LncRNA OIP5-AS1 promotes mitophagy to alleviate osteoarthritis by up-regulating PPAR-γ to activate AMPK/Akt/mTOR pathway.

BACKGROUND: Osteoarthritis (OA) is the most common chronic joint degenerative disease. Mitophagy is closely related to OA pathogenesis. Herein, we investigated the role of lncRNA OIP5-AS1 in regulating mitophagy during OA. METHODS: RT-qPCR and Western blotting were utilized to analyze gene and protein levels. RIP and RNA pull down verified the relationship between OIP5-AS1, FUS and PPAR-γ. CCK-8 assay detected cells viability. ELISA evaluated the secretion of inflammatory cytokines. Flow cytometry measured the contents of ROS and Ca2+. Immunofluorescence staining analyzed TOMM20 and LC3B levels. JC-1 staining was adopted to measure mitochondrial membrane potential. The changes of mitophagy were analyzed by TEM. RESULTS: LPS treatment contributed to the decrease of chondrocytes viability, calcium level and inhibited mitochondrial membrane potential, while elevated the secretion of inflammatory factors, ROS accumulation and TOMM20 expression. Additionally, LPS decreased the ratio of LC3II/I, Parkin and PINK1 protein levels, and increased p62 and TOMM20 protein levels. Furthermore, overexpression of OIP5-AS1 inhibited LPS-induced chondrocytes injury and activated mitophagy. OIP5-AS1 upregulated PPAR-γ mRNA level to regulate AMPK/Akt/mTOR signaling by interacting with FUS. In addition, PPAR-γ overexpression alleviated LPS induced chondrocytes injury by activating AMPK/Akt/mTOR signaling. Knockdown of PPAR-γ reversed the promotion of OIP5-AS1 upregulation on mitophagy. CONCLUSION: OIP5-AS1 promotes PPAR-γ expression to activate the AMPK/Akt/mTOR signaling, thereby enhancing mitophagy and alleviating OA progression. It is suggested that OIP5-AS1 may function as a protector in OA development.

Protective effects of pulsed electromagnetic field therapy attenuates autophagy and apoptosis in osteoporotic osteoarthritis model rats by activating PPARγ.

Osteoporotic osteoarthritis (OPOA) is a specific phenotype of OA with high incidence and severe cartilage damage. This study aimed to explore the protective efficacy of PEMF on the progression of OPOA and observed the effects of PEMF on PPARγ, autophagy- and apoptosis-related proteins in OPOA rats. Rats were randomly divided into three groups: control group, OPOA group, and PEMF group (n = 6). One week after surgery, the rats in PEMF group were subjected to PEMF (3.82 mT, 8 Hz, 40 min/day and 5 day/week) for 12 weeks. Results showed that PEMF retarded cartilage degeneration and bone loss, as evidenced by pathological staining image, decreased MMP-13 expression and increased bone mineral density. PEMF inhibited the serum levels of inflammatory cytokines, and the expressions of caspase-3 and caspase-8, while upregulated the expression of PPARγ. Moreover, PEMF significantly improved the autophagy disorders, represented by decrease expressions of Beclin-1, P62, and LC3B. The research demonstrates that PEMF can effectively prevent cartilage and subchondral bone destruction in OPOA rats. The potential mechanism may be related to upregulation of PPARγ, inhibition of chondrocyte apoptosis and inflammation, and improvement of autophagy disorder. PEMF therapy thus shows promising application prospects in the treatment of postmenopausal OA.

Osteoporotic osteoarthritis (OPOA) is a very common combination disease, that characterized by chronic pain, swollen joints and susceptibility to fractures. It is particularly common in postmenopausal women. At present, drug therapy is the main treatment method, but the adverse reactions are serious and can not stop the progression of the disease. PEMF is a safe physical therapy that has been shown to increase bone density, reduce pain, and improve joints mobility. In this study, we aimed to explore the protective effect and potential mechanism of PEMF on OPOA. We found that PEMF significantly inhibited the inflammatory response, ameliorated the damaged cartilage and subchondral bone in OPOA rats, that maybe related to the regulation of chondrocyte autophagy and apoptosis. This study provided a new vision for PEMF' treatment on OPOA and has positive significance for the clinical promotion of PEMF.

Bone marrow mesenchymal stem cell-derived exosomes miR-202-5p inhibited pyroptosis to alleviate lung ischemic-reperfusion injury by targeting CMPK2.

Bone mesenchymal stem cell-derived exosome (BMSC-exosome) is a potential candidate for lung ischemia-reperfusion injury (LIRI) treatment. This study aims to investigate the anti-pyroptosis effect of BMSC-exosomes in LIRI. The LIRI cell model was established by hypoxia/reoxygenation (H/R) treatment. Interleukin (IL)-1ß and IL-18 levels were examined by enzyme-linked immunosorbent assay. Cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay. Lactate dehydrogenase (LDH) release was examined using a LDH assay kit. The interaction between microRNA (miR)-202-5p and cytidine monophosphate kinase 2 (CMPK2) was analyzed using dual-luciferase reporter assay and RNA immunoprecipitation. BMSC-exosomes promoted cell viability and suppressed pyroptosis in H/R-treated mouse lung epithelial. miR-202-5p was enriched in BMSC-exosomes, and exosomal miR-202-5p inhibition upregulated pyroptosis-associated proteins, including cleaved N-terminal Gasdermin D, nucleotide-binding domain-like receptor family member pyrin domain-containing protein 3, and Caspase1. Meanwhile, miR-202-5p suppressed CMPK2 expression by directly targeting CMPK2. Expectedly, CMPK2 knockdown reversed the promoting effect of exosomal miR-202-5p inhibition on pyroptosis in LIRI. Therefore, BMSC-derived exosome miR-202-5p repressed pyroptosis to inhibit LIRI progression by targeting CMPK2.

Comparative Advantage of Agricultural Trade in Countries along the Belt and Road and China and Its Dynamic Evolution Characteristics.

Trade is an important means to achieve the Sustainable Development Goals (SDGs) Target 2.1 "Zero Hunger", and comparative advantage can be used to explain the causes and performance of trade. This study measures the static distribution of agricultural trade comparative advantage in countries along the Belt and Road (B&R) and China by utilizing the Balassa revealed comparative advantage (RCA) index, and further calculates its dynamic change by utilizing the revealed symmetric comparative advantage (RSCA) index and the ordinary least squares correlation analysis. The results show that: (1) in the face of multiple unfavorable factors, the initial comparative advantage of most agricultural products at Harmonized System (HS) 2-digit level in countries along the B&R and China deteriorated, simultaneously, but the initial comparative disadvantage of most and some agricultural products at HS 2-digit level in countries along the B&R and China improved, respectively; (2) the present agricultural trade comparative advantage in most countries along the B&R was higher than China and had a larger extent of change, but the current product structure of their bilateral agricultural trade was in line with each other's comparative advantage, indirectly proving the validity of the Heckscher-Ohlin theorem. Our research findings suggest that the agricultural trade comparative advantage in countries along the B&R and China need to be further utilized to improve agricultural trade performance and better play its important role in ensuring global, regional, and national food security.

CTRP15 promotes macrophage cholesterol efflux and attenuates atherosclerosis by increasing the expression of ABCA1

C1q tumor necrosis factor–related protein 15 (CTRP15), a newly identified myokine, is closely implicated in cardiovascular disease. However, the role of CTRP15 in atherosclerosis is still unclear. This study aims to determine the role of CTRP15 in atherosclerosis and explore the underlying mechanisms. Our findings revealed that lentivirus-mediated CTRP15 overexpression significantly decreased atherosclerotic plaque lesions and increased reverse cholesterol transport (RCT) efficiency and circulating HDL-C levels in apolipoprotein E-deficient (apoE−/−) mice. Consistently, in vitro, overexpression of CTRP15 also inhibited intracellular lipid accumulation and promoted cholesterol efflux from macrophages. Mechanistically, CTRP15 decreased the expression of miR-101-3p by upregulating T-cadherin, thereby facilitating ABCA1 expression and cholesterol efflux. In summary, these data indicate that CTRP15 inhibits the development of atherosclerosis by enhancing RCT efficiency and increasing plasma HDL-C levels via the T-cadherin/miR-101-3p/ABCA1 pathway. Targeting CTRP15 may serve as a novel and promising therapeutic strategy for atherosclerotic cardiovascular diseases. (AU)

Effect and Mechanism of Endothelin Receptor A Inhibitor BQ-123 Combined with Electroacupuncture on Tibia Cancer Pain in Rats.

Objective: To research the impact and mechanism of endothelin receptor A inhibitor BQ-123 combined with electroacupuncture on tibia cancer pain in rats. Methods: Sprague-Dawley (SD) rats were randomly divided into sham group (SHAM group) and bone cancer pain model group (BCP group). The behavior of SD rats was measured. The histology of the right tibia was observed by hematoxylin-eosin (HE) staining. The remaining rats were randomly divided into model, BQ-123, electroacupuncture, and BQ-123+ electroacupuncture group. Behavioral tests were performed, and mechanical pain threshold (MWT) and thermal pain threshold (TWL) were measured. The expressions of α-smooth muscle actin (αSMA), ETAR (endothelin A receptor), ETB (End of Transmission Block), P-Phosphatidylinositol 3-kinase (PI3K), and P-Protein kinase B (Akt) were detected by real-time fluorescence quantitative PCR and western blot. Results: In the BCP group, bone structure was severely damaged, local tissue swelling was obvious, bone trabecula was missing, and bone cortex was discontinuous. The optical density of Glial fibrillary acidic protein (GFAP) and CD11b immunoreactive signal in BCP group was significantly increased, and most of the ETAR of endothelin receptor was comapped with NeuN, and a small part of GFAP was comapped with CD11b, but no comapped with CD11b. The AS score of BQ-123+ electroacupuncture group was significantly lower than that of BQ-123 group and electroacupuncture group (P < 0.05), whereas the MWT and TWL values were significantly higher than that of the BQ-123 group and electroacupuncture group (P < 0.05). The mRNA expression of α-SMA and ETAR in BQ-123+ electroacupuncture group was lower than that in BQ-123 and electroacupuncture group, and the protein expression of P-PI3K and P-Akt in BQ-123+ electroacupuncture group was lower as well. Conclusion: BQ-123 may inhibit the activation of PI3K/Akt signal path combined with electroacupuncture to alleviate the effects of tibia cancer pain in rats.

CTRP15 promotes macrophage cholesterol efflux and attenuates atherosclerosis by increasing the expression of ABCA1.

C1q tumor necrosis factor-related protein 15 (CTRP15), a newly identified myokine, is closely implicated in cardiovascular disease. However, the role of CTRP15 in atherosclerosis is still unclear. This study aims to determine the role of CTRP15 in atherosclerosis and explore the underlying mechanisms. Our findings revealed that lentivirus-mediated CTRP15 overexpression significantly decreased atherosclerotic plaque lesions and increased reverse cholesterol transport (RCT) efficiency and circulating HDL-C levels in apolipoprotein E-deficient (apoE-/-) mice. Consistently, in vitro, overexpression of CTRP15 also inhibited intracellular lipid accumulation and promoted cholesterol efflux from macrophages. Mechanistically, CTRP15 decreased the expression of miR-101-3p by upregulating T-cadherin, thereby facilitating ABCA1 expression and cholesterol efflux. In summary, these data indicate that CTRP15 inhibits the development of atherosclerosis by enhancing RCT efficiency and increasing plasma HDL-C levels via the T-cadherin/miR-101-3p/ABCA1 pathway. Targeting CTRP15 may serve as a novel and promising therapeutic strategy for atherosclerotic cardiovascular diseases.

Pulsed electromagnetic field alleviates synovitis and inhibits the NLRP3/Caspase-1/GSDMD signaling pathway in osteoarthritis rats.

Low-grade inflammation is a key mediator of the pathogenesis of Osteoarthritis (OA). Pulsed electromagnetic field (PEMF) can improve the symptoms of OA and potentially acts as an anti-inflammatory. The aim of this study was to investigate the effect of the PEMF on OA and its relationship with the NLRP3/Caspase-1/GSDMD signaling pathway.18 Three-month-old Sprague-Dawley (SD) rats were randomly divided into three groups (n = 6 per group): 1) OA group, 2) OA+PEMF group (OA with PEMF exposure), 3) Control group (sham operation with placebo PEMF). Rats in the OA and OA+PEMF groups were subjected to bilateral anterior cruciate ligament transection and ovariectomy. PEMF scheme: Pulse waveform, 3.82 mT, 8 Hz, 40 min/day, 5 days a week, for 12 weeks. The expression levels of NLRP3, Caspase-1, GSDMD, IL-1ß, and MMP-13 were detected by qRT-PCR and Western blot. The pathological structures of OA were monitored with Safranin O/fast green staining and hematoxylin eosin staining. Our results showed that PEMF alleviated the degree of inflammation and degeneration of cartilage in rats with OA, based on the histopathological changes and decline of the expression of IL-1ß and MMP-13. Moreover, the over-expression of NLRP3, Caspase-1, and GSDMD in the cartilage of the OA rats decreased after PEMF treatment. These results suggested that PEMF could be a highly promising noninvasive strategy to slow down the progression of OA and inhibition of the NLRP3/Caspase-1/GSDMD signaling pathway might be involved in the beneficial effect of PEMF.

Impact of Trade Openness on Food Security: Evidence from Panel Data for Central Asian Countries.

The problem of food insecurity has become increasingly critical across the world since 2015, which threatens the lives and livelihoods of people around the world and has historically been a challenge confined primarily to developing countries, to which the countries of Central Asia, as typical transition countries, cannot be immune either. Under this context, many countries including Central Asian countries have recognized the importance of trade openness to ensure adequate levels of food security and are increasingly reliant on international trade for food security. Using the 2001-2018 panel data of Central Asian countries, based on food security's four pillars (including availability, access, stability, and utilization), this study empirically estimates the impact of trade openness and other factors on food security and traces a U-shaped (or inverted U-shaped) relationship between trade openness and food security by adopting a panel data fixed effect model as the baseline model, and then conducts the robustness test by using the least-squares (LS) procedure for the pooled data and a dynamic panel data (DPD) analysis with the generalized method of moments (GMM) approach, simultaneously. The results show that: (1) a U-shaped relationship between trade openness and the four pillars of food security was found, which means that beyond a certain threshold of trade openness, food security status tends to improve in Central Asian countries; (2) gross domestic product (GDP) per capita, GDP growth, and agricultural productivity have contributed to the improvement of food security. Employment in agriculture, arable land, freshwater withdrawals in agriculture, population growth, natural disasters, and inflation rate have negative impacts on food security; and (3) this study confirms that trade policy reforms can finally be conducive to improving food security in Central Asian countries. However, considering the effects of other factors, potential negative effects of trade openness, and vulnerability of global food trade network, ensuring reasonable levels of food self-sufficiency is still very important for Central Asian countries to achieve food security. Our research findings can provide scientific support for sustainable food system strategies in Central Asian countries.

LncRNA NEAT1 promotes apoptosis and inflammation in LPS-induced sepsis models by targeting miR-590-3p.

Sepsis is a complication of infection caused by disease or trauma. Increasing evidence have shown that long noncoding RNAs (lncRNAs) are involved in the regulation of sepsis. However, the mechanism of lncRNA nuclear enriched abundant transcript 1 (NEAT1) in the regulation of sepsis progression remains to be elucidated. Lipopolysaccharide (LPS) was used to induce a sepsis cell model. The expression levels of NEAT1 and microRNA (miR)-590-3p were determined by reverse transcription-quantitative PCR. Cell viability and apoptosis were detected using Cell Counting Kit-8 (CCK-8) assay and flow cytometry, respectively. Western blot analysis was performed to evaluate the levels of apoptosis- and NF-κB signaling pathway-related proteins. The concentration of inflammatory cytokines was determined using ELISA. In addition, dual-luciferase reporter assay, RNA immunoprecipitation and biotin-labeled RNA pull-down assay were performed to verify the interaction between NEAT1 and miR-590-3p. The results showed that NEAT1 was highly expressed in patients with sepsis and LPS-induced H9c2 cells. Knockdown of NEAT1 decreased LPS-induced cell apoptosis and inflammation response in H9c2 cells. Meanwhile, miR-590-3p showed decreased expression in sepsis, and its overexpression could relieve LPS-induced H9c2 cell damage. Further experiments revealed that NEAT1 could sponge miR-590-3p. Knockdown of miR-590-3p reversed the inhibitory effect of NEAT1 knockdown on LPS-induced H9c2 cell damage. Additionally, the NEAT1/miR-590-3p axis could regulate the activity of the NF-κB signaling pathway. To conclude, lncRNA NEAT1 accelerated apoptosis and inflammation in LPS-stimulated H9c2 cells via sponging miR-590-3p. These findings may provide a new strategy for the treatment of sepsis.