Dysregulated lung stroma drives emphysema exacerbation by potentiating resident lymphocytes to suppress an epithelial stem cell reservoir.

Aberrant tissue-immune interactions are the hallmark of diverse chronic lung diseases. Here, we sought to define these interactions in emphysema, a progressive disease characterized by infectious exacerbations and loss of alveolar epithelium. Single-cell analysis of human emphysema lungs revealed the expansion of tissue-resident lymphocytes (TRLs). Murine studies identified a stromal niche for TRLs that expresses Hhip, a disease-variant gene downregulated in emphysema. Stromal-specific deletion of Hhip induced the topographic expansion of TRLs in the lung that was mediated by a hyperactive hedgehog-IL-7 axis. 3D immune-stem cell organoids and animal models of viral exacerbations demonstrated that expanded TRLs suppressed alveolar stem cell growth through interferon gamma (IFNγ). Finally, we uncovered an IFNγ-sensitive subset of human alveolar stem cells that was preferentially lost in emphysema. Thus, we delineate a stromal-lymphocyte-epithelial stem cell axis in the lung that is modified by a disease-variant gene and confers host susceptibility to emphysema.

Adventitial Stromal Cells Define Group 2 Innate Lymphoid Cell Tissue Niches.

Type 2 lymphocytes promote both physiologic tissue remodeling and allergic pathology, yet their physical tissue niches are poorly described. Here, we used quantitative imaging to define the tissue niches of group 2 innate lymphoid cells (ILC2s), which are critical instigators of type 2 immunity. We identified a dominant adventitial niche around lung bronchi and larger vessels in multiple tissues, where ILC2s localized with subsets of dendritic and regulatory T cells. However, ILC2s were most intimately associated with adventitial stromal cells (ASCs), a mesenchymal fibroblast-like subset that expresses interleukin-33 (IL-33) and thymic stromal lymphopoietin (TSLP). In vitro, ASCs produced TSLP that supported ILC2 accumulation and activation. ILC2s and IL-13 drove reciprocal ASC expansion and IL-33 expression. During helminth infection, ASC depletion impaired lung ILC2 and Th2 cell accumulation and function, which are in part dependent on ASC-derived IL-33. These data indicate that adventitial niches are conserved sites where ASCs regulate type 2 lymphocyte expansion and function.

IRG1 restrains M2 macrophage polarization and suppresses intrahepatic cholangiocarcinoma progression via the CCL18/STAT3 pathway.

Intrahepatic cholangiocarcinoma (ICC) is a highly malignant and aggressive cancer whose incidence and mortality continue to increase, whereas its prognosis remains dismal. Tumor-associated macrophages (TAMs) promote malignant progression and immune microenvironment remodeling through direct contact and secreted mediators. Targeting TAMs has emerged as a promising strategy for ICC treatment. Here, we revealed the potential regulatory function of immune responsive gene 1 (IRG1) in macrophage polarization. We found that IRG1 expression remained at a low level in M2 macrophages. IRG1 overexpression can restrain macrophages from polarizing to the M2 type, which results in inhibition of the proliferation, invasion, and migration of ICC, whereas IRG1 knockdown exerts the opposite effects. Mechanistically, IRG1 inhibited the tumor-promoting chemokine CCL18 and thus suppressed ICC progression by regulating STAT3 phosphorylation. The intervention of IRG1 expression in TAMs may serve as a potential therapeutic target for delaying ICC progression.

Biological characteristics of pregnancy in captive Yangtze finless porpoises revealed by urinary metabolomics†.

The Yangtze finless porpoises (Neophocaena asiaeorientalis a.) are an endemic and critically endangered species in China. Intensive captive breeding is essential for understanding the biology of critically endangered species, especially their pregnancy characteristics, knowledge of which is crucial for effective breeding management. Urine metabolomics can reveal metabolic differences, arising from physiological changes across pregnancy stages. Therefore, we used the urinary metabolomic technology, to explore urinary metabolite changes in pregnant Yangtze finless porpoises. A total of 2281 metabolites were identified in all samples, which including organic acids and derivatives (24.45%), organoheterocyclic compounds (20.23%), benzenoids (18.05%), organic oxygen compounds (7.73%), and phenylpropanoids and polyketides (6.48%). There were 164, 387, and 522 metabolites demonstrating differential abundance during early pregnancy, mid pregnancy, and late pregnancy, respectively, from the levels observed in nonpregnancy. The levels of pregnenolone, 17α-hydroxyprogesterone, and tetrahydrocortisone were significantly higher during all pregnancy stages, indicating their important roles in fetal development. The differential metabolites between nonpregnancy and pregnancy were mainly associated with amino acid and carbohydrate metabolism. Moreover, metabolic activity varied across pregnancy stages; steroid hormone biosynthesis was predominant in early pregnancy, and amino acid biosynthesis and carbohydrate metabolism were predominant in mid pregnancy and late pregnancy, respectively. Our results provide new insights into metabolic characteristics in the Yangtze finless porpoises' urine during pregnancy, and indicate that the differential levels of urine metabolites can determine pregnancy in Yangtze finless porpoises, providing valuable information for the husbandry and management of pregnant Yangtze finless porpoises in captivity.

Risk factors for carotid plaque formation in type 2 diabetes mellitus.

OBJECT: Patients with type 2 diabetes mellitus (T2DM) are at higher risk of developing atherosclerosis. Previous studies have analyzed the factors associated with diabetic macrovascular disease, although whether these factors are applicable to T2DM patients with carotid atherosclerosis remains unclear. Therefore, the aim of this study was to investigate the risk factors for the formation of carotid atherosclerotic plaque in hospitalized T2DM patients and to provide a theoretical basis for early prevention and treatment of carotid atherosclerosis in these patients. METHODS: A total of 949 patients with T2DM were included in the study. Carotid ultrasound identified 531 patients with carotid atherosclerotic plaque. The waist-to-hip ratio (WHR), blood glucose, liver and kidney function, blood lipid profile, islet function, and other indicators were measured at the same time to identify the risk factors and predictive significance of T2DM carotid plaque. RESULTS: The proportions of men, diabetes nephropathy (DN) and hypertension in T2DM patients with carotid plaque are higher than those without carotid plaque(P < 0.05). Age, duration of diabetes, WHR, Postprandial glucose (PPG), lipoprotein (a) [Lip (a)], carcinoembryonic antigen(CEA) and estimated glomerular filtration rate (eGFR) in T2DM patients with carotid plaque were higher than those without plaque (P < 0.05). Age, WHR, duration of diabetes, hypertension, males, and Lip (a) were independent risk factors for T2DM patients with carotid plaque. Age, WHR, duration of diabetes, and Lip (a) had a higher AUC to predict T2DM with carotid artery plaque (AUC: 0.750, 0.640, 0.678, 0.552 respectively; P all < 0.001). After constructing the logit (P) value of the above risk factors, the area under the ROC curve was 0.816 (0.789-0.842, P < 0.001). CONCLUSION: Age, WHR, duration of diabetes, hypertension, males, and Lip (a) levels are the main risk factors for the formation of carotid plaque in T2DM patients. Combining the above risk factors provides a better prediction of carotid plaque formation in T2DM.

Soil organic matter priming: The pH effects.

Priming of soil organic matter (SOM) decomposition by microorganisms is a key phenomenon of global carbon (C) cycling. Soil pH is a main factor defining priming effects (PEs) because it (i) controls microbial community composition and activities, including enzyme activities, (ii) defines SOM stabilization and destabilization mechanisms, and (iii) regulates intensities of many biogeochemical processes. In this critical review, we focus on prerequisites and mechanisms of PE depending on pH and assess the global change consequences for PE. The highest PEs were common in soils with pH between 5.5 and 7.5, whereas low molecular weight organic compounds triggered PE mainly in slightly acidic soils. Positive PEs up to 20 times of SOM decomposition before C input were common at pH around 6.5. Negative PEs were common at soil pH below 4.5 or above 7 reflecting a suboptimal environment for microorganisms and specific SOM stabilization mechanisms at low and high pH. Short-term soil acidification (in rhizosphere, after fertilizer application) affects PE by: mineral-SOM complexation, SOM oxidation by iron reduction, enzymatic depolymerization, and pH-dependent changes in nutrient availability. Biological processes of microbial metabolism shift over the short-term, whereas long-term microbial community adaptations to slow acidification are common. The nitrogen fertilization induced soil acidification and land use intensification strongly decrease pH and thus boost the PE. Concluding, soil pH is one of the strongest but up to now disregarded factors of PE, defining SOM decomposition through short-term metabolic adaptation of microbial groups and long-term shift of microbial communities.

"Energy and enthalpy" for microbial energetics in soil.

Energy is the driver of all microbial processes in soil. The changes in Gibbs energy are equal to the enthalpy changes during all processes in soil because these processes are ongoing under constant pressure and volume-without work generation. The enthalpy change by transformation of individual organic compounds or of complex organic matter in soil can be exactly quantified by the nominal oxidation state of carbon changes. Consequently, microbial energy use efficiency can be assessed by the complete combustion enthalpy of organic compounds when microorganisms use O2 as the terminal electron acceptor for microbial processes under aerobic conditions.

MetBil as a novel molecular regulator in ischemia-induced cardiac fibrosis via METTL3-mediated m6A modification.

Cardiac fibrosis is a common pathological manifestation in multiple cardiovascular diseases and often results in myocardial stiffness and cardiac dysfunctions. LncRNA (long noncoding RNA) participates in a number of pathophysiological processes. However, its role in cardiac fibrosis remains unclear. The purpose of this study was to investigate the role and molecular mechanism of MetBil in regulating cardiac fibrosis. Our data showed that METTL3 binding lncRNA (MetBil) was significantly increased both in fibrotic tissue following myocardial infarction (MI) in mice and in cardiac fibroblasts (CFs) exposed to TGF-ß1 (20 ng/mL) or 20% FBS. Overexpression of MetBil augmented collagen deposition, CF proliferation and activation while silencing MetBil exhibited the opposite effects. Importantly, heterozygous knockout of MetBil alleviated cardiac fibrosis and improved cardiac function after MI. RNA pull-down and RNA-binding protein immunoprecipitation assay showed that METTL3 is a direct downstream target of MetBil; consistently, MetBil and METTL3 were co-localized in both the nucleus and cytoplasm of CFs. Interestingly, MetBil regulated METTL3 expression at protein level, but not mRNA level, in ubiquitin-proteasome pathway. Enforced expression of METTL3 canceled the antifibrotic effects of silencing MetBil reflected by increased collagen production, CF proliferation and activation. Most notably, the m6A-modified fibrosis-regulated genes mediated by METTL3 are profoundly involved in the regulation of MetBil in the cardiac fibrosis following MI. Our study reveals that MetBil as a novel regulator of fibrosis promotes cardiac fibrosis via interacting with METTL3 and regulating the expression of the methylated fibrosis-associated genes, providing a new intervening target for fibrosis-associated cardiac diseases.

FGF21 protects against ischaemia reperfusion injury in normal and fatty livers.

BACKGROUND: Liver ischaemia/reperfusion (I/R) injury, which is an inevitable clinical problem of liver resection, liver transplantation and haemorrhagic shock. Fibroblast growth factor 21 (FGF21) was intimately coupled with multiple metabolic processes and proved to protect against apoptosis and inflammatory response in hepatocytes during hepatic I/R injury. However, the regulatory mechanisms of FGF21 in hepatic I/R injury remains unknown. Therefore, we hypothesize that FGF21 protects hepatic tissues from I/R injury. METHODS: Blood samples were available from haemangiomas patients undergoing hepatectomy and murine liver I/R model and used to further evaluate the serum levels of FGF21 both in humans and mice. We further explored the regulatory mechanisms of FGF21 in murine liver I/R model by using FGF21-knockout mice (FGF21-KO mice) and FGF21-overexpression transgenic mice (FGF21-OE mice) fed a high-fat or ketogenic diet. RESULTS: Our results show that the circulating levels of FGF21 were robustly decreased after liver I/R in both humans and mice. Silencing FGF21 expression with FGF21-KO mice aggravates liver injury at 6 h after 75 min of partial liver ischaemia, while FGF21-OE mice display alleviated hepatic I/R injury and inflammatory response. Compared with chow diet mice, exogenous FGF21 decreases the levels of aminotransferase, histological changes, apoptosis and inflammatory response in hepatic I/R injury treatment mice with a high-fat diet. Meanwhile, ketogenic diet mice are not sensitive to hepatic I/R injury. CONCLUSIONS: The circulating contents of FGF21 are decreased during liver warm I/R injury and exogenous FGF21 exerts hepatoprotective effects on hepatic I/R injury. Thus, FGF21 regulates hepatic I/R injury and may be a key therapeutic target.

Regulation of tumor metastasis and CD8+ T cells infiltration by circRNF216/miR-576-5p/ZC3H12C axis in colorectal cancer.

BACKGROUND: The tumor immune microenvironment (TIME) is an important regulator of tumor progression, growth and metastasis. In addition, tumor metastasis is one of the principal obstacles to the treatment of colorectal cancer (CRC). Circular RNAs (circRNAs) have been recognized as important regulators in the development of malignancies. However, their specific roles and mechanisms in both CRC metastasis and TIME have not been thoroughly investigated. METHODS: High-throughput next-generation sequencing technology and real-time fluorescence quantitative PCR technology were performed to identify differential circRNAs in CRC. Functional assays including transwell assay, wound healing assay, and metastasis models were conducted to assess the effect of circRNF216 on CRC metastasis. In addition, luciferase reporter, western blot, RNA immunoprecipitation (RIP), and fluorescent in situ hybridization (FISH) were performed to explore the underlying mechanism of circRNF216. The level of immune infiltration was assessed by bioinformatics analysis and flow cytometry in CRC model. Furthermore, rescue and mutation experiments were used for verification. RESULTS: circRNF216 was identified as a putative tumor suppressor that is downregulated in CRC tissues and cells. Overexpression of circRNF216 inhibits metastasis in vitro and vivo. Mechanistically, circRNF216 acts as a competitive endogenous RNA (ceRNA) for miR-576-5p, alleviating miR-576-5p repression on its target ZC3H12C, which in turn downregulated N-cadherin. Additionally, circRNF216 could enhance the infiltration level of CD8+ T cells by upregulating ZC3H12C, ultimately inhibiting the development of CRC, which suggests that circRNF216 is a potential biomarker for the treatment of CRC. CONCLUSIONS: Here, we provide novel mechanistic insight revealing how circRNF216 functioned in CRC metastasis and TIME via the circRNF216/miR-576-5p/ZC3H12C pathway. Therefore, circRNF216 holds promise as a potential therapeutic target and novel diagnostic marker for CRC.

Therapeutic targeting of FOS in mutant TERT cancers through removing TERT suppression of apoptosis via regulating survivin and TRAIL-R2.

The telomerase reverse transcriptase (TERT) has long been pursued as a direct therapeutic target in human cancer, which is currently hindered by the lack of effective specific inhibitors of TERT. The FOS/GABPB/(mutant) TERT cascade plays a critical role in the regulation of mutant TERT, in which FOS acts as a transcriptional factor for GABPB to up-regulate the expression of GABPB, which in turn activates mutant but not wild-type TERT promoter, driving TERT-promoted oncogenesis. In the present study, we demonstrated that inhibiting this cascade by targeting FOS using FOS inhibitor T-5224 suppressed mutant TERT cancer cells and tumors by inducing robust cell apoptosis; these did not occur in wild-type TERT cells and tumors. Mechanistically, among 35 apoptotic cascade-related proteins tested, the apoptosis induced in this process specifically involved the transcriptional activation of tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL-R2) and inactivation of survivin, two key players in the apoptotic cascade, which normally initiate and suppress the apoptotic cascade, respectively. These findings with suppression of FOS were reproduced by direct knockdown of TERT and prevented by prior knockdown of TRAIL-R2. Further experiments demonstrated that TERT acted as a direct transcriptional factor of survivin, up-regulating its expression. Thus, this study identifies a therapeutic strategy for TERT promoter mutation-driven cancers by targeting FOS in the FOS/GABPB/(mutant) TERT cascade, circumventing the current challenge in pharmacologically directly targeting TERT itself. This study also uncovers a mechanism through which TERT controls cell apoptosis by transcriptionally regulating two key players in the apoptotic cascade.

The basic chemical substances of total alkaloids of Uncaria rhynchophylla and their anti-neuroinflammatory activities.

To clarify the chemical basis of the total alkaloids of Uncaria rhynchophylla, HPLC-VWD chromatogram of total alkaloids was established. Under its guidance, modern chromatographic and spectroscopic techniques were used to track, isolate and identify the representative principal components. As a result, one new monoterpenoid indole alkaloid, 3S,15S-N4-methoxymethyl-geissoschizine methyl ether (1), together with 20 known alkaloids (2-21), and 5 other known compounds (22-26) were obtained. Meanwhile, sixteen characteristic peaks were identified from the total alkaloids using HPLC analysis. Then, the anti-neuroinflammatory effect of compounds 1-21 was assessed through inhibiting nitric ---oxide (NO) production in lipopolysaccharide (LPS)-induced BV-2 microglial cells. Among them, compounds 1, 3, 7, 8, 11, 12, 19 and 21 showed potent inhibitory activities with IC50 values of 5.87-76.78 µM.

Farmland phytoremediation in bibliometric analysis.

Phytoremediation is an environmentally friendly, economical, and sustainable technique for restoring farmland. It can remove heavy metals and organic pollutants from the soil through the implementation of hyperaccumulator plants. In recent years, it has garnered significant interest from academic and industrial sectors. This article screened 368 research papers from the Web of Science core collection database related to farmland phytoremediation and conducted a bibliometric analysis of the domain based on CiteSpace. The paper intuitively demonstrates the most influential countries, the most productive institutions, the most contributing groups of authors, and the primary sources of farmland phytoremediation research domain. The findings additionally indicate that the research hotspots include: (1) mechanisms and principles of phytoremediation, (2) the improvement of restoration efficiency, (3) the economic, ecological, and sustainable development of phytoremediation. The exploration of plants with potential to accumulate heavy metals and produce large amounts of biomass is the research frontier within the field of farmland phytoremediation. Additionally, this bibliometric analysis can help scholars willing to work in this research field by concisely understanding the overall research field and frontiers. With the continuous improvement of phytoremediation and its combination with other remediation technologies, the future of farmland remediation will have a promising prospect.

Efficacy of Dexamethasone in Reducing Pain and Inflammation and Accelerating Total Hip Arthroplasty Postoperative Recovery: A Randomized Controlled Trial.

PURPOSE: To evaluate the efficacy of dexamethasone in reducing pain and accelerating recovery after total hip arthroplasty (THA). DESIGN: A prospective randomized controlled trial. METHODS: A total of 98 patients who underwent THA received either low-dose (10 mg) dexamethasone (dexa group) or isotonic saline (placebo group). C-reactive protein and interleukin-6 levels were recorded at 24, 48, and 72 hours after surgery. Pain visual analog scale (VAS) score at rest and walking, the incidence of postoperative nausea and vomiting (PONV), nausea VAS score, postoperative identity-consequence fatigue scale rating, antiemetic use, postoperative length of stay (PLOS), and complications were also recorded and compared. FINDINGS: Inflammatory marker (C-reactive protein and interleukin-6) levels at 24, 48, and 72 hours postoperatively in the dexa group were lower than that in the placebo group (P < .05). After 24 hours of rest, the dynamic pain VAS scores in the dexa group were lower than those in the placebo group (P < .05). The incidence of PONV, nausea VAS score, and identity-consequence fatigue scale score in the dexa group were lower than those in the placebo group (P < .05), and the dosages of analgesics and antiemetics were also lower (P < .05). In addition, PLOS in the dexa group was shorter than that in the placebo group (P < .05). No significant difference in perioperative complications between the two groups was observed (P > .05). CONCLUSIONS: Low-dose dexamethasone in the THA perioperative period can effectively reduce inflammatory marker levels, pain, nausea, postoperative fatigue, opioid analgesic use, and shorten PLOS without increasing complications.

Aqueous Coordination-Insertion Copolymerization for Producing High Molecular Weight Polar Polyolefins.

Hydrocarbons, when used as the medium for transition metal catalyzed organic reactions and olefin (co-)polymerization, are ubiquitous. Environmentally friendly water is highly attractive and long-sought, but is greatly challenging as coordination-insertion copolymerization reaction medium of olefin and polar monomers. Unfavorable interactions from both water and polar monomer usually lead to either catalyst deactivation or the formation of low-molecular-weight polymers. Herein, we develop well-behaved neutral phosphinophenolato nickel catalysts, which enable aqueous copolymerization of ethylene and diverse polar monomers to produce significantly high-molecular-weight linear polar polyolefins (219-549 kDa, 0.13-1.29 mol %) in a single-component fashion under mild conditions for the first time. These copolymerization reactions occur better in water than in hydrocarbons such as toluene. The dual characteristics of high molecular weight and the incorporation of a small amount of functional group result in improved surface properties while retain the desirable intrinsic properties of high-density polyethylene (HDPE).

Association of Accelerometer-Measured Sedentary Behavior Patterns With Nonalcoholic Fatty Liver Disease Among Older Adults: The MIND-China Study.

INTRODUCTION: The relationships between sedentary behavior patterns and nonalcoholic fatty liver disease (NAFLD) in older adults are not well investigated. METHODS: This population-based study included 1,899 rural-dwelling adults (aged 60 years or older). We assessed sedentary parameters with ActiGraph and defined NAFLD using ultrasonography. RESULTS: Long total and prolonged sedentary time were associated with increased likelihoods of NAFLD, whereas engaging more breaks per sedentary hour and reallocating sedentary time to light-intensity physical activity were associated with reduced likelihoods of NAFLD (P linear <0.05). DISCUSSION: Shorter sedentary time, engaging more frequent breaks in sedentary behavior, and replacing sedentary time with physical activity are associated with reduced likelihoods of NAFLD in older adults.

Energy use efficiency of soil microorganisms: Driven by carbon recycling and reduction.

Carbon use efficiency (CUE) is being intensively applied to quantify carbon (C) cycling processes from microbial cell to global scales. Energy use efficiency (EUE) is at least as important as the CUE because (i) microorganisms use organic C mainly as an energy source and not as elemental C per se, and (ii) microbial growth and maintenance are limited by energy, but not by C as a structural element. We conceptualize and review the importance of EUE by soil microorganisms and focus on (i) the energy content in organic compounds depending on the nominal oxidation state of carbon (NOSC), (ii) approaches to assess EUE, (iii) similarities and differences between CUE and EUE, and (iv) discuss mechanisms responsible for lower EUE compared to CUE. The energy content per C atom (enthalpy of combustion, the total energy stored in a compound) in organic compounds is very closely (R2 = 0.98) positively related to NOSC and increases by 108 kJ mol-1 C per one NOSC unit. For the first time we assessed the NOSC of microbial biomass in soil (-0.52) and calculated the corresponding energy content of -510 kJ mol-1 C. We linked CUE and EUE considering the NOSC of microbial biomass and element compositions of substrates utilized by microorganisms. The mean microbial EUE (0.32-0.35) is 18% lower than CUE (0.41) using glucose as a substrate. This definitely indicates that microbial growth is limited by energy relative to C. Based on the comparison of a broad range of processes of C and energy utilization for cell growth and maintenance, as well as database of experimental CUE from various compounds, we clearly explained five mechanisms and main factors why EUE is lower than CUE. The two main mechanisms behind lower EUE versus CUE are: (i) microbial recycling: C can be microbially recycled, whereas energy is always utilized only once, and (ii) chemical reduction of organic and inorganic compounds: Energy is used for reduction, which is ongoing without C utilization.

Relevance and mechanism of STAT3/miR-221-3p/Fascin-1 axis in EGFR TKI resistance of triple-negative breast cancer.

The epidermal growth factor receptor 1 (EGFR) plays a crucial role in the progression of various malignant tumors and is considered a potential target for treating triple-negative breast cancer (TNBC). However, the effectiveness of representative tyrosine kinase inhibitors (TKIs) used in EGFR-targeted therapy is limited in TNBC patients. In our study, we observed that the TNBC cell lines MDA-MB-231 and MDA-MB-468 exhibited resistance to Gefitinib. Treatment with Gefitinib caused an upregulation of Fascin-1 (FSCN1) protein expression and a downregulation of miR-221-3p in these cell lines. However, sensitivity to Gefitinib was significantly improved in both cell lines with either inhibition of FSCN1 expression or overexpression of miR-221-3p. Our luciferase reporter assay confirmed that FSCN1 is a target of miR-221-3p. Moreover, Gefitinib treatment resulted in an upregulation of phosphorylated signal transducer and activator of transcription 3 (p-STAT3) in MDA-MB-231 cells. Using Stattic, a small-molecule inhibitor of STAT3, we observed a significant enhancement in the inhibitory effect of Gefitinib on the growth, migration, and invasion of MDA-MB-231 cells. Additionally, Stattic treatment upregulated miR-221-3p expression and downregulated FSCN1 mRNA and protein expression. A strong positive correlation was noted between the expression of STAT3 and FSCN1 in breast cancer tissues. Furthermore, patients with high expression levels of both STAT3 and FSCN1 had a worse prognosis. Our findings suggest that elevated FSCN1 expression is linked to primary resistance to EGFR TKIs in TNBC. Moreover, we propose that STAT3 regulates the expression of miR-221-3p/FSCN1 and therefore modulates resistance to EGFR TKI therapy in TNBC. Combining EGFR TKI therapy with inhibition of FSCN1 or STAT3 may offer a promising new therapeutic option for TNBC.

PPARß/δ activation protects against hepatic ischaemia-reperfusion injury.

BACKGROUND AND AIMS: Hepatic ischaemia/reperfusion injury (HIRI) is a pathophysiological process that occurs during the liver resection and transplantation. Reportedly, peroxisome proliferator-activated receptor ß/δ (PPARß/δ) can ameliorate kidney and myocardial ischaemia/reperfusion injury. However, the effect of PPARß/δ in HIRI remains unclear. METHODS: Mouse hepatic ischaemia/reperfusion (I/R) models were constructed for in vivo study. Primary hepatocytes and Kupffer cells (KCs) isolated from mice and cell anoxia/reoxygenation (A/R) injury model were constructed for in vitro study. Liver injury and inflammation were investigated. Small molecular compounds (GW0742 and GSK0660) and adenoviruses were used to interfere with PPARß/δ. RESULTS: We found that PPARß/δ expression was increased in the I/R and A/R models. Overexpression of PPARß/δ in hepatocytes alleviated A/R-induced cell apoptosis, while knockdown of PPARß/δ in hepatocytes aggravated A/R injury. Activation of PPARß/δ by GW0742 protected against I/R-induced liver damage, inflammation and cell death, whereas inhibition of PPARß/δ by GSK0660 had the opposite effects. Consistent results were obtained in mouse I/R models through the tail vein injection of adenovirus-mediated PPARß/δ overexpression or knockdown vectors. Furthermore, knockdown and overexpression of PPARß/δ in KCs aggravated and ameliorated A/R-induced hepatocyte injury, respectively. Gene ontology and gene set enrichment analysis showed that PPARß/δ deletion was significantly enriched in the NF-κB pathway. PPARß/δ inhibited the expression of p-IKBα and p-P65 and decreased NF-κB activity. CONCLUSIONS: PPARß/δ exerts anti-inflammatory and anti-apoptotic effects on HIRI by inhibiting the NF-κB pathway, and hepatocytes and KCs may play a synergistic role in this phenomenon. Thus, PPARß/δ is a potential therapeutic target for HIRI.

Objectively-measured movement behaviors, systemic low-grade inflammation, and plasma neurofilament light chain in older adults: a population-based study.

BACKGROUND: Evidence has linked self-reported sedentary behavior (SB) and physical activity (PA) with cognitive impairment; however, the underlying mechanisms are poorly understood. We examined the associations of the accelerometer-measured movement behaviors with plasma neurofilament light chain (NfL) among older adults and the role of systemic low-grade inflammation in the associations. RESULTS: This population-based study included 1,029 dementia-free older adults (age ≥ 60 years, range 60-88 years; 59.48% women) who undertook the ActiGraph substudy (March 2018-December 2020) in MIND-China. There were nonlinear relationships of daily SB and PA time with plasma NfL concentration, such that more daily SB time or less time spent in daily light-intensity physical activity (LPA) and moderate-to-vigorous-intensity physical activity (MVPA) was significantly associated with increased plasma NfL only when SB time ≥ 8.00 h/day or LPA time < 5.00 h/day or MVPA time < 2.00 h/day. Furthermore, more daily SB time or less daily LPA and MVPA time was significantly associated with higher serum low-grade inflammation score, a composite measure generated from serum IL-6, IL-8, TNF-α, and ICAM-1 (P < 0.05). Finally, low-grade inflammation score accounted for 14.5% to 17.8% of the associations between movement behaviors and plasma NfL. CONCLUSIONS: More daily SB and less PA time are associated with neurodegeneration and systemic low-grade inflammation in older adults. The association of movement behaviors with neurodegeneration is partially mediated by low-grade inflammation.