combined with taxane-based therapy. The primary endpoint was safety profile and the secondary is time to progression (TTP). A subpopulation analysis was conducted to assess safety and efficacy in Chinese patients. RESULTS: Of 2264 patients treated in ATHENA, 202 were enrolled in China. Bevacizumab was combined with docetaxel in 90% of Chinese patients and paclitaxel in 10%. The most common grade 3/4 adverse events were diarrhoea (in 5.0% of patients) and hypertension (in 2.5% of patients). Grade 3/4 proteinuria occurred in 0.5%. After median follow-up of 17.6 months and events in 56% of patients, median TTP was 9.0 months (95%CI, 8.4-11.1). Overall survival data were immature. CONCLUSIONS: We found no evidence of increased bevacizumab-related toxicity or reduced efficacy in Chinese LR/mBC patients receiving first-line bevacizumab-taxane therapy compared with predominantly Western populations. The safety profile was generally similar to previously reported LR/mBC trials. Subtle differences may be attributable to different lifestyle and cardiovascular risk factors in Chinese patients compared with the overall population. It appears reasonable to extrapolate findings from bevacizumab-based randomised trials to Chinese populations.