Study of Impacts of Two Types of Cellular Aging on the Yeast Bud Morphogenesis.

Understanding the mechanisms of cellular aging processes is crucial for attempting to extend organismal lifespan and for studying age-related degenerative diseases. Yeast cells divide through budding, providing a classical biological model for studying cellular aging. With their powerful genetics, relatively short lifespan and well-established signaling pathways also found in animals, yeast cells offer valuable insights into the aging process. Recent experiments suggested the existence of two aging modes in yeast characterized by nucleolar and mitochondrial declines, respectively. In this study, by analyzing experimental data it was shown that cells evolving into those two aging modes behave differently when they are young. While buds grow linearly in both modes, cells that consistently generate spherical buds throughout their lifespan demonstrate greater efficacy in controlling bud size and growth rate at young ages. A three-dimensional chemical-mechanical model was developed and used to suggest and test hypothesized mechanisms of bud morphogenesis during aging. Experimentally calibrated simulations showed that tubular bud shape in one aging mode could be generated by locally inserting new materials at the bud tip guided by the polarized Cdc42 signal during the early stage of budding. Furthermore, the aspect ratio of the tubular bud could be stabilized during the late stage, as observed in experiments, through a reduction on the new cell surface material insertion or an expansion of the polarization site. Thus model simulations suggest the maintenance of new cell surface material insertion or chemical signal polarization could be weakened due to cellular aging in yeast and other cell types.

Association of thyroid autoimmunity with extra-thyroid diseases and the risk of mortality among adults: evidence from the NHANES.

Background: Thyroid autoimmunity is one of the most prevalent autoimmune diseases. However, its association with extra-thyroid diseases and mortality risk in the general population remains uncertain. Our study aims to evaluate the association of thyroid autoimmunity with extra-thyroid disease and the risk of mortality. Methods: A prospective cohort study was conducted using data from the National Health and Nutrition Examination Survey (NHANES) with participants from 2007-2008, 2009-2010, and 2011-2012, tracking their mortality until 2019. Associations between thyroid autoimmunity, which was defined as having positive thyroid peroxidase antibody (TPOAb) and/or thyroglobulin antibody (TgAb), and extra-thyroid disease including diabetes, hypertension, cardiovascular disease, chronic lung disease, arthritis, cancer and chronic renal disease and the risk of mortality were investigated. Results: A total of 7431 participants were included in this study. Positive The prevalence of positive TgAb was 7.54%, and positive TPOAb prevalence was 11.48%. TgAb was significantly associated with diabetes (Model 1: OR=1.64, 95% CI:1.08-2.50; Model 2: OR=1.93, 95% CI: 1.21-3.08) and hypertension (Model 1: OR=0.67, 95% CI: 0.49-0.91; Model 2: OR=0.62, 95% CI: 0.44-0.88). TPOAb was associated with a lower prevalence of chronic lung disease (model 1: OR=0.71, 95% CI: 0.54-0.95; model 2: OR=0.71, 95% CI: 0.53-0.95). No associations were observed between TgAb, TPOAb and other extra-thyroid diseases. Neither TgAb nor TPOAb were associated with all-cause mortality or heart disease mortality. Conclusion: TgAb was linked to a higher prevalence of diabetes and a lower prevalence of hypertension, while TPOAb was associated with a decreased prevalence of chronic lung disease. However, neither TgAb nor TPOAb posed a risk for all-cause mortality or heart disease mortality.

8-Oxoguanine DNA glycosylase protects cells from senescence via the p53-p21 pathway.

Cellular senescence is an important factor leading to pulmonary fibrosis. Deficiency of 8-oxoguanine DNA glycosylase (OGG1) in mice leads to alleviation of bleomycin (BLM)-induced mouse pulmonary fibrosis, and inhibition of the OGG1 enzyme reduces the epithelial mesenchymal transition (EMT) in lung cells. In the present study, we find decreased expression of OGG1 in aged mice and BLM-induced cell senescence. In addition, a decrease in OGG1 expression results in cell senescence, such as increases in the percentage of SA-ß-gal-positive cells, and in the p21 and p-H2AX protein levels in response to BLM in lung cells. Furthermore, OGG1 promotes cell transformation in A549 cells in the presence of BLM. We also find that OGG1 siRNA impedes cell cycle progression and inhibits the levels of telomerase reverse transcriptase (TERT) and LaminB1 in BLM-treated lung cells. The increase in OGG1 expression results in the opposite phenomenon. The mRNA levels of senescence-associated secretory phenotype (SASP) components, including IL-1α, IL-1ß, IL-6, IL-8, CXCL1/CXCL2, and MMP-3, in the absence of OGG1 are obviously increased in A549 cells treated with BLM. Interestingly, we demonstrate that OGG1 binds to p53 to inhibit the activation of p53 and that silencing of p53 reverses the inhibition of OGG1 on senescence in lung cells. Additionally, the augmented cell senescence is shown in vivo in OGG1-deficient mice. Overall, we provide direct evidence in vivo and in vitro that OGG1 plays an important role in protecting tissue cells against aging associated with the p53 pathway.

OGG1 promoted lung fibrosis by activating fibroblasts via interacting with Snail1.

One of abundant DNA lesions induced by reactive oxygen species is 8-oxoguanine (8-oxoG), which compromises genetic instability. 8-oxoG is recognized by the DNA repair protein 8-oxoguanine DNA glycosylase-1 (OGG1) that not only participates in base excision repair but also involves in transcriptional regulation.OGG1 has an important role inIdiopathic Pulmonary Fibrosis (IPF) processing and targeting fibroblasts is a major strategy for the treatment of pulmonary fibrosis, but whether OGG1 activate fibroblast is not clear. In this study, we show that OGG1 expression level is increased at the fibroblast activation stage in mouse lungs induced by bleomycin (BLM) treatment. OGG1 promoted the expression level of fibroblast activation markers (CTGF, fibronectin, and collagen 1) in a pro-fibrotic gene transcriptional regulation pathway via interacting with Snail1, which dependent on 8-oxoG recognition. Global inhibition of OGG1 at the middle stage of lung fibrosis also relieved BLM-induced lung fibrosis in mice. Our results suggest that OGG1 is a target for inhibiting fibroblast activation and a potential therapeutic target for IPF.

Effects of combined electroacupuncture and medication therapy on the RhoA/ROCK-2 signaling pathway in the striatal region of rats afflicted by cerebral ischemia.

OBJECTIVE: To investigate the effects of electroacupuncture(EA), gastrodin(Gas), and their combination on the signaling pathways involving Ras homologous gene family member A (RhoA) and Rho-associated frizzled helix protein kinase (ROCK-2) within the striatal region of rats subjected to cerebral ischemia. Additionally, we aim to elucidate the therapeutic effects and potential underlying mechanisms associated with the concurrent application of electroacupuncture and medication in the treatment of cerebral ischemia. METHODS: Rats were randomly assigned to one of five groups, namely, the sham operation (Sham) group, model group, EA group, Gas group, and the EA combined with Gas group (referred to as the "EA+Gas group"). Each group consisted of ten rats. Following the induction of cerebral ischemia, the EA group and EA+Gas group received EA stimulation at the Baihui(GV20) and Zusanli(ST36) acupoints for 30 min per session, administered once daily for 14 consecutive days. The Gas group and EA+Gas group were intraperitoneally injected with Gas at a dosage of 10 mg/kg, also administered once daily for 14 consecutive days. Nissl staining was employed to observe morphological alterations in the striatal nerve cells of rats in each group. Immunohistochemistry and western blot techniques were employed to evaluate the expression levels of striatal RhoA and ROCK-2 proteins. RESULTS: In comparison to the Sham group, the model group exhibited a substantial reduction in the number of striatal nerve cells on the ischemic side, accompanied by notable changes in cell morphology, characterized by reduced cytoplasm, defective and atrophied cytosol, solidified nuclei, loosely arranged cells, and enlarged intercellular spaces. Additionally, there was a notable increase in the positive expression of RhoA and ROCK-2. In contrast, when compared to the model group, the EA, Gas, and EA+Gas groups demonstrated an elevated number of normal nerve cells within the ischemic striatal region, with a significant improvement in cell count and morphology. Furthermore, positive expression levels of RhoA and ROCK-2 were notably reduced in these groups. Compared with the EA group or the GAS group, the number of normal nerve cells in the striatum on the ischemic side of the EA+GAS group was further increased, and the positive expression level of RhoA and ROCK-2 were both further reduced. CONCLUSION: The protective mechanism underlying the therapeutic efficacy of EA combined with Gas against cerebral ischemic striatal injury in rats may be associated with the inhibition of the activation of the RhoA/ROCK-2 signaling pathway. Importantly, the therapeutic effects observed with the combination of electroacupuncture and medication were superior to those achieved with EA alone or the sole administration of Gas.

Combined computational modeling and experimental study of the biomechanical mechanisms of platelet-driven contraction of fibrin clots.

While blood clot formation has been relatively well studied, little is known about the mechanisms underlying the subsequent structural and mechanical clot remodeling called contraction or retraction. Impairment of the clot contraction process is associated with both life-threatening bleeding and thrombotic conditions, such as ischemic stroke, venous thromboembolism, and others. Recently, blood clot contraction was observed to be hindered in patients with COVID-19. A three-dimensional multiscale computational model is developed and used to quantify biomechanical mechanisms of the kinetics of clot contraction driven by platelet-fibrin pulling interactions. These results provide important biological insights into contraction of platelet filopodia, the mechanically active thin protrusions of the plasma membrane, described previously as performing mostly a sensory function. The biomechanical mechanisms and modeling approach described can potentially apply to studying other systems in which cells are embedded in a filamentous network and exert forces on the extracellular matrix modulated by the substrate stiffness.

Metabolomics acts as a powerful tool for comprehensively evaluating vaccines approved under emergency: a CoronaVac retrospective study.

Introduction: To control the COVID-19 pandemic, great efforts have been made to realize herd immunity by vaccination since 2020. Unfortunately, most of the vaccines against COVID-19 were approved in emergency without a full-cycle and comprehensive evaluation process as recommended to the previous vaccines. Metabolome has a close tie with the phenotype and can sensitively reflect the responses to stimuli, rendering metabolomic analysis have the potential to appraise and monitor vaccine effects authentically. Methods: In this study, a retrospective study was carried out for 330 Chinese volunteers receiving recommended two-dose CoronaVac, a vaccine approved in emergency in 2020. Venous blood was sampled before and after vaccination at 5 separate time points for all the recipients. Routine clinical laboratory analysis, metabolomic and lipidomic analysis data were collected. Results and discussion: It was found that the serum antibody-positive rate of this population was around 81.82%. Most of the laboratory parameters were slightly perturbated within the relevant reference intervals after vaccination. The metabolomic and lipidomic analyses showed that the metabolic shift after inoculation was mainly in the glycolysis, tricarboxylic acid cycle, amino acid metabolism, urea cycle, as well as microbe-related metabolism (bile acid metabolism, tryptophan metabolism and phenylalanine metabolism). Time-course metabolome changes were found in parallel with the progress of immunity establishment and peripheral immune cell counting fluctuation, proving metabolomics analysis was an applicable solution to evaluate immune effects complementary to traditional antibody detection. Taurocholic acid, lysophosphatidylcholine 16:0 sn-1, glutamic acid, and phenylalanine were defined as valuable metabolite markers to indicate the establishment of immunity after vaccination. Integrated with the traditional laboratory analysis, this study provided a feasible metabolomics-based solution to relatively comprehensively evaluate vaccines approved under emergency.

Matrine alleviates oxidative stress and ferroptosis in severe acute pancreatitis-induced acute lung injury by activating the UCP2/SIRT3/PGC1α pathway.

Acute lung injury (ALI) is one of the most serious complications of severe acute pancreatitis (SAP). Matrine is well known for its powerful antioxidant and antiapoptotic properties, although its specific mechanism of action in SAP-ALI is unknown. In this study, we examined the effects of matrine on SAP-associated ALIand the specific signaling pathways implicated in SAP-induced ALI, such as oxidative stress, the UCP2-SIRT3-PGC1α pathway, and ferroptosis. The administration of caerulein and lipopolysaccharide (LPS) to UCP2-knockout (UCP2-/-) and wild-type (WT) mice that were pretreated with matrine resulted in pancreatic and lung injury. Changes in reactive oxygen species (ROS) levels, inflammation, and ferroptosis in BEAS-2B and MLE-12 cells were measured following knockdown or overexpression and LPS treatment. Matrine inhibited excessive ferroptosis and ROS production by activating the UCP2/SIRT3/PGC1α pathway while reducing histological damage, edema, myeloperoxidase activity and proinflammatory cytokine expression in the lung. UCP2 knockout decreased the anti-inflammatory properties of matrine and reduced the therapeutic effects of matrine on ROS accumulation and ferroptosis hyperactivation. LPS-induced ROS production and ferroptosis activation in BEAS-2B cells and MLE-12 cells were further enhanced by knockdown of UCP2, but this effect was rescued by UCP2 overexpression. This study demonstrated that matrine reduced inflammation, oxidative stress, and excessive ferroptosis in lung tissue during SAP by activating the UCP2/SIRT3/PGC1α pathway, demonstrating its therapeutic potential in SAP-ALI.

Steroid profiling for the diagnosis of congenital adrenal hyperplasia by microbore ultra-performance liquid chromatography-tandem mass spectrometry.

BACKGROUND: A rapid and accurate measurement approach for 17α-hydroxyprogesterone (17-OHP) and related steroids in amount/volume-limited clinic samples is of importance for precise newborn diagnosis of congenital adrenal hyperplasia (CAH) and its subtypes in clinic. METHODS: Sixteen steroids (17-OHP, androstenedione, cortisol, tetrahydro-11-deoxycortisol, pregnenolone, progesterone, 11-deoxycorticosterone, corticosterone, 21-deoxycortisol, 11-deoxycortisol, dehydroepiandrosterone, testosterone, aldosterone, 17α-hydroxypregnenolone, dihydrotestosterone and 18-hydroxycorticosterone) were included in the panel of high-throughput microbore ultra-performance liquid chromatography-tandem mass spectrometry. Samples were collected from 126 normal subjects and 65 patients including different subtypes of CAH. RESULTS: The method was validated with satisfactory analytical performance in linearity, repeatability, recovery and limit of detection. Reference intervals for 16 steroids were established by quantifying the level of steroids detected in normal infants. The applicability of the method was tested by differentiating steroid metabolic characteristics between normal infants and infants with CAH, as well as between infants with different CAH subtypes. The relevance of 17-OHP, 21-deoxycortisol, and 17-OHP/11-deoxycortisol for 21-hydroxylase deficiency screening was demonstrated. The level of 11-deoxycorticosterone, 11-deoxycortisol, progesterone and androstenedione can be used for the diagnosis of different rare subtypes of CAH. CONCLUSION: This study provides a strategy for highly efficient steroid analysis of amount/volume-limited clinic samples and holds great potential for clinical diagnosis of CAH.

Insight into the Crosstalk between Photodynamic Therapy and Immunotherapy in Breast Cancer.

Breast cancer (BC) is the world's second most frequent malignancy and the leading cause of mortality among women. All in situ or invasive breast cancer derives from terminal tubulobular units; when the tumor is present only in the ducts or lobules in situ, it is called ductal carcinoma in situ (DCIS)/lobular carcinoma in situ (LCIS). The biggest risk factors are age, mutations in breast cancer genes 1 or 2 (BRCA1 or BRCA2), and dense breast tissue. Current treatments are associated with various side effects, recurrence, and poor quality of life. The critical role of the immune system in breast cancer progression/regression should always be considered. Several immunotherapy techniques for BC have been studied, including tumor-targeted antibodies (bispecific antibodies), adoptive T cell therapy, vaccinations, and immune checkpoint inhibition with anti-PD-1 antibodies. In the last decade, significant breakthroughs have been made in breast cancer immunotherapy. This advancement was principally prompted by cancer cells' escape of immune regulation and the tumor's subsequent resistance to traditional therapy. Photodynamic therapy (PDT) has shown potential as a cancer treatment. It is less intrusive, more focused, and less damaging to normal cells and tissues. It entails the employment of a photosensitizer (PS) and a specific wavelength of light to create reactive oxygen species. Recently, an increasing number of studies have shown that PDT combined with immunotherapy improves the effect of tumor drugs and reduces tumor immune escape, improving the prognosis of breast cancer patients. Therefore, we objectively evaluate strategies for their limitations and benefits, which are critical to improving outcomes for breast cancer patients. In conclusion, we offer many avenues for further study on tailored immunotherapy, such as oxygen-enhanced PDT and nanoparticles.

Apurinic/apyrimidinic endonuclease 1 regulates palmitic acid-mediated apoptosis in cardiomyocytes via endoplasmic reticulum stress.

Cardiomyocyte apoptosis caused by fat metabolism disorder plays an essential role in the pathogenesis of diabetic cardiomyopathy (DCM). Apurinic/apyrimidinic endonuclease 1 (APE1) has multiple functions, including regulating redox and DNA repair. However, the role of APE1 in the pathogenesis of DCM remains unclear. To investigate the mechanism of APE1 on high-fat induced apoptosis in H9C2 cells, we treated H9C2 cells with palmitic acid (PA) as an apoptosis model caused by hyperlipidemia. We found that PA reduced the viability and increased apoptosis of H9C2 cells by inducing up-regulation of APE1 protein and endoplasmic reticulum (ER) stress. APE1 knockdown enhanced PA-induced apoptosis, and ER stress and overexpression of APE1 demonstrated the opposite effect. Furthermore, APE1 regulated PA-induced apoptosis via ER stress. The APE1 mutant (C65A, lack of redox regulation) loses its protective effect against ER stress and apoptosis. These findings indicate that APE1 protects PA-induced H9C2 cardiomyocyte apoptosis through ER stress via its redox-regulated function. This study provided new insights into the therapy for DCM.

PAK2 is essential for chromosome alignment in metaphase I oocytes.

As a highly conserved and ubiquitously expressed serine/threonine kinase, p21-activated kinase 2 (PAK2) participates in diverse biologic events. However, its roles in mouse oocyte meiotic maturation remain unclear. The present study revealed that mouse oocytes depleted of Pak2 were unable to completely progress through meiosis and that a majority were arrested at metaphase I. Pak2 depletion thus prompted MI arrest and induced meiotic chromosome alignment defects in mouse oocytes, in part due to a reduction in polo-like kinase (PLK1). We demonstrated that PAK2's interaction with PLK1 protected it from degradation by APC/CCdh1, and that it promoted meiotic progression and bipolar spindle formation. Our data collectively display critical functions for PAK2 in meiotic progression and chromosome alignment in mouse oocytes.

Macrophages in Tumor-Associated Adipose Microenvironment Accelerate Tumor Progression.

Adipose-tissue macrophages (ATMs), a complex ensemble of diverse macrophage subtypes, are prevalent in the tumor-adipose microenvironment (TAME) and facilitate tumor growth. However, the mechanisms in which the tumor-adipocyte crosstalk may enable the properties and plasticity of macrophages remain unclear. The single-cell RNA-sequence profiling reveals that a subset of macrophages expressed CD163, CCL2, and CCL5 in TAME, exhibiting an immunosuppressive subtype. It is demonstrated that CD163+ macrophages aggregate to surround adipocytes in breast cancer tissues. The expressions of CCL2 and CCL5 are also elevated in TAME and enable the recruitment and polarize macrophages. Mechanically, the level of exosomal miRNA-155 increased in the coculture of tumor cells and adipocytes, and then it promoted the generation and release of CCL2 and CCL5 from adipocytes by targeting the SOCS6/STAT3 pathway. Inhibition of exosomal miRNA-155 in tumor cells reduced the CCL2 and CCL5 levels in tumor-adipocytes coculture and further retarded tumor growth. Finally, the deletion of macrophages partially inhibited adipocyte-induced tumor proliferation. Likewise, inhibiting chemokines and their receptors or suppressing the phosphorylation of STAT3 decreased tumor burden in preclinical models. These results demonstrate that the niche factors in TAME, such as exosomal miRNA-155, regulate the function and polarity of macrophages to facilitate tumor progression.

New insights into the degradation and detoxification of methylene blue using heterogeneous-Fenton catalyzed by sustainable siderite.

The huge application of synthetic dyes caused a severe impact in the environment. In the present study, a physico-chemical strategy of heterogeneous-Fenton catalyzed by the natural ferrous ore has been established for toxic chemical degradation, of which the complex and high-expense repetitive pH adjustment procedures were escaping. And this natural heterogeneous catalyst also could be recycled and sustainable for toxic substances treatment involved in synergetic adsorption and oxidation. The siderite, served as an adsorbent and catalyst for the degradation of methylene blue (MB). Siderite exhibited a better adsorption capacity with a saturated adsorption capacity of ∼11.08 mg/g. Batch adsorption experiments have verified that adsorption rate and adsorption equilibrium followed pseudo-second-order rate model and Langmuir isotherm equation, respectively. The combination with H2O2, showed significant enhancement of MB degradation without any pH adjustment. The effect of siderite dosage, H2O2 dosage, MB concentration, initial pH, and reaction temperature on MB degradation was investigated, which also has indicated the excellent catalytic performance of siderite. About 99.71% of MB was degraded in 480 min with initial pH of 7.0, reaction temperature of 25 °C, siderite, and H2O2 dosage of 2.5 g/L and 122.38 mM, respectively. It was found that siderite could be reused and remained high degradation efficiency on MB after 5 times reutilization, which also could demonstrate the sustainable and effective process to degrade organic pollution. The generation of reactive species including ·OH and O2·- have been confirmed based on scavenger test and electron spin resonance (ESR) analysis, which was dominated by heterogeneous reaction. The possible degradation mechanisms of MB have been predicted based on spectrum scanning and GC-MS analysis. Moreover, acute toxicity assessment with marine photobacterium Vibrio fisheri was conducted to investigate the toxicity change in the adsorption/oxidation coupled process. This sustainable heterogeneous-Fenton technology has been verified as a promising and applicable process for toxic organic chemicals removal due to effective mineralization and detoxification assisted with the natural ore mineral through the simple operation and mild condtions.

Bismuth Quantum Dot (Bi QD)/Polydimethylsiloxane (PDMS) Nanocomposites with Self-Cleaning and Antibacterial Activity for Dental Applications.

In the oral microenvironment, bacteria colonies are easily aggregated on the tooth-restoration surface, in the manner of a biofilm, which usually consists of heterogeneous structures containing clusters of a variety of bacteria embedded in an extracellular matrix, leading to serious recurrent caries. In this contribution, zero-dimensional (0D) bismuth (Bi) quantum dots (QDs) synthesized by a facile solvothermal method were directly employed to fabricate a Bi QD/polydimethylsiloxane (PDMS)-modified tooth by simple curing treatment. The result demonstrates that the as-fabricated Bi QD/PDMS-modified tooth at 37 °C for 120 min not only showed significantly improved hydrophobic performance with a water contact angle of 103° and 115° on the tooth root and tooth crown, respectively, compared to that (~20° on the tooth root, and ~5° on the tooth crown) of the pristine tooth, but also exhibited excellent antibacterial activity against S. mutans, superior biocompatibility, and biosafety. In addition, due to the highly photothermal effect of Bi QDs, the antibacterial activity of the as-fabricated Bi QD/PDMS-modified tooth could be further enhanced under illumination, even at a very low power density (12 mW cm-2). Due to the facile fabrication, excellent hydrophobicity, superior antibacterial activity, and biocompatibility and biosafety of the Bi QD/PDMS-modified tooth, it is envisioned that the Bi QD/PDMS-modified tooth with a fascinating self-cleaning and antibacterial performance can pave the way to new designs of versatile multifunctional nanocomposites to prevent secondary caries in the application of dental restoration.

Induction of Fetal Hemoglobin by Introducing Natural Hereditary Persistence of Fetal Hemoglobin Mutations in the γ-Globin Gene Promoters for Genome Editing Therapies for ß-Thalassemia.

Reactivation of γ-globin expression is a promising therapeutic approach for ß-hemoglobinopathies. Here, we propose a novel Cas9/AAV6-mediated genome editing strategy for the treatment of ß-thalassemia: Natural HPFH mutations -113A > G, -114C > T, -117G>A, -175T > C, -195C > G, and -198T > C were introduced by homologous recombination following disruption of BCL11A binding sites in HBG1/HBG2 promoters. Precise on-target editing and significantly increased γ-globin expression during erythroid differentiation were observed in both HUDEP-2 cells and primary HSPCs from ß-thalassemia major patients. Moreover, edited HSPCs maintained the capacity for long-term hematopoietic reconstitution in B-NDG hTHPO mice. This study provides evidence of the effectiveness of introducing naturally occurring HPFH mutations as a genetic therapy for ß-thalassemia.

TH5487, a small molecule inhibitor of OGG1, attenuates pulmonary fibrosis by NEDD4L-mediated OGG1 degradation.

Pulmonary fibrosis is a highly aggressive and lethal disease that currently lacks effective targeting therapies. Herein, we established a mouse model of pulmonary fibrosis induced by intratracheal instillation of bleomycin (BLM) in wild-type (WT) and 8-oxoguanine DNA glycosylase-1 (OGG1) knockout (Ogg1-/-) mice. TH5487, a specific small-molecule inhibitor of OGG1, was found to ameliorate BLM-induced pulmonary fibrosis in WT mice. Concomitantly, TH5487 treatment markedly suppressed the BLM-mediated alveolar epithelial-mesenchymal transition (EMT) and increase in OGG1 protein level in the lungs of WT mice. However, administration of TH5487 did not further improve this fibrotic transformation in Ogg1-/- mice. More importantly, adeno-associated virus-mediated lung-specific OGG1 overexpression accelerated alveolar EMT and the resultant fibrosis progression antagonized by TH5487 in the fibrotic lungs of WT mice, suggesting that the down-regulation of OGG1 protein level could be essential for TH5487 to exert its anti-fibrogenic function. Mechanism study in alveolar epithelial cells demonstrated that TH5487 treatment canceled TGF-ß1-mediated suppression of NEDD4-like E3 ubiquitin ligase (NEDD4L), which ubiquitinated OGG1 and targeted it for proteasomal degradation. Furthermore, TH5487-mediated suppression of alveolar EMT and the fibrotic processes was counteracted by silencing NEDD4L in TGF-ß1-induced alveolar epithelial cells. Collectively, these data underline the potential of TH5487 as an effective anti-fibrotic agent for pulmonary fibrosis.

The Association Between Smoking and Renal Function in People Over 20 Years Old.

Background: Many conclusions have been reached in renal function studies in direct smokers. Aim: This study aimed to determine the relationship between smoking and decreased renal function to ensure that reduced chronic kidney disease incidence can be achieved by limiting smoking, we assessed the relationship between cigarette smoking and renal function. Methods: We recruited 10,267 people from the National Health and Nutrition Program Testing Survey (NHANES) aged over 20 years from 2013 to 2018 to assess smoking exposure by serum cotinine. We estimated the glomerular filtration rate (eGFR) and used multivariate linear regression models and smooth curve fittings to assess the relationship between smoking and renal function. Results: We found an inverse relationship between serum cotinine and the eGFR. In a subgroup analysis, we found a non-linear relationship between serum cotinine and the eGFR in different ethnic groups or in different sexes. In a subgroup analysis of sex, we found inflection points between men and women for the relationship between serum cotinine and the eGFR (men 183 ng/ml and 465 ng/ml; women 227 ng/ml and 412 ng/ml). However, in a subgroup analysis by age, we found that serum cotinine showed a clear negative correlation with the eGFR in people aged 20-39 years, but in people older than 40 years, a weak correlation was shown. In stratified analysis by ethnicity, we found significant negative associations in Mexican American and Other Hispanic individuals and weaker associations in Non-Hispanic White and Non-Hispanic Black individuals. Conclusion: Through the negative correlation between serum cotinine and the eGFR, we can conclude that as the smoking quantity increases, smoking leads to a decrease in renal function. The results of the subgroup analysis indicate that in young people, by advocating smoking cessation early, we can very effectively prevent kidney disease in this population and thus reduce the incidence of chronic kidney disease. Smoking should be included as an independent risk factor for chronic kidney disease.

Computational Biomechanical Modeling of Fibrin Networks and Platelet-Fiber Network Interactions.

Fibrin deformation and interaction of fibrin with other blood components play critical roles in hemostasis and thrombosis. In this review, computational and mathematical biomechanical models of fibrin network deformation and contraction at different spatio-temporal scales as well as challenges in developing and calibrating multiscale models are discussed. There are long standing challenges. For instance, applicability of models to identify and test potential mechanisms of the biomechanical processes mediating interactions between platelets and fiber networks in blood clot stretching and contraction needs to be examined carefully. How the structural and mechanical properties of major blood clot components influences biomechanical responses of the entire clot subjected to external forces, such as blood flow or vessel wall deformations needs to be investigated thoroughly.

Interleukin-22 Deficiency Reduces Angiotensin II-Induced Aortic Dissection and Abdominal Aortic Aneurysm in ApoE-/- Mice.

Background: Our previous study showed that interleukin-22 (IL-22) levels were increased in patients with aortic dissection (AD). This study evaluated the effects of IL-22 on AD/abdominal aortic aneurysm (AAA) formation in angiotensin II (Ang II)-infused ApoE-/- mice. Methods: ApoE-/- mice were treated with Ang II for 28 days, and IL-22 expression was examined. In addition, the effects of IL22 deficiency on AAA/AD formation induced by Ang II infusion in ApoE-/- mice were investigated. ApoE-/-IL-22-/- mice were transplanted with bone marrow cells isolated from ApoE-/- mice or ApoE-/-IL-22-/- mice, and AAA/AD formation was observed. Results: IL-22 expression was increased in both the aortas and serum of ApoE-/- mice after Ang II infusion and was mainly derived from aortic CD4+ T lymphocytes (CD4+ TCs). IL-22 deficiency significantly reduced the AAA/AD formation as well as the maximal aortic diameter in Ang II-infused ApoE-/- mice. Decreased elastin fragmentation and reduced fibrosis were observed in the aortas of ApoE-/-IL-22-/- mice compared with ApoE-/- mice. The deletion of IL-22 also decreased aortic M1 macrophage differentiation, alleviated M1 macrophage-induced oxidative stress, and reduced aortic smooth muscle cell loss. Furthermore, M1 macrophage-induced oxidative stress was worsened and AAA/AD formation was promoted in ApoE-/-IL-22-/- mice that received transplanted bone marrow cells from ApoE-/- mice compared with those that were transplanted with bone marrow cells isolated from ApoE-/-IL-22-/- mice. Conclusions: IL-22 deficiency inhibits AAA/AD formation by inhibiting M1 macrophage-induced oxidative stress. IL-22 potentially represents a promising new target for preventing the progression of AAA/AD.