PPARγ attenuates cellular senescence of alveolar macrophages in asthma-COPD overlap.

BACKGROUND: Asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) represents a complex condition characterized by shared clinical and pathophysiological features of asthma and COPD in older individuals. However, the pathophysiology of ACO remains unexplored. We aimed to identify the major inflammatory cells in ACO, examine senescence within these cells, and elucidate the genes responsible for regulating senescence. METHODS: Bioinformatic analyses were performed to investigate major cell types and cellular senescence signatures in a public single-cell RNA sequencing (scRNA-Seq) dataset derived from the lung tissues of patients with ACO. Similar analyses were carried out in an independent cohort study Immune Mechanisms Severe Asthma (IMSA), which included bulk RNA-Seq and CyTOF data from bronchoalveolar lavage fluid (BALF) samples. RESULTS: The analysis of the scRNA-Seq data revealed that monocytes/ macrophages were the predominant cell type in the lung tissues of ACO patients, constituting more than 50% of the cells analyzed. Lung monocytes/macrophages from patients with ACO exhibited a lower prevalence of senescence as defined by lower enrichment scores of SenMayo and expression levels of cellular senescence markers. Intriguingly, analysis of the IMSA dataset showed similar results in patients with severe asthma. They also exhibited a lower prevalence of senescence, particularly in airway CD206 + macrophages, along with increased cytokine expression (e.g., IL-4, IL-13, and IL-22). Further exploration identified alveolar macrophages as a major subtype of monocytes/macrophages driving cellular senescence in ACO. Differentially expressed genes related to oxidation-reduction, cytokines, and growth factors were implicated in regulating senescence in alveolar macrophages. PPARγ (Peroxisome Proliferator-Activated Receptor Gamma) emerged as one of the predominant regulators modulating the senescent signature of alveolar macrophages in ACO. CONCLUSION: The findings suggest that senescence in macrophages, particularly alveolar macrophages, plays a crucial role in the pathophysiology of ACO. Furthermore, PPARγ may represent a potential therapeutic target for interventions aimed at modulating senescence-associated processes in ACO.Key words ACO, Asthma, COPD, Macrophages, Senescence, PPARγ.

Bacteria-mediated resistance of neutrophil extracellular traps to enzymatic degradation drives the formation of dental calculi.

Dental calculi can cause gingival bleeding and periodontitis, yet the mechanism underlying the formation of such mineral build-ups, and in particular the role of the local microenvironment, are unclear. Here we show that the formation of dental calculi involves bacteria in local mature biofilms converting the DNA in neutrophil extracellular traps (NETs) from being degradable by the enzyme DNase I to being degradation resistant, promoting the nucleation and growth of apatite. DNase I inhibited NET-induced mineralization in vitro and ex vivo, yet plasma DNases were ineffective at inhibiting ectopic mineralization in the oral cavity in rodents. The topical application of the DNA-intercalating agent chloroquine in rodents fed with a dental calculogenic diet reverted NET DNA to its degradable form, inhibiting the formation of calculi. Our findings may motivate therapeutic strategies for the reduction of the prevalence of the deposition of bacteria-driven calculi in the oral cavity.

Brain regulates weight bearing bone through PGE2 skeletal interoception: implication of ankle osteoarthritis and pain.

Bone is a mechanosensitive tissue and undergoes constant remodeling to adapt to the mechanical loading environment. However, it is unclear whether the signals of bone cells in response to mechanical stress are processed and interpreted in the brain. In this study, we found that the hypothalamus of the brain regulates bone remodeling and structure by perceiving bone prostaglandin E2 (PGE2) concentration in response to mechanical loading. Bone PGE2 levels are in proportion to their weight bearing. When weight bearing changes in the tail-suspension mice, the PGE2 concentrations in bones change in line with their weight bearing changes. Deletion of cyclooxygenase-2 (COX2) in the osteoblast lineage cells or knockout of receptor 4 (EP4) in sensory nerve blunts bone formation in response to mechanical loading. Moreover, knockout of TrkA in sensory nerve also significantly reduces mechanical load-induced bone formation. Moreover, mechanical loading induces cAMP-response element binding protein (CREB) phosphorylation in the hypothalamic arcuate nucleus (ARC) to inhibit sympathetic tyrosine hydroxylase (TH) expression in the paraventricular nucleus (PVN) for osteogenesis. Finally, we show that elevated PGE2 is associated with ankle osteoarthritis (AOA) and pain. Together, our data demonstrate that in response to mechanical loading, skeletal interoception occurs in the form of hypothalamic processing of PGE2-driven peripheral signaling to maintain physiologic bone homeostasis, while chronically elevated PGE2 can be sensed as pain during AOA and implication of potential treatment.

Associations of residential greenness exposure and ambient air pollutants with newly-diagnosed drug-resistant tuberculosis cases.

Growing evidence has found the health protective effects of greenness exposure on tuberculosis (TB) and the impact of ambient air pollutants on TB drug-resistance. However, it remains unclear whether residential greenness is also beneficial to reduce TB drug-resistance, and whether air pollution modify the greenness-TB resistance relationship. We enrolled 5006 newly-diagnosed TB patients from Shandong, China, during 2014 to 2021. Normalized Difference Vegetation Index (NDVI) in 250 m and 500 m buffer around individuals' residential zone was used to assess greenness exposure. All patients were divided by quartiles of NDVI250-m and NDVI500-m (from low to high: Q1, Q2, Q3, Q4) respectively. Six logistic regression models (NDVI, NDVI + PM2.5/PM10/SO2/NO2/O3) were used to estimate the association of NDVI and TB drug-resistance when adjusting different air pollutants or not. All models were adjusted for age, gender, body mass index, complications, smoking, drinking, population density, nighttime light index, road density. Compared with participants in NDVI250-m Q1 and NDVI500-m Q1, other groups had lower rates of MDR-TB, PDR-TB, RFP-resistance, SM-resistance, RFP + SM resistance, INH + RFP + EMB + SM resistance. NDVI500-m reduced the risk of multidrug resistant tuberculosis (MDR-TB) and the adjusted odds ratio (aOR, 95% confidence interval, CI) compared with NDVI500-m Q1 were 0.736 (0.547-0.991) in NDVI + PM10 model, 0.733 (0.544-0.986) in NDVI + PM2.5 model, 0.735(0.546-0.99) in NDVI + SO2 model, 0.736 (0.546-0.991) in NDVI + NO2 model, respectively, P < 0.05. NDVI500-m contributed to a decreased risk of streptomycin (SM)-resistance. The aOR of rifampicin (RFP) + SM resistance were 0.132 (NDVI250-m, Q4 vs Q1, 95% CI: 0.03-0.578), 0.199 (NDVI500-m, Q3 vs. Q1, 95% CI: 0.057-0.688) and 0.264 (NDVI500-m, Q4 vs. Q1, 95% CI: 0.087-0.799). The adjusted ORs (Q2 vs. Q1, 95% CI) of isoniazid (INH) + RFP + ethambutol (EMB) + SM resistance in 500 m buffer were 0.276 (0.119-0.639) in NDVI model, 0.279 (0.11-0.705) in NDVI + PM10 model, 0.281 (0.111-0.713) in NDVI + PM2.5 model, 0.279 (0.11-0.709) in NDVI + SO2 model, 0.296 (0.117-0.754) in NDVI + NO2 model, 0.294 (0.116-0.748) in NDVI + O3 model, respectively. The study showed, for the first time, that residential greenness exposure in 500 m buffer is beneficial for reducing newly-diagnosed DR-TB (including PDR-RB, MDR-TB, MR-TB), and ambient air pollutants may partially mediate this association.

Active Components of Pueraria lobata through the MAPK/ERK Signaling Pathway Alleviate Iron Overload in Alcoholic Liver Disease.

OBJECTIVE: To delve into the primary active ingredients and mechanism of Pueraria lobata for alleviating iron overload in alcoholic liver disease. METHODS: Pueraria lobata's potential targets and signaling pathways in treating alcohol-induced iron overloads were predicted using network pharmacology analysis. Then, animal experiments were used to validate the predictions of network pharmacology. The impact of puerarin or genistein on alcohol-induced iron accumulation, liver injury, oxidative stress, and apoptosis was assessed using morphological examination, biochemical index test, and immunofluorescence. Key proteins implicated in linked pathways were identified using RT-qPCR, western blot analysis, and immunohistochemistry. RESULTS: Network pharmacological predictions combined with animal experiments suggest that the model group compared to the control group, exhibited activation of the MAPK/ERK signaling pathway, suppression of hepcidin expression, and aggravated iron overload, liver damage, oxidative stress, and hepatocyte death. Puerarin and genistein, the active compounds in Pueraria lobata, effectively mitigated the aforementioned alcohol-induced effects. No statistically significant disparities were seen in the effects above between the two groups receiving drug therapy. CONCLUSION: This study preliminarily demonstrated that puerarin and genistein in Pueraria lobata may increase hepcidin production to alleviate alcohol-induced iron overload by inhibiting the MAPK/ERK signaling pathway.

PPARγ Attenuates Cellular Senescence of Alveolar Macrophages in Asthma- COPD Overlap.

Asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) represents a complex condition characterized by shared clinical and pathophysiological features of asthma and COPD in older individuals. However, the pathophysiology of ACO remains unexplored. We aimed to identify the major inflammatory cells in ACO, examine senescence within these cells, and elucidate the genes responsible for regulating senescence. Bioinformatic analyses were performed to investigate major cell types and cellular senescence signatures in a public single-cell RNA sequencing (scRNA-Seq) dataset derived from the lung tissues of patients with ACO. Similar analyses were carried out in an independent cohort study Immune Mechanisms Severe Asthma (IMSA), which included bulk RNA-Seq and CyTOF data from bronchoalveolar lavage fluid (BALF) samples. The analysis of the scRNA-Seq data revealed that monocytes/ macrophages were the predominant cell type in the lung tissues of ACO patients, constituting more than 50% of the cells analyzed. Lung monocytes/macrophages from patients with ACO exhibited a lower prevalence of senescence as defined by lower enrichment scores of SenMayo and expression levels of cellular senescence markers. Intriguingly, analysis of the IMSA dataset showed similar results in patients with severe asthma. They also exhibited a lower prevalence of senescence, particularly in airway CD206 + macrophages, along with increased cytokine expression (e.g., IL-4, IL-13, and IL-22). Further exploration identified alveolar macrophages as a major subtype of monocytes/macrophages driving cellular senescence in ACO. Differentially expressed genes related to oxidation-reduction, cytokines, and growth factors were implicated in regulating senescence in alveolar macrophages. PPARγ (Peroxisome Proliferator-Activated Receptor Gamma) emerged as one of the predominant regulators modulating the senescent signature of alveolar macrophages in ACO. Collectively, the findings suggest that senescence in macrophages, particularly alveolar macrophages, plays a crucial role in the pathophysiology of ACO. Furthermore, PPARγ may represent a potential therapeutic target for interventions aimed at modulating senescence-associated processes in ACO.

Repositioning baloxavir marboxil as VISTA agonist that ameliorates experimental asthma.

V-type immunoglobulin domain-containing suppressor of T-cell activation (VISTA), a novel negative checkpoint regulator, plays an essential role in allergic pulmonary inflammation in mice. Treatment with a VISTA agonistic antibody could significantly improve asthma symptoms. Thus, for allergic asthma treatment, VISTA targeting may be a compelling approach. In this study, we examined the functional mechanism of VISTA in allergic pulmonary inflammation and screened the FDA-approved drugs for VISTA agonists. By using mass cytometry (CyTOF), we found that VISTA deficiency primarily increased lung macrophage infiltration in the OVA-induced asthma model, accompanied by an increased proportion of M1 macrophages (CD11b+F4/80+CD86+) and a decreased proportion of M2 macrophages (CD11b+F4/80+CD206+). Further in vitro studies showed that VISTA deficiency promoted M1 polarization and inhibited M2 polarization of bone marrow-derived macrophages (BMDMs). Importantly, we discovered baloxavir marboxil (BXM) as a VISTA agonist by virtual screening of FDA-approved drugs. The surface plasmon resonance (SPR) assays revealed that BXM (KD = 1.07 µM) as well as its active form, baloxavir acid (BXA) (KD = 0.21 µM), could directly bind to VISTA with high affinity. Notably, treatment with BXM significantly ameliorated asthma symptoms, including less lung inflammation, mucus secretion, and the generation of Th2 cytokines (IL-5, IL-13, and IL-4), which were dramatically attenuated by anti-VISTA monoclonal antibody treatment. BXM administration also reduced the pulmonary infiltration of M1 macrophages and raised M2 macrophages. Collectively, our study indicates that VISTA regulates pulmonary inflammation in allergic asthma by regulating macrophage polarization and baloxavir marboxil, and an old drug might be a new treatment for allergic asthma through targeting VISTA.

Senescence of endplate osteoclasts induces sensory innervation and spinal pain.

Spinal pain affects individuals of all ages and is the most common musculoskeletal problem globally. Its clinical management remains a challenge as the underlying mechanisms leading to it are still unclear. Here, we report that significantly increased numbers of senescent osteoclasts (SnOCs) are observed in mouse models of spinal hypersensitivity, like lumbar spine instability (LSI) or aging, compared to controls. The larger population of SnOCs is associated with induced sensory nerve innervation, as well as the growth of H-type vessels, in the porous endplate. We show that deletion of senescent cells by administration of the senolytic drug Navitoclax (ABT263) results in significantly less spinal hypersensitivity, spinal degeneration, porosity of the endplate, sensory nerve innervation and H-type vessel growth in the endplate. We also show that there is significantly increased SnOC-mediated secretion of Netrin-1 and NGF, two well-established sensory nerve growth factors, compared to non-senescent OCs. These findings suggest that pharmacological elimination of SnOCs may be a potent therapy to treat spinal pain.

Transmission dynamics and phylogeography of Mycobacterium tuberculosis in China based on whole-genome phylogenetic analysis.

OBJECTIVES: This study aimed to describe the lineage-specific transmissibility and epidemiological migration of Mycobacterium tuberculosis in China. METHODS: We curated a large set of whole-genome sequences from 3204 M. tuberculosis isolates, including thousands of newly sequenced genomes, and applied a series of metrics to compare the transmissibility of M. tuberculosis strains between lineages and sublineages. The countrywide transmission patterns of major lineages were explored. RESULTS: We found that lineage 2 (L2) was the most prevalent lineage in China (85.7%), with the major sublineage 2.2.1 (80.9%), followed by lineage 4 (L4) (13.8%), which comprises major sublineages 4.2 (1.5%), 4.4 (6.2%) and 4.5 (5.8%). We showed evidence for frequent cross-regional spread and large cluster formation of L2.2.1 strains, whereas L4 strains were relatively geographically restricted in China. Next, we applied a series of genomic indices to evaluate M. tuberculosis strain transmissibility and uncovered higher transmissibility of L2.2.1 compared with the L2.2.2 and L4 sublineages. Phylogeographic analysis showed that southern, eastern, and northern China were highly connected regions for countrywide L2.2.1 strain spread. CONCLUSIONS: The present study provides insights into the different transmission and migration patterns of the major M. tuberculosis lineages in China and highlights that transmissible L2.2.1 is a threat to tuberculosis control.

Effective delivery of miR-511-3p with mannose-decorated exosomes with RNA nanoparticles confers protection against asthma.

Our previous studies have shown that miR-511-3p treatment has a beneficial effect in alleviating allergic airway inflammation. Here, we sought to explore its therapeutic potential in animal models and gain a deeper understanding of its therapeutic value for asthma. miR-511-3p knockout mice (miR-511-3p-/-) were generated by CRISPR/Cas and showed exacerbated airway hyper-responsiveness and Th2-associated allergic airway inflammation compared with wild-type (WT) mice after exposed to cockroach allergen. RNA nanoparticles with mannose decorated EV-miR-511-3p were also created by loading miR-511-3p mimics into the mannose decorated EVs with engineered RNA nanoparticle PRNA-3WJ (Man-EV-miR-511-3p). Intra-tracheal inhalation of Man-EV-miR-511-3p, which could effectively penetrate the airway mucus barrier and deliver functional miR-511-3p to lung macrophages, successfully reversed the increased airway inflammation observed in miR-511-3p-/- mice. Through microarray analysis, complement C3 (C3) was identified as one of the major targets of miR-511-3p. C3 was increased in LPS-treated macrophages but decreased after miR-511-3p treatment. Consistent with these findings, C3 expression was elevated in the lung macrophages of an asthma mouse model but decreased in mice treated with miR-511-3p. Further experiments, including miRNA-mRNA pulldown and luciferase reporter assays, confirmed that miR-511-3p directly binds to C3 and activates the C3 gene. Thus, miR-511-3p represents a promising therapeutic target for asthma, and RNA nanotechnology reprogrammed EVs are efficient carriers for miRNA delivery for disease treatment.

Statin use and longitudinal changes in quantitative MRI-based biomarkers of thigh muscle quality: data from Osteoarthritis Initiative.

OBJECTIVE: To assess whether changes in MRI-based measures of thigh muscle quality associated with statin use in participants with and without/at-risk of knee osteoarthritis. METHODS: This retrospective cohort study used data from the Osteoarthritis Initiative study. Statin users and non-users were matched for relevant covariates using 1:1 propensity-score matching. Participants were further stratified according to baseline radiographic knee osteoarthritis status. We used a validated deep-learning method for thigh muscle MRI segmentation and calculation of muscle quality biomarkers at baseline, 2nd, and 4th visits. Mean difference and 95% confidence intervals (CI) in longitudinal 4-year measurements of muscle quality biomarkers, including cross-sectional area, intramuscular adipose tissue, contractile percent, and knee extensors and flexors maximum and specific contractile force (force/muscle area) were the outcomes of interest. RESULTS: After matching, 3772 thighs of 1910 participants were included (1886 thighs of statin-users: 1886 of non-users; age: 62 ± 9 years (average ± standard deviation), range: 45-79; female/male: 1). During 4 years, statin use was associated with a slight decrease in muscle quality, indicated by decreased knee extension maximum (mean-difference, 95% CI: - 1.85 N/year, - 3.23 to - 0.47) and specific contractile force (- 0.04 N/cm2/year, - 0.07 to - 0.01), decreased thigh muscle contractile percent (- 0.03%/year, - 0.06 to - 0.01), and increased thigh intramuscular adipose tissue (3.06 mm2/year, 0.53 to 5.59). Stratified analyses showed decreased muscle quality only in participants without/at-risk of knee osteoarthritis but not those with established knee osteoarthritis. CONCLUSIONS: Statin use is associated with a slight decrease in MRI-based measures of thigh muscle quality over 4 years. However, considering statins' substantial cardiovascular benefits, these slight muscle changes may be relatively less important in overall patient care.

Associations of serum gamma-linolenic acid levels with erythema severity and anxiety/depression status in patients with rosacea.

BACKGROUND: The development of rosacea is suggested to be closely associated with lipid metabolism, inflammation, and anxiety/depression. Gamma linolenic acid (GLA) is a key factor participating in lipid metabolism, which is also confirmed to regulate the inflammatory response. However, the associations of serum GLA levels with rosacea severity and psychological status still remain unclear. OBJECTIVE AND LIMITATIONS OF THE STUDY: The present study aimed to investigate the associations of gamma linolenic acid (GLA), a key factor participating in lipid metabolism and the inflammatory response, with rosacea severity and psychological status. The present study still had some limitations. First, this study is a cross-sectional study and does not provide longitudinal evidence about the relationship between GLA and rosacea; Second, the cohort in this study is also relatively small, and a larger cohort is needed in further investigation to reveal the potential role of lipid metabolism in the pathogenesis of rosacea. METHODS: A total of 62 rosacea patients were consecutively recruited. Patient's Self-Assessment (PSA) scale and Clinician Erythema Assessment (CEA) as well as 7-item Generalized Anxiety Disorder (GAD-7) and 9-item Patient Health Questionnaire (PHQ-9) were conducted to evaluate the degree of erythema severity and anxiety/depression, respectively. Serum GLA levels were determined by gas chromatography mass. RESULTS: Lower levels of serum GLA in rosacea patients were observed (p<0.001), and subgroup analysis revealed that patients with higher-level GLA had lower scores of PSA, CEA, GAD-7 and PHQ-9. Moreover, Spearman correlation analysis uncovered that serum GLA levels were negatively associated with PSA, CEA, GAD-7 as well and PHQ-9 scores, respectively. Linear regression model found that serum GLA levels at baseline were a predictive factor for prognosis of clinical outcomes after 1-month conventional treatment. CONCLUSION: The present study indicates that lower levels of serum GLA in rosacea patients are negatively associated with the degree of erythema and anxiety/depression status.

Genomic analysis of lineage-specific transmission of multidrug resistance tuberculosis in China.

OBJECTIVES: We investigated the genetic diversities and lineage-specific transmission dynamics of multidrug-resistant tuberculosis (MDR-TB), with the goal of determining the potential factors driving the MDR epidemics in China. METHODS: We curated a large nationwide Mycobacterium tuberculosis (M. tuberculosis) whole genome sequence data set, including 1313 MDR strains. We reconstructed the phylogeny and mapped the transmission networks of MDR-TB across China using Bayesian inference. To identify drug-resistance variants linked to enhanced transmissibility, we employed ordinary least-squares (OLS) regression analysis. RESULT: The majority of MDR-TB strains in China belong to lineage 2.2.1. Transmission chain analysis has indicated that the repeated and frequent transmission of L2.2.1 plays a central role in the establishment of MDR epidemic in China, but no occurrence of a large predominant MDR outbreak was detected. Using OLS regression, the most common single nucleotide polymorphisms (SNPs) associated with resistance to isoniazid (katG_p.Ser315Thr and katG_p.Ser315Asn) and rifampicin (rpoB_p.Ser450Leu, rpoB_p.His445Tyr, rpoB_p.His445Arg, rpoB_p.His445Asp, and rpoB_p.His445Asn) were more likely to be found in L2 clustered strains. Several putative compensatory mutations in rpoA, rpoC, and katG were significantly associated with clustering. The eastern, central, and southern regions of China had a high level of connectivity for the migration of L2 MDR strains throughout the country. The skyline plot showed distinct population size expansion dynamics for MDR-TB lineages in China. CONCLUSION: MDR-TB epidemic in China is predominantly driven by the spread of highly transmissible Beijing strains. A range of drug-resistance mutations of L2 MDR-TB strains displayed minimal fitness costs and may facilitate their transmission.

Fibrocyte: A missing piece in the pathogenesis of fibrous epulis.

OBJECTIVES: To explore the role of fibrocytes in the recurrence and calcification of fibrous epulides. METHODS: Different subtypes of fibrous epulides and normal gingival tissue specimens were first collected for histological and immunofluorescence analyses to see if fibrocytes were present and whether they differentiated into myofibroblasts and osteoblasts upon stimulated by transforming growth factor-ß1 (TGF-ß1). Electron microscopy and elemental analysis were used to characterize the extracellular microenvironment in different subtypes of fibrous epulides. Human peripheral blood mononuclear cells (PBMCs) were subsequently isolated from in vitro models to mimic the microenvironment in fibrous epulides to identify whether TGF-ß1 as well as the calcium and phosphorus ion concentration in the extracellular matrix (ECM) of a fibrous epulis trigger fibrocyte differentiation. RESULTS: Fibrous epulides contain fibrocytes that accumulate in the local inflammatory environment and have the ability to differentiate into myofibroblasts or osteoblasts. TGF-ß1 promotes fibrocytes differentiation into myofibroblasts in a concentration-dependent manner, while TGF-ß1 stimulates the fibrocytes to differentiate into osteoblasts when combined with a high calcium and phosphorus environment. CONCLUSIONS: Our study revealed fibrocytes play an important role in the fibrogenesis and osteogenesis in fibrous epulis, and might serve as a therapeutic target for the inhibition of recurrence of fibrous epulides.

Parathyroid hormone treatment partially reverses endplate remodeling and attenuates low back pain in animal models of spine degeneration.

Low back pain (LBP) is one of the most prevalent diseases affecting quality of life, with no disease-modifying therapy. During aging and spinal degeneration, the balance between the normal endplate (EP) bilayers of cartilage and bone shifts to more bone. The aged/degenerated bony EP has increased porosity because of osteoclastic remodeling activity and may be a source of LBP due to aberrant sensory innervation within the pores. We used two mouse models of spinal degeneration to show that parathyroid hormone (PTH) treatment induced osteogenesis and angiogenesis and reduced the porosity of bony EPs. PTH increased the cartilaginous volume and improved the mechanical properties of EPs, which was accompanied by a reduction of the inflammatory factors cyclooxygenase-2 and prostaglandin E2. PTH treatment furthermore partially reversed the innervation of porous EPs and reversed LBP-related behaviors. Conditional knockout of PTH 1 receptors in the nucleus pulposus (NP) did not abolish the treatment effects of PTH, suggesting that the NP is not the primary source of LBP in our mouse models. Last, we showed that aged rhesus macaques with spontaneous spinal degeneration also had decreased EP porosity and sensory innervation when treated with PTH, demonstrating a similar mechanism of PTH action on EP sclerosis between mice and macaques. In summary, our results suggest that PTH treatment could partially reverse EP restructuring during spinal regeneration and support further investigation into this potentially disease-modifying treatment strategy for LBP.

Unloading-Induced Skeletal Interoception Alters Hypothalamic Signaling to Promote Bone Loss and Fat Metabolism.

Microgravity is the primary factor that affects human physiology in spaceflight, particularly bone loss and disturbances of the central nervous system. However, little is known about the cellular and molecular mechanisms of these effects. Here, it is reported that in mice hindlimb unloading stimulates expression of neuropeptide Y (NPY) and tyrosine hydroxylase (TH) in the hypothalamus, resulting in bone loss and altered fat metabolism. Enhanced expression of TH and NPY in the hypothalamus occurs downstream of a reduced prostaglandin E2 (PGE2)-mediated ascending interoceptive signaling of the skeletal interoception. Sympathetic antagonist propranolol or deletion of Adrb2 in osteocytes rescue bone loss in the unloading model. Moreover, depletion of TH+ sympathetic nerves or inhibition of norepinephrine release ameliorated bone resorption. Stereotactic inhibition of NPY expression in the hypothalamic neurons reduces the food intake with altered energy expenditure with a limited effect on bone, indicating hypothalamic neuroendocrine factor NPY in the facilitation of bone formation by sympathetic TH activity. These findings suggest that reduced PGE2-mediated interoceptive signaling in response to microgravity or unloading has impacts on the skeletal and central nervous systems that are reciprocally regulated.

Mechanical loading-induced change of bone homeostasis is mediated by PGE2-driven hypothalamic interoception.

Bone is a mechanosensitive tissue and undergoes constant remodeling to adapt to the mechanical loading environment. However, it is unclear whether the signals of bone cells in response to mechanical stress are processed and interpreted in the brain. In this study, we found that the hypothalamus of the brain regulates bone remodeling and structure by perceiving bone PGE2 concentration in response to mechanical loading. Bone PGE2 levels are in proportion to their weight bearing. When weight bearing changes in the tail-suspension mice, the PGE2 concentrations in bones change in line with their weight bearing changes. Deletion of Cox2 or Pge2 in the osteoblast lineage cells or knockout Ep4 in sensory nerve blunts bone formation in response to mechanical loading. And sensory denervation also significantly reduces mechanical load-induced bone formation. Moreover, mechanical loading induces CREB phosphorylation in the hypothalamic ARC region to inhibit sympathetic TH expression in the PVN for osteogenesis. Finally, we show that elevated PGE2 is associated with ankle osteoarthritis (AOA) and pain. Together, our data demonstrate that in response to mechanical loading, skeletal interoception occurs in the form of hypothalamic processing of PGE2-driven peripheral signaling to maintain physiologic bone homeostasis, while chronically elevated PGE2 can be sensed as pain during AOA and implication of potential treatment.

Bone-derived PDGF-BB drives brain vascular calcification in male mice.

Brain vascular calcification is a prevalent age-related condition often accompanying neurodegenerative and neuroinflammatory diseases. The pathogenesis of large-vessel calcifications in peripheral tissue is well studied, but microvascular calcification in the brain remains poorly understood. Here, we report that elevated platelet-derived growth factor BB (PDGF-BB) from bone preosteoclasts contributed to cerebrovascular calcification in male mice. Aged male mice had higher serum PDGF-BB levels and a higher incidence of brain calcification compared with young mice, mainly in the thalamus. Transgenic mice with preosteoclast-specific Pdgfb overexpression exhibited elevated serum PDGF-BB levels and recapitulated age-associated thalamic calcification. Conversely, mice with preosteoclast-specific Pdgfb deletion displayed diminished age-associated thalamic calcification. In an ex vivo cerebral microvascular culture system, PDGF-BB dose-dependently promoted vascular calcification. Analysis of osteogenic gene array and single-cell RNA-Seq (scRNA-Seq) revealed that PDGF-BB upregulated multiple osteogenic differentiation genes and the phosphate transporter Slc20a1 in cerebral microvessels. Mechanistically, PDGF-BB stimulated the phosphorylation of its receptor PDGFRß (p-PDGFRß) and ERK (p-ERK), leading to the activation of RUNX2. This activation, in turn, induced the transcription of osteoblast differentiation genes in PCs and upregulated Slc20a1 in astrocytes. Thus, bone-derived PDGF-BB induced brain vascular calcification by activating the p-PDGFRß/p-ERK/RUNX2 signaling cascade in cerebrovascular cells.

Zinc Hydroxystannate/Carbon Nanotube Hybrids as Flame Retardant and Smoke Suppressant for Epoxy Resins.

Novel hybrid flame retardants containing zinc hydroxystannate and carbon nanotubes (ZHS-CNTs) were synthesized using the coprecipitation method, and the structure and morphology of ZHS-CNTs were investigate using an X-ray powder diffractometer (XRD), scanning electron microscope (SEM), transmission electron microscopy (TEM) and thermogravimetric analyzer (TGA). Then, the ZHS, CNTs and ZHS-CNTs were incorporated into EP, respectively, and the flame-retardant and smoke inhibition performance of the composites were compared and studied. Among the three composites, the EP/ZHS-CNT composites have the highest improvements on the fire resistance and smoke inhibition properties. With only 2.0 wt.% ZHS-CNT hybrids, the pHRR of EP/ZHS-CNT composite materials is reduced by 34.2% compared with EP. Moreover, the release of toxic gases including CO, CO2 and SPR from the composites was also effectively inhibited. The mechanisms of flame retardant and smoke inhibition were investigated and the improved properties were generally ascribed to the synergistic flame-retardant effects between ZHS and CNTs, the catalyzing effect of ZHS and the stable network structure of CNTs.