Stress response and tolerance mechanisms of NaHCO3 exposure based on biochemical assays and multi-omics approach in the liver of crucian carp (Carassius auratus).

The development and utilization of saline-alkaline water, an important backup resource, has received widespread attention. However, the underuse of saline-alkaline water, threatened by the single species of saline-alkaline aquaculture, seriously affects the development of the fishery economy. In this work, a 30-day NaHCO3 stress experimental study combined with analyses of untargeted metabolomics, transcriptome, and biochemical approaches was conducted on crucian carp to provide a better understanding of the saline-alkaline stress response mechanism in freshwater fish. This work revealed the relationships among the biochemical parameters, endogenous differentially expressed metabolites (DEMs), and differentially expressed genes (DEGs) in the crucian carp livers. The biochemical analysis showed that NaHCO3 exposure changed the levels of several physiological parameters associated with the liver, including antioxidant enzymes (SOD, CAT, GSH-Px), MDA, AKP, and CPS. According to the metabolomics study, 90 DEMs are involved in various metabolic pathways such as ketone synthesis and degradation metabolism, glycerophospholipid metabolism, arachidonic acid metabolism, and linoleic acid metabolism. In addition, transcriptomics data analysis showed that a total of 301 DEGs were screened between the control group and the high NaHCO3 concentration group, of which 129 up-regulated genes and 172 down-regulated genes. Overall, NaHCO3 exposure could cause lipid metabolism disorders and induce energy metabolism imbalance in the crucian carp liver. Simultaneously, crucian carp might regulate its saline-alkaline resistance mechanism by enhancing the synthesis of glycerophospholipid metabolism, ketone bodies, and degradation metabolism, at the same time increasing the vitality of antioxidant enzymes (SOD, CAT, GSH-Px) and nonspecific immune enzyme (AKP). Herein, all results will provide new insights into the molecular mechanisms underlying the stress responses and tolerance to saline-alkaline exposure in crucian carp.

Aescin can alleviate NAFLD through Keap1-Nrf2 by activating antioxidant and autophagy.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a common metabolic liver disease worldwide. It has been proven that aescin (Aes), a bioactive compound derived from the ripe dried fruit of Aesculus chinensis Bunge, has a number of physiologically active properties like anti-inflammatory and anti-edema, however it has not been investigated as a potential solution for NAFLD. PURPOSE: This study's major goal was to determine whether Aes can treat NAFLD and the mechanism underlying its therapeutic benefits. METHODS: We constructed HepG2 cell models in vitro that were affected by oleic and palmitic acids, as well as in vivo models for acute lipid metabolism disorder caused by tyloxapol and chronic NAFLD caused by high-fat diet. RESULTS: We discovered that Aes could promote autophagy, activate the Nrf2 pathway, and ameliorate lipid accumulation and oxidative stress both in vitro and in vivo. Nevertheless, in Autophagy-related proteins 5 (Atg5) and Nrf2 knockout mice, Aes lost its curative impact on NAFLD. Computer simulations show that Aes might interact with Keap1, which might allow Aes to increase Nrf2 transfer into the nucleus and perform its function. Importantly, Aes's stimulation of autophagy in the liver was hampered in Nrf2 knockout mice. This suggested that the impact of Aes in inducing autophagy may be connected to the Nrf2 pathway. CONCLUSION: We first discovered Aes's regulating effects on liver autophagy and oxidative stress in NAFLD. And we found Aes may combine the Keap1 and regulate autophagy in the liver by affecting Nrf2 activation to exert its protective effect.

Effects of Saline-Alkaline Stress on Metabolome, Biochemical Parameters, and Histopathology in the Kidney of Crucian Carp (Carassius auratus).

The salinization of the water environment caused by human activities and global warming has increased which has brought great survival challenges to aquatic animals. Crucian carp (Carassius auratus) is an essential freshwater economic fish with superior adaptability to saline-alkali water. However, the physiological regulation mechanism of crucian carp adapting to saline-alkali stress remains still unclear. In this study, crucian carp were exposed to freshwater or 20, 40, and 60 mmol/L NaHCO3 water environments for 30 days, the effects of saline-alkali stress on the kidney were evaluated by histopathology, biochemical assays and metabolomics analysis from renal function, antioxidant capacity and metabolites level. Our results showed different degrees of kidney damage at different exposure concentrations, which were characterized by glomerular atrophy and swelling, renal tubular degranulation, obstruction and degeneration, renal interstitial edema, renal cell proliferation and necrosis. Saline-alkali stress could change the levels of several physiological parameters with renal function and antioxidant capacity, including creatinine (CREA), urea nitrogen (BUN), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) and malondialdehyde (MDA). In addition, metabolomics analysis showed that differential metabolites (DMs) were involved in various metabolic pathways, including phenylalanine, tyrosine, and tryptophan biosynthesis, aminoacyl-tRNA biosynthesis, purine metabolism, glycerophospholipid metabolism, sphingolipid metabolism, glycolysis/gluconeogenesis and the TCA cycle. In general, our study revealed that saline-alkaline stress could cause significant changes in renal function and metabolic profiles, and induce severe damage in the crucian carp kidney through destroying the anti-oxidant system and energy homeostasis, inhibiting protein and amino acid catabolism, as well as disordering purine metabolism and lipid metabolism. This study could contribute to a deeper understanding the adverse effects of saline-alkali stress on crucian carp kidney and the regulatory mechanism in the crucian carp of saline-alkali adaptation at the metabolic level.

TIM-4 orchestrates mitochondrial homeostasis to promote lung cancer progression via ANXA2/PI3K/AKT/OPA1 axis.

Mitochondrial function and homeostasis are critical to the proliferation of lung cancer cells. T-cell immunoglobulin and mucin domain-containing molecule 4 (TIM-4) promotes the development and progression of lung cancer. However, the role of TIM-4 in mitochondria homeostasis in tumor cells remains completely unknown. In this study, we found that TIM-4 promoted growth and proliferation of lung cancer cells by the oxidative phosphorylation (OXPHOS) pathway. Consistently, inhibition of OXPHOS reversed TIM-4-induced proliferation of lung cancer cells. Notably, TIM-4 promoted mitochondrial fusion via enhancing L-OPA1 protein expression. Mechanistically, TIM-4 regulated protein of L-OPA1 through the PI3K/AKT pathway, and TIM-4 interacted with ANXA2 to promote the activation of PI3K/AKT signaling. Collectively, TIM-4 promotes oxidative phosphorylation of lung cancer cells to accelerate tumor progress via ANXA2/PI3K/AKT/OPA1 axis, which sheds significant new lights on the potential role of TIM-4 in regulating tumor cell metabolism.

Qimai Feiluoping decoction inhibits mitochondrial complex I-mediated oxidative stress to ameliorate bleomycin-induced pulmonary fibrosis.

BACKGROUND: Qimai Feiluoping decoction (QM), a Traditional Chinese Medicine formula, has been included in rehabilitation program for functional disorders of discharged COVID-19 patients. QM has been proved to effectively improve the clinical symptoms and imaging signs of PF in COVID-19 convalescent patients. PURPOSE: This study to explore the pharmacological effect of QM against PF from the perspectives of imaging, pathological staining, and molecular mechanisms, and identify possible active components. METHODS: Micro-CT imaging and immunohistochemical staining were investigated to verify the therapeutic effect of QM in the bleomycin (BLM)-induced PF mouse model. The 4D-label-free proteomics analysis of lung tissues was then conducted to explore the novel mechanisms of QM against PF, which were further validated by a series of experiments. The possible components of QM in plasma and lung tissues were identified with UHPLC/IM-QTOF-MS analysis. RESULTS: The results from micro-CT imaging and pathological staining revealed that QM treatment can inhibit BLM-induced lung injury, extracellular matrix accumulation and TGF-ß expression in the mouse model with PF. The 4D-label-free proteomics analysis demonstrated that the partial subunit proteins of mitochondrial complex I and complex II might be potential targets of QM against PF. Furthermore, QM treatment can inhibit BLM-induced mitochondrial ROS content to promote ATP production and decrease oxidative stress injury in the mouse and cell models of PF, which was mediated by the inhibition of mitochondrial complex I. Finally, a total of 13 protype compounds and 15 metabolites from QM in plasma and lung tissues were identified by UHPLC/IM-QTOF-MS, and liquiritin and isoliquiritigenin from Glycyrrhizae radix et rhizoma could be possible active compounds against PF. CONCLUSION: It concludes that QM treatment could treat PF by inhibiting mitochondrial complex I-mediated mitochondrial oxidated stress injury, which could offer new insights into the pharmacological mechanisms of QM in the clinical application of PF patients.

Kirenol inhibits inflammation challenged by lipopolysaccharide through the AMPK-mTOR-ULK1 autophagy pathway.

Kirenol is a bioactive substance isolated from Herba Siegesbeckiae. Although the anti-inflammatory activity of kirenol has been well documented, its role in autophagy remains unknown. The present study aimed to investigate the protective role of kirenol on inflammation challenged by lipopolysaccharide (LPS) in acute lung injury (ALI) cell and mouse models and unravel the underlying mechanisms, with a particular focus on autophagy. For this purpose, an ALI cell and mouse models were established, and the effects of kirenol on the expression of molecules related to inflammation and autophagy were examined. The present results revealed that kirenol could significantly inhibit inflammatory cytokines secretion in cells and in the mice injured by LPS; this effect may be attributed to enhanced autophagy as evidenced by the up-regulation of LC3-II and the down-regulation of p62 both in vitro and in vivo. Phosphorylated AMPK and ULK1 increased, while phosphorylated mTOR decreased in the kirenol-treated ALI cell model. Moreover, inhibition of autophagy using AMPK inhibitor or 3-MA or chloroquine (CQ) reversed the anti-inflammatory and autophagy-enhancement effects of kirenol exposure in vitro, indicating that kirenol could enhance autophagy by activating the AMPK-mTOR-ULK1 pathway. The results of RNA sequencing suggested that kirenol was strongly related to the biological functions of acute inflammatory response and the AMPK signaling pathway. Further in vivo ALI mouse model studies demonstrated the protective role of kirenol against lung inflammation, such as improved histopathology, decreased lung edema, and leukocyte infiltration were abolished by 3-MA. These findings implicate that kirenol can inhibit LPS-induced inflammation via the AMPK-mTOR-ULK1 autophagy pathway.

Recent advances in ginsenosides against respiratory diseases: Therapeutic targets and potential mechanisms.

BACKGROUND: Respiratory diseases mainly include asthma, influenza, pneumonia, chronic obstructive pulmonary disease, pulmonary hypertension, lung fibrosis, and lung cancer. Given their high prevalence and poor prognosis, the prevention and treatment of respiratory diseases are increasingly essential. In particular, the development for the novel strategies of drug treatment has been a hot topic in the research field. Ginsenosides are the major component of Panax ginseng C. A. Meyer (ginseng), a food homology and well-known medicinal herb. In this review, we summarize the current therapeutic effects and molecular mechanisms of ginsenosides in respiratory diseases. METHODS: The reviewed studies were retrieved via a thorough analysis of numerous articles using electronic search tools including Sci-Finder, ScienceDirect, PubMed, and Web of Science. The following keywords were used for the online search: ginsenosides, asthma, influenza, pneumonia, chronic obstructive pulmonary disease (COPD), pulmonary hypertension (PH), lung fibrosis, lung cancer, and clinical trials. We summarized the findings and the conclusions from 176 manuscripts on ginsenosides, including research articles and reviews. RESULTS: Ginsenosides Rb1, Rg1, Rg3, Rh2, and CK, which are the most commonly reported ginsenosides for treating of respiratory diseases, and other ginsenosides such as Rh1, Rk1, Rg5, Rd and Re, all primarily reduce pneumonia, fibrosis, and inhibit tumor progression by targeting NF-κB, TGF-ß/Smad, PI3K/AKT/mTOR, and JNK pathways, thereby ameliorating respiratory diseases. CONCLUSION: This review provides novel ideas and important aspects for the future research of ginsenosides for treating respiratory diseases.

Serum metabolomics identified metabolite biomarkers and distinguished maturity-onset diabetes of the young from type 1 diabetes in the Chinese population.

BACKGROUND: Maturity-onset diabetes of the young (MODY) patients have unique clinical manifestations and need individualized treatments. We identified novel serum metabolic biomarkers to distinguish MODY and explore the possible mechanism of the clinical manifestation and complications of MODY. METHODS: Fasting serum samples were collected from MODY3 (n = 17), MODY2 (n = 33), type 1 diabetes (T1DM) (n = 34) and healthy individuals (n = 30), and were analyzed using the ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) metabolomic platform. RESULTS: 4 metabolites were found significantly fluctuated between groups, including glycerophosphocholine, LysoPC(18:2(9Z,12Z)), sphinganine and l-Phenylalanine. Glycerophosphocholine was selected as a diagnostic biomarker. The the area under the ROC curve (AUC) for distinguishing MODYs from healthy controls and differentiating MODY3 from T1DM reached 1.0. The combination of metabolites also gained good diagnostic value. The AUC of the combination of LysoPC(18:2(9Z,12Z)), sphinganine and l-Phenylalanine for discriminating MODY3 from T1DM was 0.983. Besides, the combination of clinical indices and metabolites helped to better differentiate the 2 MODY subtypes. CONCLUSIONS: We identified the metabolic profiles of MODY2 and MODY3 and found promising biomarkers for distinguishing MODY from T1DM, which provides evidence for the pathogenesis and characteristic clinical manifestations of patients with MODY2 and MODY3.

Cell Infiltrative Inner Connected Porous Hydrogel Improves Neural Stem Cell Migration and Differentiation for Functional Repair of Spinal Cord Injury.

The disadvantages of cell-adaptive microenvironments and cellular diffusion out of the lesion have limited hydrogel-based scaffold transplantation treatment for neural connectivity, leading to permanent neurological disability from spinal cord injury. Herein, porous GelMA scaffold was prepared, in which the inner porous structure was optimized. The average pore size was 168 ± 71 µm with a porosity of 77.1%. The modulus of porous hydrogel was 593 ± 4 Pa compared to 1535 ± 85 Pa of bulk GelMA. The inner connected porous structure provided a cell-infiltrative matrix for neural stem cell migration and differentiation in vitro and eventually enhanced neuron differentiation and hindlimb strength and movement of animals in in vivo experiments. Furthermore, inflammation response and apoptosis were also alleviated after implantation. This work demonstrated that the porous hydrogel with appropriately connected micropores exhibit favorable cellular responses compared with traditional non-porous GelMA hydrogel. Taken together, our findings suggest that porous hydrogel is a promising scaffold for future delivery of stem cells and has prospects in material design for the treatment of spinal cord injury.

TM9SF1 knockdown decreases inflammation by enhancing autophagy in a mouse model of acute lung injury.

TM9SF1 is a member of the TM9SF (Transmembrane 9 Superfamily Member) family, which usually has a long N-terminal extracellular region and nine transmembrane domains. TM9SF1's biological function and mechanisms in inflammation are yet unknown. Tm9sf1 was shown to be upregulated in the lung tissues of mice suffering from LPS-induced acute lung injury (ALI). Tm9sf1 knockout mice were studied, and it was shown that Tm9sf1 knockout significantly alleviated LPS-induced ALI, as evidenced by higher survival rate, improved pulmonary vascular permeability, decreased inflammatory cell infiltration, and downregulated inflammatory cytokines. TM9SF1 was also demonstrated to be a negative regulator of autophagy in the LPS-induced ALI model in vitro and in vivo. The autophagy inhibitor 3-MA could counteract the beneficial effects of Tm9sf1 knockout on ALI. Therefore, we discover for the first time the role and mechanism of TM9SF1 in LPS-induced ALI and establish a relationship between TM9SF1 regulated autophagy and ALI progression, which may provide novel targets for the treatment of ALI.

Circulating extracellular vesicle-containing microRNAs reveal potential pathogenesis of Alzheimer's disease.

The pathogenesis of Alzheimer's disease (AD) remains unknown till today, hindering the research and development of AD therapeutics and diagnostics. Circulating extracellular vesicles (EVs) can be utilized as a new window to spy upon AD pathogenesis. Altered microRNA profiles were noted in both the cerebrospinal fluid (CSF)- and blood-isolated EVs of AD patients, implying the outstanding potential of circulating EV-containing miRNAs (CEmiRs) to serve as important regulators in AD pathogenesis. Although several CEmiRs were found to play a part in AD, the association of globally altered miRNA profiles in patients' serum-derived EVs with AD pathogenesis remains unclear. In this study, we first investigated the miRNA profile in serum-derived EVs from AD, mild cognitive impairment (MCI) patients, and healthy individuals. We observed differential expression patterns of CEmiRs and classified them into 10 clusters. We identified the predicted targets of these differentially expressed CEmiRs (DECEmiRs) and analyzed their biological functions and interactions. Our study revealed the temporal regulation of complex and precise signaling networks on AD pathogenesis, shedding light on the development of novel therapeutic strategies, including multi-target drug combination for AD treatment.

UPLC-QTOF/MS Metabolomics and Biochemical Assays Reveal Changes in Hepatic Nutrition and Energy Metabolism during Sexual Maturation in Female Rainbow Trout (Oncorhynchus mykiss).

Mobilization and repartition of nutrients and energy are prerequisites for the normal sexual maturity of broodstock. However, there are few studies on the mechanisms of hepatic nutrients and energy metabolism during sexual maturation in female rainbow trout (Oncorhynchus mykiss). This study investigated hepatic metabolite changes and explored the potential nutritional regulation mechanism between mature and immature female rainbow trout by combining UPLC-QTOF/MS metabolomics and biochemical assays. It was observed that hepatic biochemical assays differed considerably between the two groups, such as glucose, triglycerides, hexokinase, lipase, and aspartate aminotransferase. Liver metabolomics showed that various differential metabolites involved in amino acid and lipid metabolism markedly increased, suggesting the enhancement of lipid metabolism and amino acid anabolism in the liver provides the necessary material basis for ovarian development. Meanwhile, glycogen catabolism and glycolysis hold the key to maintaining organismal energy homeostasis with normal sexual maturation of female rainbow trout. Overall, the results from this study suggested that the liver undergoes drastic reprogramming of the metabolic profile in response to mobilization and repartition of nutrients and energy during the sexual maturation of female rainbow trout. This study further deepened the understanding of the reproductive biology of rainbow trout, and provided the theoretical basis and practical ramifications for nutritional requirements of breeding high-quality broodstock in the artificial propagation of rainbow trout.

Tim-4 reprograms cholesterol metabolism to suppress antiviral innate immunity by disturbing the Insig1-SCAP interaction in macrophages.

Accumulating evidence indicates that macrophages reshape their cholesterol metabolism in response to pathogens to support host defense. Intervention of host cholesterol homeostasis has emerged as a promising strategy for antiviral therapy. T cell immunoglobulin and mucin domain-containing molecule 4 (Tim-4) is indispensable in maintaining the homeostasis of macrophages. However, its role in antiviral innate immunity and cholesterol metabolism remains unknown. Here, we report that Tim-4 deficiency results in boosted interferon (IFN) signaling and decreased viral load. Mechanistically, Tim-4 disturbs the Insig1-SCAP interaction and promotes SCAP-SREBP2 complex translocation to the Golgi apparatus, eventually leading to the upregulation of cholesterol biosynthesis in macrophages, which limits the type I IFN response. Our findings demonstrate that Tim-4 suppresses type I IFN signaling by enhancing SREBP2 activation, delineating the role of Tim-4 in antiviral innate immunity and cholesterol metabolism, which sheds light on the mechanism by which Tim-4 orchestrates macrophage homeostasis.

A high-fat diet disrupts the hepatic and adipose circadian rhythms and modulates the diurnal rhythm of gut microbiota-derived short-chain fatty acids in gestational mice.

The prevalence of gestational obesity has reached epidemic proportions. Evidence supported that the interactions between the gut microbiota and circadian clocks far reached, affecting host metabolism. Our study aimed to investigate the effect of a high-fat diet (HF) on the hepatic and adipose circadian rhythms in gestational mice and to explore the role of gut microbiota-derived short-chain fatty acids (SCFAs) in mediating the effects. C57BL/6 female mice were randomly fed a standard chow diet (Ctr) or HF prior to and during pregnancy. Samples were collected every 4 h over 24 h (six time points), and 16S rRNA and metabonomics were carried out. Rhythmic patterns were identified and compared using CircaCompare. The results showed that the HF before and during pregnancy significantly induced obesity and worsen glucose tolerance, insulin sensitivity, and lipid metabolism in the gestational mice. Furthermore, the HF significantly disrupted the rhythmic pattern of hepatic and adipose circadian clock genes and downstream metabolic genes. Importantly, our results revealed that the HF altered the diurnal rhythm of the gut microbiota in a diverse manner, which was assessed across three categories: phase shift, loss rhythmicity, and gained rhythmicity. We report here, for the first time, a parallel alteration of the rhythmic phase of butyric acid and butyrate-producing Clostridiaceae_1, which was confirmed by a positive correlation between them. Overall, our research emphasized the importance of the rhythmicity of gut microbiota-derived SCFAs in mediating circadian disruption in response to the HF in gestational mice, which may provide novel insights into the prevention and treatment of gestational obesity.

Potential benefits of metformin and pioglitazone combination therapy via gut microbiota and metabolites in high-fat diet-fed mice.

Metformin and pioglitazone monotherapy have been proven to alter gut microbiota in diabetes and obesity. The present study aimed to investigated whether the combined administration of pioglitazone and metformin achieved superior protective effects on high-fat diet (HFD)-fed obese mice and elucidated its molecular mechanism via the gut microbiota and its metabolites. C57BL/6 males were randomly divided into five groups: the control group, fed a normal control diet; the HFD group, fed an HFD; the metformin monotherapy group, fed an HFD and treated with metformin; the pioglitazone monotherapy group, fed an HFD and treated with pioglitazone; and the combination therapy group, fed an HFD and treated with metformin and pioglitazone combination therapy. The cecal contents were collected for 16S rDNA amplicon sequencing and untargeted metabolomics analysis. The results showed that the combination therapy of metformin and pioglitazone significantly improved insulin sensitivity and glucolipid metabolism in HFD-fed mice. Combination therapy markedly altered gut microbiota by increasing beneficial bacteria, such as Bifidobacterium, Christensenellaceae_R-7_group, Faecalibacterium and Roseburia, and decreasing harmful bacteria, such as Oscillibacter and Eubacterium_xylanophilum_group. Fecal metabolites were significantly changed in the combination therapy group, including a reduction in amino acid metabolism and augmentation of lipid metabolism, such as citrulline, sarcosine, D-glutamine, lipoxin A4, prostaglandin E2, stearidonic acid and lucidenic acid A. These results revealed that combined metformin and pioglitazone therapy had synergistic effects or at least have an additive effect on modifying gut microbiota and metabolites, closely associated with improved glucolipid metabolic parameters in HFD-fed mice, which provides novel evidence and promising targets for metformin and pioglitazone combination therapy in type 2 diabetes.

Preferential subcortical collateral projections of pedunculopontine nucleus-targeting cortical pyramidal neurons revealed by brain-wide single fiber tracing.

The pedunculopontine nucleus (PPN) is a heterogeneous midbrain structure involved in various brain functions, such as motor control, learning, reward, and sleep. Previous studies using conventional tracers have shown that the PPN receives extensive afferent inputs from various cortical areas. To examine how these cortical axons make collateral projections to other subcortical areas, we used a dual-viral injection strategy to sparsely label PPN-targeting cortical pyramidal neurons in CaMKIIα-Cre transgenic mice. Using a high-speed volumetric imaging with on-the-fly-scan and Readout (VISoR) technique, we visualized brain-wide axonal projections of individual PPN-targeting neurons from several cortical areas, including the prelimbic region (PL), anterior cingulate area (ACA) and secondary motor cortex (MOs). We found that each PPN-projecting neuron had a unique profile of collateralization, with some subcortical areas being preferential targets. In particular, PPN-projecting neurons from all three traced cortical areas exhibited common preferential collateralization to several nuclei, with most neurons targeting the striatum (STR), lateral hypothalamic area (LHA) and periaqueductal gray (PAG), and a substantial portion of neurons also targeting the zona incerta (ZI), median raphe nucleus (MRN) and substantia nigra pars reticulata (SNr). Meanwhile, very specific collateralization patterns were found for other nuclei, including the intermediate reticular nucleus (IRN), parvicellular reticular nucleus (PARN) and gigantocellular reticular nucleus (GRN), which receive collateral inputs almost exclusively from the MOs. These observations provide potential anatomical mechanisms for cortical neurons to coordinate the PPN with other subcortical areas in performing different physiological functions.

Coupling spin defects in hexagonal boron nitride to titanium dioxide ring resonators.

Spin-dependent optical transitions are attractive for a plethora of applications in quantum technologies. Here we report on utilization of high quality ring resonators fabricated from TiO2 to enhance the emission from negatively charged boron vacancies (VB-) in hexagonal Boron Nitride. We show that the emission from these defects can efficiently couple into the whispering gallery modes of the ring resonators. Optically coupled VB- showed photoluminescence contrast in optically detected magnetic resonance signals from the hybrid coupled devices. Our results demonstrate a practical method for integration of spin defects in 2D materials with dielectric resonators which is a promising platform for quantum technologies.

Autophagy inhibition restores CD200 expression under IL-1ß microenvironment in placental mesenchymal stem cells of fetal origin and improves its pulmonary fibrosis therapeutic potential.

BACKGROUND: Mesenchymal stem cells (MSCs) are promising remedies for various inflammatory disease including pulmonary fibrosis (PF). However, the properties of MSCs in PF pathological microenvironment remain unclear. In this study, the efficacy of autophagy in placental mesenchymal stem cells of fetal origin (fPMSCs) in either IL-1ß treatment or BLM induced pulmonary fibrosis mice model was examined. METHODS: The characteristic of fPMSCs was identified by morphological observation, flow cytometry and differentiation potential. In vitro experiments, fPMSCs were stimulated with IL-1ß, to mimic inflammatory microenvironment of pulmonary fibrosis. The immunosuppressive properties and autophagic function in fPMSCs treated with IL-1ß were evaluated by both macrophage cells THP-1 activation and the expression of CD200 situation, autophagy marker and MAPK signaling pathway. The in vivo anti-fibrotic activity of fPMSCs interfering autophagy was evaluated by using BLM induced pulmonary fibrosis mice model. RESULTS: fPMSCs belonged to CD73+CD90+CD105+/CD14- CD34-CD45-HLA-DR- cells, and capable differentiation to adipogenic, osteogenic and chondrogenic cells. In addition, immunoinhibitory activity of fPMSCs for macrophage was restrained by IL-1ß treatment in CD200 dependent manner. Suppression of autophagy by sh-Atg5 lentivirus increased the expression of CD200 and ratio of CD200 positive fPMSCs, and enhanced fPMSCs immunosuppression for THP-1 activation. Mechanistically, IL-1ß induced autophagy regulated by p38 signaling cascade. In vivo, autophagy inhibition induced by Atg5 knockdown in fPMSCs resulted in strengthening antifibrotic effects on PF mice model. CONCLUSIONS: Collectively, autophagy derived from inflammatory microenvironment hampered the immunoinhibitory properties of MSCs. Based on this, adjustment of autophagy may be a valid approach to facilitate their immunomodulatory and anti-fibrotic efficacy.

Qizhi Kebitong Formula Ameliorates Streptozocin-Induced Diabetic Osteoporosis through Regulating the PI3K/Akt/NF-κB Pathway.

Background: Diabetic osteoporosis (DOP) is a progressive osteoblast dysfunction induced by high glucose, which has negative impacts on bone homeostasis. Qizhi Kebitong formula (QKF) is a traditional Chinese medicine (TCM) formula for treating DOP. However, its role in the protection of DOP has not been clarified yet. Here, we aimed to explore the potential mechanisms of QKF on DOP development via in vivo experiment. Methods: Network pharmacology was used to detect the key targets and signaling pathways of QKF on DOP. The effects of QKF on DOP were examined by the phenotypic characteristics, micro-CT, and hematoxylin-eosin (H&E) staining. The predicted targets and pathways were validated by a streptozocin- (STZ-) induced mouse model. Subsequently, the levels of the selected genes and proteins were analyzed using qRT-PCR and Western blot. Finally, AutoDock and PyMOL were used for molecular docking. Results: In this study, 90 active compounds and 2970 related disease targets have been found through network pharmacology. And QKF could improve the microstructures of femur bone mass, reduce inflammatory cell infiltration, and downregulate the levels of TNF-α, IKBKB, IL-6, and IL-1ß. Moreover, the underlying effect of PI3K/Akt/NF-κB pathways was also recommended in the treatment. Conclusion: Altogether, our findings suggested that QKF could markedly alleviate osteoblast dysfunction by modulating the key targets and PI3K/Akt/NF-κB signaling pathway.

The complete chloroplast genome sequence of Elatostema stewardii Merr. (Urticaceae).

Elatostema stewardii is an important medicinal plant endemic to China. In this study, the complete chloroplast genome of E. stewardii was sequenced and assembled using next-generation sequencing technology. The complete chloroplast genome length of E. stewardii was 150,263 bp, including two inverted repeats (IRs) of 24,681 bp, which are separated by LSC and SSC of 83,791 bp and 17,110 bp, respectively. A total of 129 genes were included in the genome, consisting 85 protein-coding genes, eight rRNA genes, and 36 tRNA genes, the overall GC content of this genome was 36.3%. There are few studies on the genus Elatostema of Urticaceae, this chloroplast genome sequence will provide useful data for further research on solving the generic and familial relationships in Urticaceae.