Thin-film nanocomposite NF membrane with GO on macroporous hollow fiber ceramic substrate for efficient heavy metals removal.

The ceramic membrane has been widely used in the wastewater treatment based on the chemical resistance and superior separation performance. A robust and defect-free thin-film nanocomposite (TFN) nanofiltration (NF) membrane on the macroporous hollow fiber ceramic (HFC) substrate was novelly developed for heavy metals removal. Before interfacial polymerization (IP), the aqueous solution of graphene oxide (GO) grafted with ethylenediamine (EDA) was deposited on the HFC substrate by vacuum filtration. Then, a thin polyamide (PA) film was fabricated by EDA and 1,3,5-trimesoyl chloride (TMC), followed by heat treatment. The effects of GO content and EDA concentration on the performance of the NF membrane have been systematically investigated. The results showed that when the GO content was 0.015 mg·mL-1 and the EDA concentration was 0.75 wt.%, the as-prepared eGO3/PA-HFC membrane had a rejection rate of 94.12% for MgCl2 and a pure water flux of 18.03 L·m-2·h-1. Additionally, the removal ability of eGO3/PA-HFC membranes for heavy metal ions was satisfactory (93.33%, 92.73%, 90.45% and 88.35% for Zn2+, Cu2+, Ni2+ and Pb2+, respectively). The study explored further that it was efficient and stable for heavy metal ions removal during 30 h in the simulated tap water and mining wastewater, which indicated that the eGO/PA-HFC membrane has great application potential in wastewater treatment.

Laparoscopic resection of hepatic epithelioid hemangioendothelioma: report of eleven rare cases and literature review.

BACKGROUND: Hepatic epithelioid hemangioendothelioma (HEHE) is an extremely rare borderline tumor of vascular endothelial origin. Laparoscopic resection of HEHE has never been reported. METHODS: The clinical data of eleven patients with HEHE (4 women and 7 men) who were diagnosed and treated at the Union Hospital (Wuhan, China), and Wuhan Asia General Hospital (Wuhan, China), between March 2012 and July 2020 were analyzed retrospectively. RESULTS: The mean age of HEHE patients was 42.4 ± 13.9 years (range 22-67 years). All patients underwent laparoscopic surgery alone or in combination with radiofrequency ablation. Most tumors showed aggressive growth or metastasis. By immunohistochemistry, tumor cells were positive for CD31, CD34, ERG, PCK, FLi-1, TFE-3, and Ki-67 (labeling index range, 5-15%). In one of the patients, the tumor was accompanied by partial necrosis with a local appearance of epithelioid angiosarcoma. Postoperative adjuvant treatment included chemotherapy, sorafenib, and Huaier granule. As of July 2020, the median follow-up duration was 36 months (range, 9-60 months), with 2 (18.2%) patients experiencing tumor recurrence. CONCLUSIONS: This is the first report of laparoscopic hepatectomy of HEHE. Curative laparoscopic hepatectomy might be an acceptable treatment for appropriate HEHE patients.

Oxygen reduction reaction performance of Fe-N/C catalysts from ligand-iron coordinative supramolecular precursors.

Simultaneous introduction of both transition metal and other inorganic elements into the carbon matrix has attracted great attention in the fabrication of carbon materials with high electrochemical properties. Herein, rational design of ligand-iron coordinative supramolecular precursors is achieved for the fabrication of Fe-N/C catalysts, which possess high oxygen reduction reaction (ORR) performance. A series of precursors are prepared by a simple coordination reaction between a three armed catechol monomer and iron ions. Particular interest is focused on tuning the doping species, surface area and morphology of the Fe-N/C catalysts through a simple selection of iron resources. We show that an Fe-N/C catalyst derived from Fe2(SO4)3 at a carbonization temperature of 800 °C, has the optimized ORR performance with an onset potential of 0.930 V and half-wave potential of 0.801 V. Detailed investigation indicates that the synergistic effect among doping elements of nitrogen and sulfur and the unique carbon structure determines the performance of the Fe-N/C catalysts. Our findings may be of significance for the fabrication of doped carbon materials using coordinative supramolecular polymers as precursors.

Strategies for risk management in urban-rural conflict: Two case studies of land acquisition in urbanising China.

Urban and rural environments show clear differences in morphology, production mode and culture. With rapid urbanisation, these differences have become a major cause of urban-rural conflict. One of the most significant challenges arises from land acquisition, particularly in China, where cities have experienced substantial growth in the 21st century. Different types of risk are associated with land acquisition conflict in different Chinese cities. In this study, two types of cities are discussed: those with a historically low level of development but recent rapid economic growth, such as Yueqing; and cities that have maintained a relatively high level of development and experienced stable growth, such as Jiaxing. Land acquisition conflict in these two representative cities is then analysed in terms of property rights, access to resources and development. Analysis is performed at the institutional level to provide more accurate insights into the dynamics of conflict. The findings of the study suggest that different risk-management strategies are used in the two kinds of city, and that conflict is more likely to occur in cities with historically weaker development, such as Yueqing. To avoid such conflict, systematic risk-management strategies should be established in these cities.

Transforming growth factor ß-activated kinase 1 negatively regulates interleukin-1α-induced stromal-derived factor-1 expression in vascular smooth muscle cells.

Stromal-derived Factor-1 (SDF-1) derived from vascular smooth muscle cells (VSMCs) contributes to vascular repair and remodeling in various vascular diseases. In this study, the mechanism underlying regulation of SDF-1 expression by interleukin-1α (IL-1α) was investigated in primary rat VSMCs. We found IL-1α promotes SDF-1 expression by up-regulating CCAAT-enhancer-binding protein ß (C/EBPß) in an IκB kinase ß (IKKß) signaling-dependent manner. Moreover, IL-1α-induced expression of C/EBPß and SDF-1 was significantly potentiated by knockdown of transforming growth factor ß-activated kinase 1 (TAK1), an upstream activator of IKKß signaling. In addition, we also demonstrated that TAK1/p38 mitogen-activated protein kinase (p38 MAPK) signaling exerted negative effect on IL-1α-induced expression of C/EBPß and SDF-1 through counteracting ROS-dependent up-regulation of nuclear factor erythroid 2-related factor 2 (NRF2). In conclusion, TAK1 acts as an important regulator of IL-1α-induced SDF-1 expression in VSMCs, and modulating activity of TAK1 may serve as a potential strategy for modulating vascular repair and remodeling.

Synthesis and biological evaluation of novel pyrazoline derivatives as potent anti-inflammatory agents.

Twenty-eight pyrazoline derivatives, which originated from pyranochalcones, have been synthesized and evaluated for their inhibitory potency on the production of inflammatory mediator nitric oxide (NO) in LPS-stimulated RAW 264.7 cells. Among them, three compounds (1c, 11c, and 15c) exhibited potent inhibitory effects on NO production and iNOS activity superior to positive control Indomethacin, with 1c being most efficacious. Furthermore, 1c could suppress the progress of carrageenan-induced hind paw edema at a dosage of 50 mg/kg/day and dose-dependently ameliorate the development of adjuvant-induced arthritis (AIA). Docking study confirmed that 1c was an iNOS inhibitor with good binding into the active site of murine iNOS.

Synthesis and biological evaluation of diarylthiazole derivatives as antimitotic and antivascular agents with potent antitumor activity.

By switching position of the N and S atom in the thiazole ring which were similar to the previously reported agent 5-(4-ethoxyphenyl)-4-(3',4',5'-trimethoxyphenyl)thiazol-2-amine, a series of 4,5-diarylthiazole derivatives were synthesized using Friedel-Crafts reaction based on chemical modification of Combrestatatin A-4 (CA-4). Their antiproliferative activities were evaluated and identified as new microtubule destabilizing agents. Structure-activity relationship study indicated that compound 8a with 3,4,5-trimethoxyphenyl group at the C-4 position and 4-ethoxyphenyl group at the C-5 position of 2-amino substituted thiazole was of the most potent inhibitory activity in this series. 8a was found to exhibit the IC50 values of 8.4-26.4nM in five human cancer cell lines, with comparable inhibition effects to CA-4. Moreover, 8a showed potency as a tubulin polymerization inhibitor, with colchicine site binding ability and comparable extent of inhibition against the growth of P-glycoprotein over-expressing multidrug resistant cell lines. Mechanism studies revealed that 8a could block the progression of cell cycle in the G2/M phase and result in cellular apoptosis in cancer cells. As a new tubulin destabilizing agent, 8a was also found high antivascular activity as it concentration-dependently reduced the cell migration and disrupted capillary like tube formation of HUVEC cells. Furthermore, 8a significantly suppressed the tumor growth in HCT116 and SK-OV-3 xenograft models with tumor growth inhibitory rate of 55.12% and 72.7%, respectively. Our studies highlighted that 8a was a promising microtubule targeting antitumor agent.

Scaffold-based design of xanthine as highly potent inhibitors of DPP-IV for improving glucose homeostasis in DIO mice.

Diabetes mellitus, commonly characterized by hyperglycemia, is a group of metabolic diseases. Some oral anti-diabetic drugs show poor tolerability during chronic treatment, and associate with undesired side effects. Recent advances in the understanding of physiological functions of incretins and their degrading enzyme dipeptidyl peptidase DPP-IV have led to the discovery of DPP-IV inhibitors as a new class of oral anti-diabetic drugs. Several DPP-IV inhibitors have different chemical structures of which the xanthine scaffold has specific advantages. Combining previous work with the research strategy of pharmacophore hybridization, we retained this scaffold and synthesized a new series of amino-alcohol or diamino-modified xanthine compounds. Some xanthines exhibited submicromolar inhibitory activities against DPP-IV. The most potent compound 40 [Formula: see text] exhibits a good in vivo efficacy in reducing glucose excursion at a single dose and a better chronic effect in reducing body weight than metformin in DIO mice. In other words, the combined effect improved the pathological state of DIO mice.

Synthesis and biological evaluation of 4-oxoquinoline-3-carboxamides derivatives as potent anti-fibrosis agents.

Thirty-one 4-oxoquinoline-3-carboxamides derivatives were synthesized and evaluated for their anti-fibrotic activities by the inhibition of TGF-ß1-induced total collagen accumulation and anti-inflammatory activities by the inhibition of LPS-stimulated TNF-α production. Among them, three compounds (10a, 10l and 11g) exhibited potent inhibitory effects on both TGF-ß1-induced total collagen accumulation and LPS-stimulated TNF-α production. Furthermore, oral administrations of 10l at a dose of 20 mg/kg/day for 4 weeks effectively alleviated lung inflammation and injury, and decreased lung collagen accumulation in bleomycin-induced pulmonary fibrosis model. Histopathological evaluation of lung tissue confirmed 10l as a potential, orally active agent for the treatment of pulmonary fibrosis.

Synthesis and biological evaluation of 3-methyl-5-phenylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione derivatives for the treatment of diet-induced obesity.

Triglycerides are the main part of fats and half of the lipids in hepatocytes, and play an important role in metabolism as energy sources and transporters of dietary fat. In this study, 33 derivatives based on 3-methyl-5-phenylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione were synthesized and evaluated for their lipid-lowering activity. Among them, compound 1i was found to exhibit potent triglyceride-lowering potency in 3T3-L1 adipocytes which was comparable to that of the adenosine monophosphate-activated protein kinase (AMPK) agonist Acadesine (AIACR). Furthermore, oral administration of 1i at a dose of 50 mg kg(-1) d(-1) for 5 weeks could reduce the mean body weight and liver weight by 12.02% and 32.00%, respectively, and regulated serum levels of triglycerides in diet-induced obese mice. The results indicate that compound 1i is a potential small-molecule for the treatment of diet-induced obesity and related diseases.

Exploring the role of parthanatos in CNS injury: Molecular insights and therapeutic approaches.

BACKGROUND: Central nervous system (CNS) injury causes severe organ damage due to both damage resulting from the injury and subsequent cell death. However, there are currently no effective treatments for countering the irreversible loss of cell function. Parthanatos is a poly (ADP-ribose) polymerase 1 (PARP-1)-dependent form of programmed cell death that is partly responsible for neural cell death. Consequently, the mechanism by which parthanatos promotes CNS injury has attracted significant scientific interest. AIM OF REVIEW: Our review aims to summarize the potential role of parthanatos in CNS injury and its molecular and pathophysiological mechanisms. Understanding the role of parthanatos and related molecules in CNS injury is crucial for developing effective treatment strategies and identifying important directions for future in-depth research. KEY SCIENTIFIC CONCEPTS OF REVIEW: Parthanatos (from Thanatos, the personification of death according to Greek mythology) is a type of programmed cell death that is initiated by the overactivation of PARP-1. This process triggers a cascade of reactions, including the accumulation of poly(ADP-ribose) (PAR), the nuclear translocation of apoptosis-inducing factor (AIF) after its release from mitochondria, and subsequent massive DNA fragmentation caused by migration inhibitory factor (MIF) forming a complex with AIF. Secondary molecular mechanisms, such as excitotoxicity and oxidative stress-induced overactivation of PARP-1, significantly exacerbate neuronal damage following initial mechanical injury to the CNS. Furthermore, parthanatos is not only associated with neuronal damage but also interacts with various other types of cell death. This review focuses on the latest research concerning the parthanatos cell death pathway, particularly considering its regulatory mechanisms and functions in CNS damage. We highlight the associations between parthanatos and different cell types involved in CNS damage and discuss potential therapeutic agents targeting the parthanatos pathway.

Bioremoval of Co(II) by a novel halotolerant microalgae Dunaliella sp. FACHB-558 from saltwater.

Cobalt pollution is harmful to both the aquatic ecosystem and human health. As the primary producer of aquatic ecosystems in hypersaline environments, unicellular planktonic Dunaliella microalgae is considered to be a low-energy and eco-friendly biosorbent that removes excess cobalt and enhances the vitality of coastal and marine ecosystems. In this study, we found that the halotolerant microalga named Dunaliella sp. FACHB-558 could grow under a salinity condition with 0.5-4.5 M NaCl. A phylogenetic analysis based on the rbcL gene revealed that Dunaliella sp. FACHB-558 is a close relative of Dunaliella primolecta TS-3. At lab-scale culture, Dunaliella sp. FACHB-558 exhibited high tolerance to heavy metal stresses, including cobalt, nickel, and cadmium. Treatment with 60 µM cobalt delayed its stationary phase but ultimately led to a higher population density. Furthermore, Dunaliella sp. FACHB-558 has the ability to adsorb the cobalt ions in the aquatic environment, which was evidenced by the decreased amount of cobalt in the culture medium. In addition, the tolerance of Dunaliella sp. FACHB-558 to cobalt stress was correlated with enhanced nitric oxide content and peroxidase activity. The autophagy inhibitor 3-MA enhanced nitric oxide burst, increased peroxidase activity, and accelerated the bioremoval of cobalt, suggesting that the autophagy pathway played a negative role in response to cobalt stress in Dunaliella sp. FACHB-558. In summary, our study identified a novel microalga possessing high cobalt tolerance and provided a promising natural biosorbent for the research and application of heavy metal bioremediation technology.

Underlying Mechanism of Lysosomal Membrane Permeabilization in CNS Injury: A Literature Review.

Lysosomes play a crucial role in various intracellular pathways as their final destination. Various stressors, whether mild or severe, can induce lysosomal membrane permeabilization (LMP), resulting in the release of lysosomal enzymes into the cytoplasm. LMP not only plays a pivotal role in various cellular events but also significantly contributes to programmed cell death (PCD). Previous research has demonstrated the participation of LMP in central nervous system (CNS) injuries, including traumatic brain injury (TBI), spinal cord injury (SCI), subarachnoid hemorrhage (SAH), and hypoxic-ischemic encephalopathy (HIE). However, the mechanisms underlying LMP in CNS injuries are poorly understood. The occurrence of LMP leads to the activation of inflammatory pathways, increased levels of oxidative stress, and PCD. Herein, we present a comprehensive overview of the latest findings regarding LMP and highlight its functions in cellular events and PCDs (lysosome-dependent cell death, apoptosis, pyroptosis, ferroptosis, and autophagy). In addition, we consolidate the most recent insights into LMP in CNS injury by summarizing and exploring the latest advances. We also review potential therapeutic strategies that aim to preserve LMP or inhibit the release of enzymes from lysosomes to alleviate the consequences of LMP in CNS injury. A better understanding of the role that LMP plays in CNS injury may facilitate the development of strategic treatment options for CNS injury.

Low-intensity focused ultrasound modulation of the paraventricular nucleus to prevent myocardial infarction-induced ventricular arrhythmia.

BACKGROUND: Our previous study showed that light-emitting diode modulation of the hypothalamic paraventricular nucleus (PVN), which is the control center of the sympathetic nervous system, might attenuate neuroinflammation in the PVN and prevent ventricular arrhythmias (VAs) after myocardial infarction (MI). Low-intensity focused ultrasound (LIFU) has deeper penetration than does light-emitting diode, while its effect on the PVN has not been reported. OBJECTIVE: This study aimed to explore the effect of LIFU modulation of the PVN on the inducibility of post-MI VAs. METHODS: Fifty-four Sprague-Dawley rats were randomly divided into acute control (n = 12, 22.22%), acute MI (AMI, n = 12, 22.22%), AMI + LIFU (n = 12, 22.22%), chronic control (n = 6, 11.11%), chronic MI (CMI, n = 6, 11.11%), and CMI + LIFU (n = 6, 11.11%) groups. MI was induced by left anterior artery ligation, and electrocardiographic recording for 0.5 hours after MI and programmed electrophysiological stimulation were used to test the vulnerability of VAs. Peripheral sympathetic neural activity was assessed by measuring left stellate ganglion neural activity. Finally, hearts and brains were extracted for Western blotting and histopathological analysis, respectively. RESULTS: Compared with the AMI group, AMI-induced VAs (P < .05) and left stellate ganglion neural activity (P < .05) were significantly attenuated in the AMI + LIFU group. In addition, LIFU resulted in a significant reduction of microglial activation in the PVN and expression of inflammatory cytokines in the peri-ischemic myocardium. In the CMI + LIFU group, there was no obvious tissue damage in the brain. CONCLUSION: LIFU modulation of the PVN may prevent the incidence of post-MI VAs by attenuating MI-induced sympathetic neural activation and inflammatory response.

Rural Land Transfer and Urban Settlement Intentions of Rural Migrants: Evidence from a Rural Land System Reform in China.

Using data from the China Migrants Dynamic Survey, this paper provides new evidence on the impact of rural land transfer on urban settlement intentions of rural migrants. There was a rural land system reform in rural China that provided increased compensation for rural land expropriation and allowed the transaction of collective construction land for business purposes. We determine an increase in urban settlement intentions of rural migrants following the reform as an exogenous change in rural land transfer of rural migrants. We examine two mechanisms that may explain how the reform increased the settlement intentions of rural migrants, and our empirical evidence suggests that the reform increased social integration and reduced rural place attachment of rural migrants. Furthermore, we determine variations in the effect of the reform across migrants of various ages, social security benefits, and migration distances. Overall, this study extends the implications of the market-oriented rural land reform to sustainable and inclusive urbanization and highlights the role of social integration and rural place attachment in migration decisions.

Allocation of Land Factors in China Looking Forward to 2035: Planning and Market.

Land factors are natural resources with fundamental and strategic significance in the achievement of China's 2035 modernization goals. Dilemmas caused by market-oriented or planning-oriented allocation of land factors urgently call for new theoretical guidance and mode. After conducting a systematic review of the literature, this paper built a new framework from the perspective of production-living-ecological spaces to facilitate a better understanding of China's land factors allocation looking forward to 2035. Inductive and deductive methods were both used to interpret the applications of planning and market in land factors allocation. Our results show that: (1) The allocation of land factors for production space is truth-oriented and needs the guidance of market efficiency. The essential feature of "production" as the driving force in production space requires that the allocation of land factors in production space must "respect rules, give play to the agglomeration effect, and rationally carry out regional economic layout". (2) For the allocation of land factors for living space, it is necessary to pursue a kindness-oriented approach and establish a reasonable housing supply system based on people. Among them, the ordinary commercial housing and improving housing should rely on market forces to achieve multi-subject supply, while affordable housing should be ensured through government intervention in a multi-channel way. (3) For the allocation of land factors in ecological space, aesthetic-oriented planning should follow the rule of territorial differentiation and realize the transformation of ecological function into ecological value through market mechanisms. Top-down planning and bottom-up market represents the logic of overall and individual rationality, respectively. The effective allocation of land factors requires the utilization of both planning and market forces. However, the intersection needs be guided by boundary selection theory. This research indicates that "middle-around" theory could be a possible theoretical solution for future study.

Metformin-containing hydrogel scaffold to augment CAR-T therapy against post-surgical solid tumors.

Physiological barriers and immunosuppressive microenvironments of solid tumors present considerable hurdles to Chimeric antigen receptor T (CAR-T) cell therapy. Herein, we discovered that metformin, a prescribed drug for type 2 diabetes, could up-regulate the oxidative phosphorylation of CAR-T cells, increase their energy metabolism, and further promote their proliferation. Inspired by this finding, we designed a hydrogel scaffold to co-deliver metformin and CAR-T cells by adding CAR-T cells into a lyophilized alginate hydrogel containing metformin. The obtained hydrogel scaffold after being implanted into the tumor resection cavity could act as a cell reservoir to sustainably release both CAR-T cells and metformin. While the released metformin could suppress oxidative and glycolytic metabolism of cancer cells and lead to decreased tumor hypoxia, CAR-T cells would respond to metformin by markedly up-regulating oxidative metabolism and adopting a long-lived, highly activated phenotype, contributing to elevated antitumor responses. As demonstrated in several post-surgical tumor models, the proliferation and tumor-infiltration of CAR-T cells were significantly enhanced and the treatment efficacy of CAR-T cells was augmented, against both local tumors and distant abscopal tumors, while showing reduced systemic immune-related adverse effects. Our work presents a new strategy to achieve effective yet safe CAR-T therapy against solid tumors using a cell-delivery scaffold based on clinically validated drugs and biomaterials.

Nitrite soaking pretreatment induced initial denitrifying nitrite accumulation.

Partial denitrification (PD) could be another method for obtaining nitrite. However, PD startup takes a long time limiting its investigation and application. This study proposed nitrite soaking as a pretreatment method for starting PD. Results showed that denitrifying nitrite accumulation (4.20 mg/L) emerged after previously soaking by 10 mg/L nitrite for 9 h. When the duration was 6 h, comparing different soaked nitrite concentrations, the highest denitrifying nitrite accumulation amount (4.92 mg/L) was obtained in the 20 mg/L group. Nevertheless, high pH of 9 and frequent feeding could further advantage denitrifying nitrite accumulation. Pretreatment as a disturbance would impel the microbial community to change from complete denitrification towards PD.

Glycosylated, Lipid-Binding, CDR-Like Domains of SARS-CoV-2 ORF8 Indicate Unique Sites of Immune Regulation.

The outbreak of the novel coronavirus SARS-CoV-2 has posed a significant threat to human health and the global economy since the end of 2019. Unfortunately, due to the virus's rapid evolution, preventingand controlling the epidemic remains challenging. The ORF8 protein is a unique accessory protein in SARS-CoV-2 that plays a crucial role in immune regulation, but its molecular details are still largely unknown. In this study, we successfully expressed SARS-CoV-2 ORF8 in mammalian cells and determined its structure using X-ray crystallography at a resolution of 2.3 Å. Our findings reveal several novel features of ORF8. We found that four pairs of disulfide bonds and glycosylation at residue N78 are essential for stabilizing ORF8's protein structure. Additionally, we identified a lipid-binding pocket and three functional loops that tend to form CDR-like domains that may interact with immune-related proteins to regulate the host immune system. On cellular experiments also demonstrated that glycosylation at N78 regulats of ORF8's ability to bind to monocytes cells. These novel features of ORF8 provide structural insights to into its immune-related function and may serve as new targets for developing ORF8-mediated immune regulation inhibitors. IMPORTANCE COVID-19, caused by the novel coronavirus SARS-CoV-2 virus, has triggered a global outbreak. The virus's continuous mutation increases its infectivity and may be directly related to the immune escape response of viral proteins. In this study, we used X-ray crystallography to determine the structure of SARS-CoV-2 ORF8 protein, a unique accessory protein expressed in mammalian cells, at a resolution of 2.3 Å. Our novel structure reveals important structure details that shed light on ORF8's involvement in immune regulation, including conservation disulfide bonds, a glycosylation site at N78, a lipid-binding pocket, and three functional loops that tend to form CDR-like domains that may interact with immune-related proteins to modulate the host immune system. We also conducted preliminary validation experiments on immune cells. These new insights into ORF8's structure and function provide potential targets for developing inhibitors to block the ORF8-mediated immune regulation between viral protein and host, ultimately contributing to the development of novel therapeutics for COVID-19.

Proteus mirabilis Vesicles Induce Mitochondrial Apoptosis by Regulating miR96-5p/Abca1 to Inhibit Osteoclastogenesis and Bone Loss.

Bone loss due to an increased osteoclast activity is common in osteoporosis and rheumatoid arthritis. For the first time, we observed an inhibition of osteoclast formation and bone resorption by outer-membrane vesicles (OMVs) from a Gram-negative, pathogenic bacterium, Proteus mirabilis (P.M). Gene ontogeny and KEGG enrichment analyses of miRNA and mRNA sequencing data demonstrated a significant effect of P.M OMVs on mitochondrial functions and apoptotic pathways. OMVs induced mitochondrial dysfunction through an increased level of intracellular ROS, collapse of mitochondrial membrane potential (ΔΨm), and modulation of Bax, Bcl-2, caspase-3, and cytochrome c expression. In addition, P.M OMVs strongly inhibited miR-96-5p expression, which caused an upregulation of ATP binding cassette subfamily A member 1 (Abca1) in osteoclasts leading to an increased level of mitochondria-dependent apoptosis. Moreover, treatment with P.M but not Escherichia coli OMVs attenuated bone loss in experimental osteoporosis and collagen-induced arthritis. Collectively, we demonstrated osteoprotective functions of OMVs from Proteus mirabilis, which downregulated miR-96-5p causing an increased Abca1 expression and mitochondria-dependent apoptosis.