The efficacy of endoscopic dacryocystorhinostomy in the treatment of dacryocystitis: A systematic review and meta-analysis.

BACKGROUND: This article aimed to discuss the efficacy and safety of endoscopic dacryocystorhinostomy (EDCR) versus external dacryocystorhinostomy (EX-DCR) for the treatment of dacryocystitis by meta-analysis. METHODS: All randomized controlled trials that met the inclusion and exclusion criteria were collected by searching the following databases: PubMed, Web of Science, China National Knowledge Infrastructure, and Wanfang, from the establishment of the database to June 2023. Meta-analysis was performed using Stata 17.0 software and review manager 5.4 software. In the collected trials, the observation group was treated with EDCR, whereas the control group was treated with EX-DCR. RESULTS: A total of 10 studies involving 969 patients were included in this analysis. There was a similar surgical success rate in the treatment of dacryocystitis between the 2 groups (RR = 1.021, 95% CI [0. 803, 1.297], P = 0. 865). However, compared with the control group, patients in the observation group had a higher total effective rate of treatment (RR = 1. 195, 95% CI [1. 063, 1.343], P = .003), and shorter operative time (WMD = -23.640, 95% CI [-35.533, -11.747], P < .001), and less intraoperative blood loss (WMD = -50.797, 95% CI [-80.339, -21.255], P = .001), shorter length of hospital stays (WMD = -4.570, 95% CI [-5.992, -3.148], P < .001), and lower incidence of adverse events (RR = 0.295, 95% CI [0.173, 0.504], P < .001). CONCLUSION: EDCR is an effective and safe surgical procedure for the treatment of dacryocystitis and can be used as an alternative to EX-DCR.

The chromatin remodeling factor Arid1a cooperates with Jun/Fos to promote osteoclastogenesis by epigenetically upregulating Siglec15 expression.

Osteoporosis is characterized by an imbalance between osteoclast-mediated bone resorption and osteoblast-related bone formation, particularly increased osteoclastogenesis. However, the mechanisms by which epigenetic factors regulate osteoclast precursor differentiation during osteoclastogenesis remain poorly understood. Here, we show that the specific knockout of the chromatin remodeling factor Arid1a in bone marrow-derived macrophages (BMDMs) results in increased bone mass. The loss of Arid1a in BMDM inhibits cell-cell fusion and maturation of osteoclast precursors, thereby suppressing osteoclast differentiation. Mechanistically, Arid1a increases the chromatin access in the gene promoter region of sialic acid-binding Ig-like lectin 15 (Siglec15) by transcription factor Jun/Fos, which results in the upregulation of Siglec15 and promotion of osteoclast differentiation. However, the loss of Arid1a reprograms the chromatin structure to restrict Siglec15 expression in osteoclast precursors, thereby inhibiting BMDM differentiation into mature osteoclasts. Deleting Arid1a after ovariectomy (a model for postmenopausal bone loss) alleviated bone loss and maintained bone mass. In summary, epigenetic reprogramming mediated by Arid1a loss suppresses osteoclast differentiation and may serve as a promising therapeutic strategy for treating bone loss diseases.

Osteoporosis is a common disease, usually diagnosed by decreased bone density and increased fragility. The people with osteoporosis has higher risk of fractures. Nearly one third of the aged people will suffer from osteoporosis-related fractures and even lose their lives because of this. Therefore, there is an urgent need for early intervention and effective treatment options for osteoporosis in the aging population. Bone tissue is a highly dynamic tissue that undergoes continuous remodeling throughout an individual's entire life. The balance of remodeling depends on the bone formation mediated by osteoblasts and bone resorption by osteoclasts. When this balance is disrupted, osteoporosis occurs. Thus, the aim of our research is to explore the behind mechanism of this imbalance. Here, we demonstrate that the loss of Arid1a, a chromatin remodeler, leads to chromatin reprogramming that restricts access to promoters by transcription factors such as Jun/Fos, thereby suppressing osteoclast activation and bone resorption. Our findings offer insights into the epigenetic mechanisms underlying osteoporosis and suggest potential strategies for its prevention and treatment.

Interleukin-22 Alleviates Caerulein-Induced Acute Pancreatitis by Activating AKT/mTOR Pathway.

BACKGROUND: Acute pancreatitis (AP) is one of the most common acute abdominal disorders; due to the lack of specific treatment, the treatment of acute pancreatitis, especially serious acute pancreatitis (SAP), is difficult and challenging. We will observe the changes of Interleukin -22 levels in acute pancreatitis animal models, and explore the mechanism of Interleukin -22 in acute pancreatitis. OBJECTIVE: This study aims to assess the potential protective effect of Interleukin -22 on caerulein-induced acute pancreatitis and to explore its mechanism. METHODS: Blood levels of amylase and lipase and Interleukin -22 were assessed in mice with acute pancreatitis. In animal model and cell model of caerulein-induced acute pancreatitis, the mRNA levels of P62 and Beclin-1 were determined using PCR, and the protein expression of P62, LC3-II, mTOR, AKT, p-mTOR, and p-AKT were evaluated through Western blot analysis. RESULTS: Interleukin -22 administration reduced blood amylase and lipase levels and mitigated tissue damage in acute pancreatitis mice model. Interleukin -22 inhibited the relative mRNA levels of P62 and Beclin-1, and the Interleukin -22 group showed a decreased protein expression of LC3-II and P62 and the phosphorylation of the AKT/mTOR pathway. Furthermore, we obtained similar results in the cell model of acute pancreatitis. CONCLUSION: This study suggests that Interleukin -22 administration could alleviate pancreatic damage in caerulein-induced acute pancreatitis. This effect may result from the activation of the AKT/mTOR pathway, leading to the inhibition of autophagy. Consequently, Interleukin -22 shows potential as a treatment.

A new metal ion chelator attenuates human tau accumulation-induced neurodegeneration and memory deficits in mice.

Neuronal neurofibrillary tangles containing Tau hyperphosphorylation proteins are a typical pathological marker of Alzheimer's disease (AD). The level of tangles in neurons correlates positively with severe dementia. However, how Tau induces cognitive dysfunction is still unknown, which leads to a lack of effective treatments for AD. Metal ions deposition occurs with tangles in AD brain autopsy. Reduced metal ion can improve the pathology of AD. To explore whether abnormally phosphorylated Tau causes metal ion deposition, we overexpressed human full-length Tau (hTau) in the hippocampal CA3 area of mice and primary cultured hippocampal neurons (CPHN) and found that Tau accumulation induced iron deposition and activated calcineurin (CaN), which dephosphorylates glycogen synthase kinase 3 beta (GSK3ß), mediating Tau hyperphosphorylation. Simultaneous activation of CaN dephosphorylates cyclic-AMP response binding protein (CREB), leading to synaptic deficits and memory impairment, as shown in our previous study; this seems to be a vicious cycle exacerbating tauopathy. In the current study, we developed a new metal ion chelator that displayed a significant inhibitory effect on Tau phosphorylation and memory impairment by chelating iron ions in vivo and in vitro. These findings provide new insight into the mechanism of memory impairment induced by Tau accumulation and develop a novel potential treatment for tauopathy in AD.

The role of autophagy in the treatment of type II diabetes and its complications: a review.

Type II diabetes mellitus (T2DM) is a chronic metabolic disease characterized by prolonged hyperglycemia and insulin resistance (IR). Its incidence is increasing annually, posing a significant threat to human life and health. Consequently, there is an urgent requirement to discover effective drugs and investigate the pathogenesis of T2DM. Autophagy plays a crucial role in maintaining normal islet structure. However, in a state of high glucose, autophagy is inhibited, resulting in impaired islet function, insulin resistance, and complications. Studies have shown that modulating autophagy through activation or inhibition can have a positive impact on the treatment of T2DM and its complications. However, it is important to note that the specific regulatory mechanisms vary depending on the target organ. This review explores the role of autophagy in the pathogenesis of T2DM, taking into account both genetic and external factors. It also provides a summary of reported chemical drugs and traditional Chinese medicine that target the autophagic pathway for the treatment of T2DM and its complications.

Protective effect of vitamin B6 against doxorubicin-induced cardiotoxicity by modulating NHE1 expression.

Doxorubicin (DOX) has been used to treat various types of cancer, but its application is limited due to its heart toxicity as well as other drawbacks. Chronic inhibition of Na+ /H+ exchanger (NHE1) reduces heart failure and reduces the production of reactive oxygen species (ROS); vitamin B6 (VitB6 ) has been demonstrated to have a crucial role in antioxidant mechanism. So, this study was designed to explore the effect of VitB6 supplement on the DOX-induced cardiotoxicity and to imply whether NHE1 is involved. Ultrasonic cardiogram analysis revealed that VitB6 supplement could alleviate DOX-induced cardiotoxicity; hematoxylin and eosin (HE) and Masson's staining further confirmed this effect. Furthermore, VitB6 supplement exhibited significant antioxidative stress and antiapoptosis effect, which was evidenced by decreased serum malondialdehyde (MDA) content and increased serum superoxide dismutase (SOD) content, and decreased Bcl-2-associated X protein/B-cell lymphoma-2 ratio, respectively. Collectively, VitB6 supplement may exert antioxidative and antiapoptosis effects to improve cardiac function by decreasing NHE1 expression and improve DOX-induced cardiotoxicity.

Amorphous selenium inhibits oxidative stress injury of neurons in vascular dementia rats by activating NMDAR pathway.

Vascular dementia (VD) is one of the most common causes of dementia, taking account for about 20% of all cases. Although studies have found that selenium supplementation can improve the cognitive ability of Alzheimer's patients, there is currently no research on the cognitive impairment caused by VD. This study aimed to investigate the role and mechanism of Amorphous selenium nanodots (A SeNDs) in the prevention of VD. The bilateral common carotid artery occlusion (BCCAO) method was used to establish a VD model. The neuroprotective effect of A SeNDs was evaluated by Morris water maze, Transcranial Doppler TCD, hematoxylin-eosin (HE) staining, Neuron-specific nuclear protein (Neu N) staining and Golgi staining. Detect the expression levels of oxidative stress and Calcium-calmodulin dependent protein kinase II (CaMK II), N-methyl-D-aspartate receptor subunit NR2A, and postsynaptic dense protein 95 (PSD95). Finally, measure the concentration of calcium ions in neuronal cells. The results showed that A SeNDs could significantly improve the learning and memory ability of VD rats, restore the posterior arterial blood flow of the brain, improve the neuronal morphology and dendritic remodeling of pyramidal cells in hippocampal CA1 area, reduce the level of oxidative stress in VD rats, increase the expression of NR2A, PSD95, CaMK II proteins and reduce intracellular calcium ion concentration, but the addition of selective NR2A antagonist NVP-AAMO77 eliminated these benefits. It suggests that A SeNDs may improve cognitive dysfunction in vascular dementia rats by regulating the NMDAR pathway.

Propylene glycol-mixed steam enhanced extraction for an efficient and sustainable remediation of PAHs-contaminated soil.

An innovative thermal desorption method, propylene glycol (PG)-mixed steam enhanced extraction, is proposed for a highly efficient remediation of polycyclic aromatic hydrocarbons (PAHs)-contaminated soil. It is found that injecting PG-mixed steam into soil column could obtain > 99% removal efficiencies of PAHs either for the pyrene-spiked soil, or for the contaminated field soil with high-molecular-weight PAHs. PG is a safe and low-cost dihydric alcohol with a boiling point higher than water. When the PG-mixed steam penetrated the contaminated soil, the PG vapor preferentially condensed to form a hot liquid with concentrated PG (e.g., from 30 wt% PG in gas phase to 90 wt% PG in the liquid phase), which would significantly solubilize the PAHs and enhance their desorption from soils. The results also revealed that the effluents derived from the PG-mixed steam could be purified by removing the desorbed PAHs using a simple coagulation treatment, and the recovered PG solution could be reused. The plant assay using wheat seeds showed that the remediated soil had a good regreening potential. Our results demonstrate that PG-mixed steam injection is a promising thermal desorption method for an efficient and sustainable remediation of PAHs-contaminated soil.

Premature aging of skeletal stem/progenitor cells rather than osteoblasts causes bone loss with decreased mechanosensation.

A distinct population of skeletal stem/progenitor cells (SSPCs) has been identified that is indispensable for the maintenance and remodeling of the adult skeleton. However, the cell types that are responsible for age-related bone loss and the characteristic changes in these cells during aging remain to be determined. Here, we established models of premature aging by conditional depletion of Zmpste24 (Z24) in mice and found that Prx1-dependent Z24 deletion, but not Osx-dependent Z24 deletion, caused significant bone loss. However, Acan-associated Z24 depletion caused only trabecular bone loss. Single-cell RNA sequencing (scRNA-seq) revealed that two populations of SSPCs, one that differentiates into trabecular bone cells and another that differentiates into cortical bone cells, were significantly decreased in Prx1-Cre; Z24f/f mice. Both premature SSPC populations exhibited apoptotic signaling pathway activation and decreased mechanosensation. Physical exercise reversed the effects of Z24 depletion on cellular apoptosis, extracellular matrix expression and bone mass. This study identified two populations of SSPCs that are responsible for premature aging-related bone loss. The impairment of mechanosensation in Z24-deficient SSPCs provides new insight into how physical exercise can be used to prevent bone aging.

Inhibition of MiR-106b-5p mediated by exosomes mitigates acute kidney injury by modulating transmissible endoplasmic reticulum stress and M1 macrophage polarization.

Acute kidney injury (AKI), mainly caused by Ischemia/reperfusion injury (IRI), is a common and severe life-threatening disease with high mortality. Accumulating evidence suggested a direct relationship between endoplasmic reticulum (ER) stress response and AKI progression. However, the role of the transmissible ER stress response, a new modulator of cell-to-cell communication, in influencing intercellular communication between renal tubular epithelial cells (TECs) and macrophages in the AKI microenvironment remains to be determined. To address this issue, we first demonstrate that TECs undergoing ER stress are able to transmit ER stress to macrophages via exosomes, promoting macrophage polarization towards the pro-inflammatory M1 phenotype in vitro and in vivo. Besides, the miR-106b-5p/ATL3 signalling axis plays a pivotal role in the transmission of ER stress in the intercellular crosstalk between TECs and macrophages. We observed an apparent increase in the expression of miR-106b-5p in ER-stressed TECs. Furthermore, we confirmed that ALT3 is a potential target protein of miR-106b-5p. Notably, the inhibition of miR-106b-5p expression in macrophages not only restores ATL3 protein level but also decreases transmissible ER stress and hinders M1 polarization, thus alleviating AKI progression. Additionally, our results suggest that the level of exosomal miR-106b-5p in urine is closely correlated with the severity of AKI patients. Taken together, our study sheds new light on the crucial role of transmissible ER stress in the treatment of AKI through the regulation of the miR-106b-5p/ATL3 axis, offering new ideas for treating AKI.

Primary cilia support cartilage regeneration after injury.

In growing children, growth plate cartilage has limited self-repair ability upon fracture injury always leading to limb growth arrest. Interestingly, one type of fracture injuries within the growth plate achieve amazing self-healing, however, the mechanism is unclear. Using this type of fracture mouse model, we discovered the activation of Hedgehog (Hh) signaling in the injured growth plate, which could activate chondrocytes in growth plate and promote cartilage repair. Primary cilia are the central transduction mediator of Hh signaling. Notably, ciliary Hh-Smo-Gli signaling pathways were enriched in the growth plate during development. Moreover, chondrocytes in resting and proliferating zone were dynamically ciliated during growth plate repair. Furthermore, conditional deletion of the ciliary core gene Ift140 in cartilage disrupted cilia-mediated Hh signaling in growth plate. More importantly, activating ciliary Hh signaling by Smoothened agonist (SAG) significantly accelerated growth plate repair after injury. In sum, primary cilia mediate Hh signaling induced the activation of stem/progenitor chondrocytes and growth plate repair after fracture injury.

In Situ Insight into the Availability and Desorption Kinetics of Per- and Polyfluoroalkyl Substances in Soils with Diffusive Gradients in Thin Films.

The physicochemical exchange dynamics between the solid and solution phases of per- and polyfluoroalkyl substances (PFAS) in soils needs to be better understood. This study employed an in situ tool, diffusive gradients in thin films (DGT), to understand the distribution and exchange kinetics of five typical PFAS in four soils. Results show a nonlinear relationship between the PFAS masses in DGT and time, implying that PFAS were partially supplied by the solid phase in all of the soils. A dynamic model DGT-induced fluxes in soils/sediments (DIFS) was used to interpret the results and derive the distribution coefficients for the labile fraction (Kdl), response time (tc), and adsorption/desorption rates (k1 and k-1). The larger labile pool size (indicated by Kdl) for the longer chain PFAS implies their higher potential availability. The shorter chain PFAS tend to have a larger tc and relatively smaller k-1, implying that the release of these PFAS in soils might be kinetically limited but not for more hydrophobic compounds, such as perfluorooctanesulfonic acid (PFOS), although soil properties might play an important role. Kdl ultimately controls the PFAS availability in soils, while the PFAS release from soils might be kinetically constrained (which may also hold for biota uptake), particularly for more hydrophilic PFAS.

Research progress of volatile organic compounds produced by plant endophytic bacteria in control of postharvest diseases of fruits and vegetables.

Pathogen infestation results in significant losses of fruits and vegetables during handling, transportation, and storage. The use of synthetic fungicides has been a common measure for controlling plant pathogens. However, their excessive use of chemicals has led to increased environmental pollution, leaving large amounts of chemicals in agricultural products, posing a threat to human and animal health. There is now an increasing amount of research activities to explore safer and more innovative ways to control plant pathogens. In this regard, endophytic bacteria contribute significantly. Endophytic bacteria are ubiquitous in the internal tissues of plants without causing damage or disease to the host. Due to their high volatility and difficulties in residue in fruits and vegetables, volatile organic chemicals (VOCs) produced by endophytic bacteria have received a lot of attention in recent years. VOCs are a potential biofumigant for the effective control of postharvest fruits and vegetables diseases. This review focuses mainly on the recent progress in using endophytic bacteria VOCs to control post-harvest fruits and vegetables disease. This review provides a brief overview of the concept, characteristics, and summarises the types, application effect, and control mechanisms of endophytic bacterial VOCs. The research area that is being developed has great application value in agriculture and living practice.

Harnessing matrix stiffness to engineer a bone marrow niche for hematopoietic stem cell rejuvenation.

Hematopoietic stem cell (HSC) self-renewal and aging are tightly regulated by paracrine factors from the bone marrow niche. However, whether HSC rejuvenation could be achieved by engineering a bone marrow niche ex vivo remains unknown. Here, we show that matrix stiffness fine-tunes HSC niche factor expression by bone marrow stromal cells (BMSCs). Increased stiffness activates Yap/Taz signaling to promote BMSC expansion upon 2D culture, which is largely reversed by 3D culture in soft gelatin methacrylate hydrogels. Notably, 3D co-culture with BMSCs promotes HSC maintenance and lymphopoiesis, reverses aging hallmarks of HSCs, and restores their long-term multilineage reconstitution capacity. In situ atomic force microscopy analysis reveals that mouse bone marrow stiffens with age, which correlates with a compromised HSC niche. Taken together, this study highlights the biomechanical regulation of the HSC niche by BMSCs, which could be harnessed to engineer a soft bone marrow niche for HSC rejuvenation.

Do factors associated with older pedestrian crash severity differ? A causal factor analysis based on exposure level of pedestrians.

OBJECTIVE: Older pedestrians are more likely to have severe or fatal consequences when involved in traffic crashes. Identifying the factors contributing to the severity and possible interdependencies between factors in specific exposure areas is the first step to improving safety. Therefore, examining the causal factors' impact on pedestrian-vehicle crash severity in a given area is vital for formulating effective measures to reduce the risk of pedestrian fatalities and injuries. METHODS: This study implements the Thiessen polygon algorithm deployed to define older pedestrians' exposure influence area. Enabling trip characteristics and built environment information as exposure index settings for the background of the pedestrian severity causal analysis. Then, structural equation modeling (SEM) was applied to conduct a factor analysis of the crash severity in high- and low-exposure areas. The SEM evaluates latent factors such as driver risk attitude, risky driving behavior, lack of risk perception among older pedestrians, natural environment, adverse road conditions for driving or walking, and vehicle conditions. The SEM crash model also establishes the relationship between each latent factor. RESULTS: In total, drivers' risky driving behavior (0.270, p < 0.05) in low-exposure areas significantly impacts older pedestrian crash severity more than in high-exposure areas. Lack of risk perception among older pedestrians (0.232, p < 0.05) is the most critical factor promoting crash severity in high-exposure areas. The natural environment (0.634, p < 0.05) in high-exposure areas positively influences older pedestrians' lack of risk perception more than in low-exposure areas. CONCLUSIONS: Significant group differences (p-values ∼ 0.001-0.049) existed between the causal factors of the high-exposure risk areas and the low-exposure risk factors. Different exposure intervals require detailed scenarios based on the critical risks identified. The crash severity promotion measures in different exposure areas can be focused on according to the critical causes analyzed. Those clues, in turn, can be used by transportation authorities in prioritizing their plans, policies, and programs toward improving the safety and mobility of older pedestrians.

Enhanced Light Extraction Efficiency by Self-Masking Technology with Carbonized Photoresist for Light-Emitting Diodes.

This work investigates a self-masking technology for roughening the surface of light-emitting diodes (LEDs). The carbonized photoresist with a naturally nano/micro-textured rough surface was used as a mask layer. After growing the Si3N4 passivation layer on LEDs, the texture pattern of the mask layer was transferred to the surface of the passivation layer via reactive ion beam (RIE) dry etching, resulting in LEDs with nano-textured surfaces. This nano-textured surface achieved by self-masking technology can alleviate the total internal reflection at the top interface and enhance light scattering, thereby improving the light extraction efficiency. As a result, the wall-plug efficiency (WPE) and external quantum efficiency (EQE) of rough-surface LEDs reached 53.9% and 58.8% at 60 mA, respectively, which were improved by 10.3% and 10.5% compared to that of the flat-surface Si3N4-passivated LED. Additionally, at the same peak, both LEDs emit a wavelength of 451 nm at 350 mA. There is also almost no difference between the I-V characteristics of LEDs before and after roughening. The proposed self-masking surface roughening technology provides a strategy for LEE enhancement that is both cost-effective and compatible with conventional fabrication processes.

Role of allopregnanolone-mediated γ-aminobutyric acid A receptor sensitivity in the pathogenesis of premenstrual dysphoric disorder: Toward precise targets for translational medicine and drug development.

Premenstrual dysphoric disorder (PMDD) can be conceptualized as a disorder of suboptimal sensitivity to neuroactive steroid hormones. Its core symptoms (emotional instability, irritability, depression, and anxiety) are related to the increase of stress sensitivity due to the fluctuation of hormone level in luteal phase of the menstrual cycle. In this review, we describe the emotional regulatory effect of allopregnanolone (ALLO), and summarize the relationship between ALLO and γ-aminobutyric acid A (GABAA) receptor subunits based on rodent experiments and clinical observations. A rapid decrease in ALLO reduces the sensitivity of GABAA receptor, and reduces the chloride influx, hindered the inhibitory effect of GABAergic neurons on pyramidal neurons, and then increased the excitability of pyramidal neurons, resulting in PMDD-like behavior. Finally, we discuss in depth the treatment of PMDD with targeted GABAA receptors, hoping to find a precise target for drug development and subsequent clinical application. In conclusion, PMDD pathophysiology is rooted in GABAA receptor sensitivity changes caused by rapid changes in ALLO levels. Targeting GABAA receptors may alleviate the occurrence of PMDD.

GSH-Activatable Aggregation-Induced Emission Cationic Lipid for Efficient Gene Delivery.

The key to gene therapy is the design of biocompatible and efficient delivery systems. In this work, a glutathione (GSH)-activated aggregation-induced-emission (AIE) cationic amphiphilic lipid, termed QM-SS-KK, was prepared for nonviral gene delivery. QM-SS-KK was composed of a hydrophilic biocompatible lysine tripeptide headgroup, a GSH-triggered disulfide linkage, and a hydrophobic AIE fluorophore QM-OH (QM: quinoline-malononitrile) tail. The peptide moiety could not only efficiently compact DNA but also well modulate the dispersion properties of QM-SS-KK, leading to the fluorescence-off state before GSH treatment. The cleavage of disulfide in QM-SS-KK by GSH generated AIE signals in situ with a tracking ability. The liposomes consisted of QM-SS-KK, and 1,2-dioleoylphosphatidylethanolamine (DOPE) (QM-SS-KK/DOPE) delivered plasmid DNAs (pDNAs) into cells with high efficiency. In particular, QM-SS-KK/DOPE had an enhanced transfection efficiency (TE) in the presence of 10% serum, which was two times higher than that of the commercial transfection agent PEI25K. These results highlighted the great potential of peptide and QM-based fluorescence AIE lipids for gene delivery applications.

Inhibition of Fap Promotes Cardiac Repair by Stabilizing BNP.

BACKGROUND: Myocardial infarction (MI) elicits cardiac fibroblast activation and extracellular matrix (ECM) deposition to maintain the structural integrity of the heart. Recent studies demonstrate that Fap (fibroblast activation protein)-a prolyl-specific serine protease-is an important marker of activated cardiac fibroblasts after MI. METHODS: Left ventricle and plasma samples from patients and healthy donors were used to analyze the expression level of FAP and its prognostic value. Echocardiography and histological analysis of heart sections were used to analyze cardiac functions, scar formation, ECM deposition and angiogenesis after MI. RNA-Sequencing, biochemical analysis, cardiac fibroblasts (CFs) and endothelial cells co-culture were used to reveal the molecular and cellular mechanisms by which Fap regulates angiogenesis. RESULTS: We found that Fap is upregulated in patient cardiac fibroblasts after cardiac injuries, while plasma Fap is downregulated and functions as a prognostic marker for cardiac repair. Genetic or pharmacological inhibition of Fap in mice significantly improved cardiac function after MI. Histological and transcriptomic analyses showed that Fap inhibition leads to increased angiogenesis in the peri-infarct zone, which promotes ECM deposition and alignment by cardiac fibroblasts and prevents their overactivation, thereby limiting scar expansion. Mechanistically, we found that BNP (brain natriuretic peptide) is a novel substrate of Fap that mediates postischemic angiogenesis. Fap degrades BNP to inhibit vascular endothelial cell migration and tube formation. Pharmacological inhibition of Fap in Nppb (encoding pre-proBNP) or Npr1 (encoding the BNP receptor)-deficient mice showed no cardioprotective effects, suggesting that BNP is a physiological substrate of Fap. CONCLUSIONS: This study identifies Fap as a negative regulator of cardiac repair and a potential drug target to treat MI. Inhibition of Fap stabilizes BNP to promote angiogenesis and cardiac repair.

Bone metabolism characteristics and gender differences in patients with COPD: a cross-sectional study.

BACKGROUND: Gender differences in bone metabolism of people with chronic obstructive pulmonary disease (COPD) remain unclear. We aim to explore the characteristics of bone metabolism and its clinical significance for patients with COPD. METHODS: A total of 564 cases (282 COPD cases and 282 controls) were preselected. Clinical and analytical characteristics of these cases were assessed. After excluding patients with other conditions known to disturb calcium metabolism, 333 patients (152 COPD cases and 181 controls) were identified. The medical records, indexes of bone turnover markers, serum calcium and phosphorus of the 333 patients were collected and their correlation was analyzed. RESULTS: The 152 cases with COPD were 82.61 ± 7.745 years, 78.3% males, and the 181 age- and sex-matched control cases were 79.73 ± 11.742 years, 72.4% males. Levels of total procollagen type I amino-terminal propeptide (tPINP), osteocalcin (OC), serum calcium and phosphate were significantly lower (P < 0.001) while the level of parathormone (PTH) was significantly higher (P = 0.004) in COPD than in controls. The 25-hydroxycholecalciferol (25(OH)D3) was below the lower limit of normal value (LLN) in both groups, which was significantly lower in COPD males than in control males (P = 0.026). In COPD group, PTH level was significantly higher in females (P = 0.006), and serum P was lower in males (P = 0.006). The adjusted linear regression analysis showed that the levels of tPINP, OC and serum Ca were decreasing greatly in COPD group [ß (95%CI) - 8.958 (- 15.255 to - 2.662), P = 0.005; - 4.584 (- 6.627 to - 2.542), P < 0.001; - 0.065 (- 0.100 to - 0.031), P < 0.001]. Besides, smoke exposure, gender (male) were also related to hypocalcemia [ß (95%CI) - 0.025 (- 0.045 to - 0.005), P = 0.017; - 0.041 (- 0.083 to - 0.001), P = 0.047], and 25(OH)D3 was correlated with serum calcium, phosphorus, and PTH [ß (95%CI) 15.392(7.032-23.753), P < 0.001; - 7.287 (- 13.450 to - 1.124), P = 0.021; - 0.103(- 0.145 to - 0.061), P < 0.001], and female was more likely to have secondary hyperparathyroidism [ß (95%CI) 12.141 (4.047-20.235), P = 0.002]. CONCLUSION: COPD patients have remarkably low bone turnover (indicated by OC) and impaired bone formation (low tPINP), and they are also more prone to low calcium. Smoking and male may play roles in the formation of hypocalcemia, and the secondary hyperparathyroidism is more significant in COPD women. There may be gender differences in bone metabolism abnormalities and their mechanisms of COPD. The conclusion above still need further research and demonstration.