Withaferin A as a Potential Therapeutic Target for the Treatment of Angiotensin II-Induced Cardiac Cachexia.

In our previous studies, we showed that the generation of ovarian tumors in NSG mice (immune-compromised) resulted in the induction of muscle and cardiac cachexia, and treatment with withaferin A (WFA; a steroidal lactone) attenuated both muscle and cardiac cachexia. However, our studies could not address if these restorations by WFA were mediated by its anti-tumorigenic properties that might, in turn, reduce the tumor burden or WFA's direct, inherent anti-cachectic properties. To address this important issue, in our present study, we used a cachectic model induced by the continuous infusion of Ang II by implanting osmotic pumps in immunocompetent C57BL/6 mice. The continuous infusion of Ang II resulted in the loss of the normal functions of the left ventricle (LV) (both systolic and diastolic), including a significant reduction in fractional shortening, an increase in heart weight and LV wall thickness, and the development of cardiac hypertrophy. The infusion of Ang II also resulted in the development of cardiac fibrosis, and significant increases in the expression levels of genes (ANP, BNP, and MHCß) associated with cardiac hypertrophy and the chemical staining of the collagen abundance as an indication of fibrosis. In addition, Ang II caused a significant increase in expression levels of inflammatory cytokines (IL-6, IL-17, MIP-2, and IFNγ), NLRP3 inflammasomes, AT1 receptor, and a decrease in AT2 receptor. Treatment with WFA rescued the LV functions and heart hypertrophy and fibrosis. Our results demonstrated, for the first time, that, while WFA has anti-tumorigenic properties, it also ameliorates the cardiac dysfunction induced by Ang II, suggesting that it could be an anticachectic agent that induces direct effects on cardiac muscles.

Excessive fat expenditure in MCT-induced heart failure rats is associated with BMAL1/REV-ERBα circadian rhythmic loop disruption.

Fat loss predicts adverse outcomes in advanced heart failure (HF). Disrupted circadian clocks are a primary cause of lipid metabolic issues, but it's unclear if this disruption affects fat expenditure in HF. To address this issue, we investigated the effects of disruption of the BMAL1/REV-ERBα circadian rhythmic loop on adipose tissue metabolism in HF.50 Wistar rats were initially divided into control (n = 10) and model (n = 40) groups. The model rats were induced with HF via monocrotaline (MCT) injections, while the control group received equivalent solvent injections. After establishing the HF model, the model group was further subdivided into four groups: normal rhythm (LD), inverted rhythm (DL), lentivirus vector carrying Bmal1 short hairpin RNA (LV-Bmal1 shRNA), and empty lentivirus vector control (LV-Control shRNA) groups, each with 10 rats. The DL subgroup was exposed to a reversed light-dark cycle of 8 h: 16 h (dark: light), while the rest adhered to normal light-dark conditions (light: dark 12 h: 12 h). Histological analyses were conducted using H&E, Oil Red O, and Picrosirius red stains to examine adipose and liver tissues. Immunohistochemical staining, RT-qPCR, and Western blotting were performed to detect markers of lipolysis, lipogenesis, and beiging of white adipose tissue (WAT), while thermogenesis indicators were detected in brown adipose tissue (BAT). The LD group rats exhibited decreased levels of BMAL1 protein, increased levels of REV-ERBα protein, and disrupted circadian circuits in adipose tissue compared to controls. Additionally, HF rats showed reduced adipose mass and increased ectopic lipid deposition, along with smaller adipocytes containing lower lipid content and fibrotic adipose tissue. In the LD group WAT, expression of ATGL, HSL, PKA, and p-PKA proteins increased, alongside elevated mRNA levels of lipase genes (Hsl, Atgl, Peripilin) and FFA ß-oxidation genes (Cpt1, acyl-CoA). Conversely, lipogenic gene expression (Scd1, Fas, Mgat, Dgat2) decreased, while beige adipocyte markers (Cd137, Tbx-1, Ucp-1, Zic-1) and UCP-1 protein expression increased. In BAT, HF rats exhibited elevated levels of PKA, p-PKA, and UCP-1 proteins, along with increased expression of thermogenic genes (Ucp-1, Pparγ, Pgc-1α) and lipid transportation genes (Cd36, Fatp-1, Cpt-1). Plasma NT-proBNP levels were higher in LD rats, accompanied by elevated NE and IL-6 levels in adipose tissue. Remarkably, morphologically, the adipocytes in the DL and LV-Bmal1 shRNA groups showed reduced size and lower lipid content, while lipid deposition in the liver was more pronounced in these groups compared to the LD group. At the gene/protein level, the BMAL1/REV-ERBα circadian loop exhibited severe disruption in LV-Bmal1 shRNA rats compared to LD rats. Additionally, there was increased expression of lipase genes, FFA ß oxidation genes, and beige adipocyte markers in WAT, as well as higher expression of thermogenic genes and lipid transportation genes in BAT. Furthermore, plasma NT-proBNP levels and adipose tissue levels of NE and IL-6 were elevated in LV-Bmal1 shRNA rats compared with LD rats. The present study demonstrates that disruption of the BMAL1/REV-ERBα circadian rhythmic loop is associated with fat expenditure in HF. This result suggests that restoring circadian rhythms in adipose tissue may help counteract disorders of adipose metabolism and reduce fat loss in HF.

Alzheimer's disease and low-dose radiation therapy: A new hope.

The concept of low-dose radiation (LDR)-induced hormetic responses was initially observed approximately 70 years ago and systematically reviewed along with the discovery of LDR-induced adaptive responses in a cytogenetic in vitro study in 1980s. By the end of the 1990s, discussions regarding the potential applications of LDR-induced hormesis and adaptive responses for preventing or treating chronic diseases, such as Alzheimer's disease (AD) had taken place. Until 2016, reports on radiotherapy for the subjects with AD and for genetic AD model mice were published. Subsequently, several preclinical studies with animal models of AD and clinical studies in AD subjects were conducted. A significant milestone was achieved with the online availability of a new Systematic Review based on qualified publications from these preclinical and clinical studies. This mini-review provides a concise historical introduction to LDR-induced hormesis and adaptive responses with discussion of AD radiotherapy with either LDR or relatively high dose radiation. Highlights of this Systematic Review cover promising outcomes, challenges, and new questions, followed by discussion of potential mechanisms.

Investigation of Metabolic and Inflammatory Disorder in the Aging FGF21 Knockout Mouse.

Aging is a physiological condition accomplished with persistent low-grade inflammation and metabolic disorders. FGF21 has been reported to act as a potent longevity determinant, involving inflammatory response and energy metabolism. In this study, we engineered aging FGF21 knockout mice of 36-40 weeks and observed that FGF21 deficiency manifests a spontaneous inflammatory response of lung and abnormal accumulation of lipids in liver. On one hand, inflamed state in lungs and increased circulating inflammatory cytokines were found in FGF21 knockout mice of 36-40 weeks. To evaluate the ability of FGF21 to suppress inflammation, a subsequent study found that FGF21 knockout aggravated LPS-induced pulmonary exudation and inflammatory infiltration in mice, while exogenous administration of FGF21 reversed these malignant phenotypes by enhancing microvascular endothelial junction. On the other hand, FGF21 knockout induces fatty liver in aging mice, characterized by excessive accumulation of triglycerides within hepatocytes. Further quantitative metabolomics and lipidomics analysis revealed perturbed metabolic profile in liver lacking FGF21, including disrupted glucose and lipids metabolism, glycerophospholipid metabolism, and amino acid metabolism. Taken together, this investigation reveals the protective role of FGF21 during aging by weakening the inflammatory response and balancing energy metabolism.

Analysis of drug-induced posterior reversible encephalopathy syndrome using the food and drug administration adverse drug events reporting system database.

OBJECTIVE: In this retrospective pharmacovigilance study, we gathered data on drug-induced posterior reversible encephalopathy syndrome (PRES). Our goal was to identify the primary suspect drugs in PRES by analyzing the Food and Drug Administration Adverse Events Reporting System (FAERS) database. METHODS: We identified and analyzed reports of PRES listed in the FAERS database between 2004 and 2021. Using the reporting odds ratio and 95% confidence interval, we evaluated the safety signals for each of the drugs associated with PRES. RESULTS: We reviewed 11,077 reports of adverse events corresponding to PRES. The primary suspect drug categories were antineoplastics, immunosuppressants, and glucocorticoids. PRES was 24.77% more likely to occur in females than in males. Drug-induced PRES usually occurs in individuals with cancer, those who have undergone an organ/stem cell transplant, and those with autoimmune conditions. CONCLUSION: Our results show that the drugs most commonly suspected to cause PRES were antineoplastics, immunosuppressants, and glucocorticoids. Future studies are needed to illuminate the pathophysiological alterations that underlie PRES. In the meantime, prescribers and patients should be made aware of the potential risks of PRES associated with pharmaceutical therapy, and the summaries of product characteristics for individual drugs should be updated to include this information.

Adenosine Triphosphate/Chitin Whisker/Phenylboronic Acid-Modified Wool Fabrics with Enhanced Dyeability.

Promoting the uptake of dyes is an important part of the sustainable processing of wool products. This study presents an effective modification approach to enhance the dyeability of wool fabric with adenosine triphosphate as an activator, 3-carboxyphenyl boronic acid as a ligand-binding agent, and chitin whisker as a couple agent. The structure and surface morphology of the as-prepared wool fabric was characterized in detail. Natural luteolin and acid red 1 were used to dye the modified wool fabric, and the effect of different dyeing parameters on dyeing properties was discussed. The results indicated that the modified wool gained better surface color depth (K/S) and uptake without additional agents than the untreated wool fabric. When the modified wool fabric was dyed at 45 °C with luteolin and at 60 °C with acid red 1, the dyeing processes of the two dyes on the modified wool fabrics followed the Langmuir isotherm and the pseudo-second-order kinetic model. Furthermore, the dyed modified wool fabrics possessed improved color fastness. Overall, this work offers a facile, effective, and sustainable way to improve the low-temperature dyeability of wool products.

A hypothesis: Potential contributions of metals to the pathogenesis of pulmonary artery hypertension.

Pulmonary artery hypertension (PAH) is characterized by vasoconstriction and vascular remodeling resulting in both increased pulmonary vascular resistance (PVR) and pulmonary artery pressure (PAP). The chronic and high-pressure stress experienced by endothelial cells can give rise to inflammation, oxidative stress, and infiltration by immune cells. However, there is no clearly defined mechanism for PAH and available treatment options only provide limited symptomatic relief. Due to the far-reaching effects of metal exposures, the interaction between metals and the pulmonary vasculature is of particular interest. This review will briefly introduce the pathophysiology of PAH and then focus on the potential roles of metals, including essential and non-essential metals in the pathogenic process in the pulmonary arteries and right heart, which may be linked to PAH. Based on available data from human studies of occupational or environmental metal exposure, including lead, antimony, iron, and copper, the hypothesis of metals contributing to the pathogenesis of PAH is proposed as potential risk factors and underlying mechanisms for PAH. We propose that metals may initiate or exacerbate the pathogenesis of PAH, by providing potential mechanism by which metals interact with hypoxia-inducible factor and tumor suppressor p53 to modulate their downstream cellular proliferation pathways. These need further investigation. Additionally, we present future research directions on roles of metals in PAH.

An efficient instance segmentation approach for studying fission gas bubbles in irradiated metallic nuclear fuel.

Gaseous fission products from nuclear fission reactions tend to form fission gas bubbles of various shapes and sizes inside nuclear fuel. The behavior of fission gas bubbles dictates nuclear fuel performances, such as fission gas release, grain growth, swelling, and fuel cladding mechanical interaction. Although mechanical understanding of the overall evolution behavior of fission gas bubbles is well known, lacking the quantitative data and high-level correlation between burnup/temperature and microstructure evolution blocks the development of predictive models and reduces the possibility of accelerating the qualification for new fuel forms. Historical characterization of fission gas bubbles in irradiated nuclear fuel relied on a simple threshold method working on low-resolution optical microscopy images. Advanced characterization of fission gas bubbles using scanning electron microscopic images reveals unprecedented details and extensive morphological data, which strains the effectiveness of conventional methods. This paper proposes a hybrid framework, based on digital image processing and deep learning models, to efficiently detect and classify fission gas bubbles from scanning electron microscopic images. The developed bubble annotation tool used a multitask deep learning network that integrates U-Net and ResNet to accomplish instance-level bubble segmentation. With limited annotated data, the model achieves a recall ratio of more than 90%, a leap forward compared to the threshold method. The model has the capability to identify fission gas bubbles with and without lanthanides to better understand the movement of lanthanide fission products and fuel cladding chemical interaction. Lastly, the deep learning model is versatile and applicable to the micro-structure segmentation of similar materials.

The effect of gel pads on the measurement of breast superficial lesions by shear wave elastography.

OBJECTIVE: This study aimed to compare the repeatability and diagnostic efficiency of shear wave elastography (SWE) while using coupling gel and gel pads in the diagnosis of superficial breast lesions. METHODS: Two experienced sonographers, trained in SWE, used different methods to perform the maximum Young's modulus (Emax) measurement of the lesion while using coupling gel SWE and gel pad SWE at different time points. All 80 lesions were in the superficial layer of the breast. The interclass correlation coefficient (ICC) was calculated to evaluate the intraobserver and interobserver repeatability. Meanwhile, the receiver operating characteristic curve (ROC curve) was used to calculate the sensitivity, specificity and area under the curve of the two methods. RESULTS: In the 80 breast lesions, the intraobserver and interobserver reproducibility of SWE measurements using coupling gel were considered good, and the ICCs were 0.728 (95% CI: 0.509-0.813) and 0.702 (95% CI: 0.492-0.795), respectively. The intraobserver and interobserver reproducibility of the SWE measured by the gel pad were also considered good, and the ICCs were 0.745 (95% CI: 0.501-0.801) and 0.713 (95% CI: 0.498-0.802), respectively. The sensitivity, specificity and area under the curve were 0.711 and 0.737, 0.929 and 0.905, and 0.873 and 0.878, respectively. CONCLUSIONS: In the SWE measurement of superficial breast lesions, the use of a gel pad does not affect the repeatability and diagnostic efficiency of the measurement.

The use of gel pads does not affect repeatability and diagnostic efficiency but also improves the near-field resolution of images.The gel pad has certain advantages in the observation of superficial lesions.

Sludge biodrying coupled with photocatalysis improves the degradation of extracellular polymeric substances.

The efficiency of sludge dewatering is limited by extracellular polymeric substances (EPS) during biodrying. This study investigated the effect of photocatalysis-mediated EPS degradation on sludge dewatering performance during the sludge biodrying process. The photocatalysis of municipal sludge was first carried out to choose a cost-efficient catalyst. Then sludge biodrying tests were performed using TiO2-coated amendment (TCA) and uncoated amendment (TUCA) as the control. Municipal sludge photocatalysis results showed that using TiO2 could efficiently degrade carbohydrates and proteins in the EPS within 60 min. After 20-day biodrying, photocatalysis significantly promoted a reduction in the moisture content and EPS by 17.64% and 6.88%, respectively. The surface-enhanced Raman scattering (SERS) intensities of the C-C-O symmetric stretching vibration peak of D-lactose and the C-S stretching vibration peak of cysteine were significantly decreased by approximately 33.19% and 44.76%, respectively, indicating that photocatalysis indeed promoted the reduction of polysaccharides and cysteine in the EPS, especially after the thermophilic phase. The hydrophilic amino acid content decreased by 23.02%, verifying that photocatalysis could improve EPS hydrophobicity. Consequently, municipal sludge biodrying coupled with photocatalysis promotes sludge EPS degradation and enhances sludge dewaterability, improving the efficiency of sludge biodrying.

The abundance, characteristics and distribution of microplastics (MPs) in farmland soil-Based on research in China.

Microplastics (MPs) in farmland soil deteriorate soil environment and increase food toxicity, thereby threatening the agricultural production environment and human safety. However, a systematic understanding of MPs pollution in farmland soil is lacking in China. Therefore, the relevant literature was comprehensively discussed to discuss the abundance, characteristics, distribution and influencing factors of MPs in farmland soil. The conclusions are as follows: (1) The highest and lowest MPs abundance were in marginal tropical humid and plateau temperate semi-arid regions, accounting for 7579 n/kg and 48 n/kg, respectively. (2) The main shapes of MPs in farmland soil are fragment/flake and fiber, accounting for 44.0 % and 34.4 %, respectively. The MPs are mostly transparent (21.8 %) and black (21.5 %). Among the MPs types, polyethylene (PE) and polypropylene (PP) are dominant, accounting for 26.2 % and 19.0 %, respectively. The main size of MPs in farmland soil is 0.1-0.5 mm, with average proportions was 51.4 %. (3) Compared with non-fertilizing and non-mulching, the MPs abundance in the fertilizing and mulching farmland soils increased by 170 % and 232 %, respectively. (4) In the farmland soil, the MPs abundance was significantly positive with temperature, sunshine hour, and altitude. (5) In farmland soil of China, the most commonly used MPs dispersion treatment was H2O2 solution digestion, the extracting solution commonly used for density flotation was NaCl solution, and microscopic and spectroscopic measurements were typically used measurements. The results could provide a basis for monitoring the MP abundances in farmland soil and preventing the transfer of MPs pollution in soil.

Metallomics in pulmonary arterial hypertension patients.

Pulmonary arterial hypertension (PAH) prevalence is increasing worldwide, and the prognosis is poor with 5-year survival < 50% in high risk patients. The relationship between metal exposure/essential metal dyshomeostasis and PAH/right ventricular dysfunction is less investigated. The aim of this study is to investigate vegetable consumptions and metal levels between PAH patients and controls. This was a prospective, single center pilot study. Questionnaires were completed by all study subjects (20 PAH patients and 10 healthy controls) on smoking, metal exposure risks, metal supplements, and vegetable consumptions. Blood and urine samples were collected to measure 25 metal levels in blood, plasma, and urine using an X Series II quadrupole inductively coupled plasma mass spectrometry. Statistical analysis was conducted using SAS 9.5 and results with p value < 0.05 were considered significant. Vegetables consumptions (broccoli risk ratio [RR] = 0.4, CI = (0.2, 0.9)], cabbage [RR = 0.2, CI = (0.1, 0.8)], and brussel sprouts [RR = 0.2, CI = (0.1, 0.5)]) are associated with less risks of PAH. In the plasma samples, silver (p < 0.001), and copper (p = 0.002) levels were significantly higher in PAH patients. There was significant positive correlation between cardiac output and cardiac index with plasma levels of silver (r = 0.665, p = 0.001 and r = 0.678 p = 0.001), respectively. There was significant correlation between mixed venous saturation, 6-min walk distance, and last BNP with plasma levels of chromium (r = -0.520, p = 0.022; r = -0.55, p = 0.014; r = 0.463, p = 0.039), respectively. In conclusion, there are significant differences between PAH and control groups in terms of vegetable consumptions and metal concentrations. Silver and chromium levels are correlated with clinical indicators of PAH severities.

Does maternal low-dose cadmium exposure increase the risk of offspring to develop metabolic syndrome and/or type 2 diabetes?

Cadmium is a hazardous metal with multiple organ toxicity that causes great harm to human health. Cadmium enters the human body through occupational exposure, diet, drinking water, breathing, and smoking. Cadmium accumulation in the human body is associated with increased risk of developing obesity, cardiovascular disease, diabetes, and metabolic syndrome (MetS). Cadmium uptake is enhanced during pregnancy and can cross the placenta affecting placental development and function. Subsequently, cadmium can pass to fetus, gathering in multiple organs such as the liver and pancreas. Early-life cadmium exposure can induce hepatic oxidative stress and pancreatic ß-cell dysfunction, resulting in insulin resistance and glucose metabolic dyshomeostasis in the offspring. Prenatal exposure to cadmium is also associated with increasing epigenetic effects on the offspring's multi-organ functions. However, whether and how maternal exposure to low-dose cadmium impacts the risks of developing type 2 diabetes (T2D) in the young and/or adult offspring remains unclear. This review collected available data to address the current evidence for the potential role of cadmium exposure, leading to insulin resistance and the development of T2D in offspring. However, this review reveals that underlying mechanisms linking prenatal cadmium exposure during pregnancy with T2D in offspring remain to be adequately investigated.

Astragalus polysaccharide prevents heart failure-induced cachexia by alleviating excessive adipose expenditure in white and brown adipose tissue.

BACKGROUND: Astragalus polysaccharide (APS) is a key active ingredient isolated from Astragalus membranaceus that has been reported to be a potential treatment for obesity and diabetes by regulating lipid metabolism and adipogenesis, alleviating inflammation, and improving insulin resistance. However, whether APS regulates lipid metabolism in the context of cachexia remains unclear. Therefore, this study analysed the effects of APS on lipid metabolism and adipose expenditure in a heart failure (HF)-induced cardiac cachexia rat model.  METHODS: A salt-sensitive hypertension-induced cardiac cachexia rat model was used in the present study. Cardiac function was detected by echocardiography. The histological features and fat droplets in fat tissue and liver were observed by H&E staining and Oil O Red staining. Immunohistochemical staining, Western blotting and RT‒qPCR were used to detect markers of lipolysis and adipose browning in white adipose tissue (WAT) and thermogenesis in brown adipose tissue (BAT). Additionally, sympathetic nerve activity and inflammation in adipose tissue were detected. RESULTS: Rats with HF exhibited decreased cardiac function and reduced adipose accumulation as well as adipocyte atrophy. In contrast, administration of APS not only improved cardiac function and increased adipose weight but also prevented adipose atrophy and FFA efflux in HF-induced cachexia. Moreover, APS inhibited HF-induced lipolysis and browning of white adipocytes since the expression levels of lipid droplet enzymes, including HSL and perilipin, and beige adipocyte markers, including UCP-1, Cd137 and Zic-1, were suppressed after administration of APS. In BAT, treatment with APS inhibited PKA-p38 MAPK signalling, and these effects were accompanied by decreased thermogenesis reflected by decreased expression of UCP-1, PPAR-γ and PGC-1α and reduced FFA ß-oxidation in mitochondria reflected by decreased Cd36, Fatp-1 and Cpt1. Moreover, sympathetic nerve activity and interleukin-6 levels were abnormally elevated in HF rats, and astragalus polysaccharide could inhibit their activity. CONCLUSION: APS prevented lipolysis and adipose browning in WAT and decreased BAT thermogenesis. These effects may be related to suppressed sympathetic activity and inflammation. This study provides a potential approach to treat HF-induced cardiac cachexia.

Occurrence and distribution of microplastics in surface sediments of a typical river with a highly eroded catchment, a case of the Yan River, a tributary of the Yellow River.

Investigation of microplastic contamination in riverbed sediments can help clarify long-term microplastic pollution and establish prevention measures in watersheds. However, little research has been conducted on riverbed sediment pollution on the Loess Plateau, a highly eroded area in Northwest China. This research investigates the Yan River as a case study. The occurrence and distribution of microplastics were surveyed and analyzed to explore the microplastic pollution in the riverbed of the Loess Plateau. Microplastics were found in all sediment samples, with an abundance of 208.89-686.67 items kg-1. Polypropylene and polyethylene were the main microplastic components identified using Fourier transform infrared spectrometry and imaging systems. Particles 0.5-1.0 mm in size accounted for 38.5 % of the total microplastics in this region. The main microplastic colors were black, white, and transparent, which accounted for 40.75 %, 20.75 %, and 20.38 % of the total microplastics, respectively. There was an increasing trend in the microplastic abundance in sediments in the downstream direction that accompanied the increase in population density from 55.31 persons km-2 upstream to 230.05 persons km-2 downstream. Microplastic pollution was related to the complex geographical, semiarid monsoon climate, elevation, grassland, per capita GDP, and anthropogenic factors in the Yan River basin. The erodible loess and high-intensity rainstorm promoted severe soil erosion, which caused microplastics absorbed in the soil to migrate to the river. Poorly managed solid wastes, such as agricultural mulch, plastic bottles, and other plastic products are also sources of microplastics in the riverbed. This study further clarifies microplastic pollution in typical rivers of highly erosive areas and provides useful information for basin management.

CXCR7 Agonist TC14012 Improves Angiogenic Function of Endothelial Progenitor Cells via Activating Akt/eNOS Pathway and Promotes Ischemic Angiogenesis in Diabetic Limb Ischemia.

PURPOSE: Endothelial progenitor cells (EPCs) play a critical role in repairing damaged vessels and triggering ischemic angiogenesis, but their number is reduced and function is impaired under diabetic conditions. Improving EPC function has been considered a promising strategy to ameliorate diabetic vascular complications. In the present study, we aim to investigate whether and how CXCR7 agonist TC14012 promotes the angiogenic function of diabetic EPCs. METHODS: High glucose (HG) treatment was used to mimic the hyperglycemia in diabetes. Tube formation, cell scratch recovery and transwell assay, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, and cleaved-caspase3 expression were used to evaluate the angiogenic capability, cell migration, and apoptosis of EPCs, respectively. Hind limb ischemia (HLI) model was used to appraise the ability of TC14012 in promoting diabetic ischemic angiogenesis in vivo. RESULTS: HG treatment impaired EPC tube formation and migration, and induced EPC apoptosis and oxidative damage, while TC14012 rescued tube formation and migration, and prevented HG-induced apoptosis and oxidative damage of EPCs. Furthermore, these beneficial effects of TC14012 on EPCs were attenuated by specific siRNAs against CXCR7, validating that CXCR7 is a functional target of TC14012 in EPCs. Mechanistic studies demonstrated that HG treatment reduced CXCR7 expression in EPCs, and impaired Akt and endothelial nitric oxide synthase (eNOS) phosphorylation and nitric oxide (NO) production; similarly, these signal impairments in HG-exposed EPCs could be rescued by TC14012. However, the protective effects of TC14012 on tube formation and migration, Akt and eNOS phosphorylation, and NO production in HG-treated EPCs were almost completely abolished by siRNAs against CXCR7 or Akt specific inhibitor wortmannin. More importantly, in vivo study showed that TC14012 administration enhanced blood perfusion recovery and angiogenesis in the ischemic hind limb and increased the EPC number in peripheral circulation of db/db mice, demonstrating the capability of TC14012 in promoting EPC mobilization and ischemia angiogenic function. CONCLUSION: TC14012 can prevent EPCs from HG-induced dysfunction and apoptosis, improve eNOS activity and NO production via CXCR7/Akt signal pathway, and promote EPC mobilization and diabetic ischemia angiogenesis.

Hypoxia-Induced Downregulation of miR-29 in Renal Tumor Cells Affects Collagen IV Subunit Expression through Multiple Sites.

Multiple tumor exacerbations and treatment procedures, such as extracellular matrix remodeling, metabolic reprogramming, immunological evasion, and resistance to chemotherapy and radiotherapy, are influenced by intratumoral hypoxia. It is becoming increasingly clear how hypoxia interacts with the extracellular matrix and how this affects the growth of cancer. We analyzed the published sequencing results of hypoxia-stressed mouse kidney tumor cells and found that the expression of miR-29b was significantly downregulated. There are several sites that are complementary to the miR-29 seed sequence in the 3' non-coding regions (3'UTRs) of various extracellular matrix-related genes, including collagen IV. We analyzed the sequences of the 3'UTRs of different subunits of collagen IV in different species and constructed the corresponding phylogenetic trees. We found that the 3'UTRs of Col4a1 and Col4a4 may have been subjected to particular evolutionary pressures. By cloning the 3'UTRs of collagen IV subunits into the psiCHECKTM-2 vector, we found that seven of the eight sites in the Col4a3-Col4a6 gene complementary to miR-29 were significantly repressed by miR-29a, b (except for the 7774-7781 of Col4a3 gene). The inhibitory efficiency of miR-29a, b on these seven sites was between 27% and 57%. The research on the regulation of miR-29 and extracellular matrix by hypoxia can provide a theoretical basis for tumor and fibrosis research and treatment.

Nrf2 transcriptional upregulation of IDH2 to tune mitochondrial dynamics and rescue angiogenic function of diabetic EPCs.

Endothelial progenitor cells (EPCs) are reduced in number and impaired in function in diabetic patients. Whether and how Nrf2 regulates the function of diabetic EPCs remains unclear. In this study, we found that the expression of Nrf2 and its downstream genes were decreased in EPCs from both diabetic patients and db/db mice. Survival ability and angiogenic function of EPCs from diabetic patients and db/db mice also were impaired. Gain- and loss-of-function studies, respectively, showed that knockdown of Nrf2 increased apoptosis and impaired tube formation in EPCs from healthy donors and wild-type mice, while Nrf2 overexpression decreased apoptosis and rescued tube formation in EPCs from diabetic patients and db/db mice. Additionally, proangiogenic function of Nrf2-manipulated mouse EPCs was validated in db/db mice with hind limb ischemia. Mechanistic studies demonstrated that diabetes induced mitochondrial fragmentation and dysfunction of EPCs by dysregulating the abundance of proteins controlling mitochondrial dynamics; upregulating Nrf2 expression attenuated diabetes-induced mitochondrial fragmentation and dysfunction and rectified the abundance of proteins controlling mitochondrial dynamics. Further RNA-sequencing analysis demonstrated that Nrf2 specifically upregulated the transcription of isocitrate dehydrogenase 2 (IDH2), a key enzyme regulating tricarboxylic acid cycle and mitochondrial function. Overexpression of IDH2 rectified Nrf2 knockdown- or diabetes-induced mitochondrial fragmentation and EPC dysfunction. In a therapeutic approach, supplementation of an Nrf2 activator sulforaphane enhanced angiogenesis and blood perfusion recovery in db/db mice with hind limb ischemia. Collectively, these findings indicate that Nrf2 is a potential therapeutic target for improving diabetic EPC function. Thus, elevating Nrf2 expression enhances EPC resistance to diabetes-induced oxidative damage and improves therapeutic efficacy of EPCs in treating diabetic limb ischemia likely via transcriptional upregulating IDH2 expression and improving mitochondrial function of diabetic EPCs.

Identification of a Novel Cuproptosis-Related Gene Signature for Prognostic Implication in Head and Neck Squamous Carcinomas.

Head and neck squamous carcinoma (HNSC) is a frequent and deadly malignancy that is challenging to manage. The existing treatment options have considerable efficacy limitations. Hence, the identification of new therapeutic targets and the development of efficacious treatments are urgent needs. Cuproptosis, a non-apoptotic programmed cell death caused by excess copper, has only very recently been discovered. The present study investigated the prognostic importance of genes involved in cuproptosis through the mRNA expression data and related clinical information of HNSC patients downloaded from public databases. Our results revealed that many cuproptosis-related genes were differentially expressed between normal and HNSC tissues in the TCGA cohort. Moreover, 39 differentially expressed genes were associated with the prognosis of HNSC patients. Then, a 24-gene signature was identified in the TCGA cohort utilizing the LASSO Cox regression model. HNSC expression data used for validation were obtained from the GEO database. Consequently, we divided patients into high- and low-risk groups based on the 24-gene signature. Furthermore, we demonstrated that the high-risk group had a worse prognosis when compared to the low-risk group. Additionally, significant differences were found between the two groups in metabolic pathways, immune microenvironment, etc. In conclusion, we found a cuproptosis-related gene signature that can be used effectively to predict OS in HNSC patients. Thus, targeting cuproptosis might be an alternative and promising strategy for HNSC patients.