Long-term effects of nitrogen and phosphorus fertilization on profile distribution and characteristics of dissolved organic matter in fluvo-aquic soil.

Dissolved organic matter (DOM) drives numerous biogeochemical processes (e.g. carbon cycling) in agro-ecosystems and is sensitive to fertilization management. Nevertheless, changes in the quantity and quality of DOM in the vertical soil profile following long-term continuous nitrogen (N) and phosphorus (P) inputs remain unclear. In this study, the contents and optical characteristics of DOM along a 2-m soil profile were investigated using a 40-year wheat/maize rotation combined with experiments using different N and P fertilization rates in the North China Plain. The results revealed that the dissolved organic carbon (DOC) content decreased with an increase in soil depths. Compared with that in the control (no fertilization), 40-year N, P, and N + P additions increased the soil DOC content by 26%-69%, except for 270-kg N, and 67.5-kg P treatments. N + P application resulted in higher DOC contents than N-alone and P-alone applications. N, P, and N + P inputs increased or did not affect the aromaticity and hydrophobicity of DOM at 0-40 cm but reduced them from 40 to 200 cm. Compared with that in the control, N, P, and N + P inputs enhanced the content of humic acid-like substances (C1+C2+C3+C4) and decreased the content of protein-like substance (C5). C1 was the dominant component among the five DOM, representing the microbial humic component. Optical indices also indicated that soil DOM primarily originated from microbial sources. Nutrient addition accelerated transformation between complex C1 and simple C5 via promoting microbial activities. These results imply that N and P fertilizers increased the DOM content and altered its composition, thereby potentially affecting the stability of soil organic matter in the agroe-cosystems.

Targeting foamy macrophages by manipulating ABCA1 expression to facilitate lesion healing in the injured spinal cord.

Spinal cord injury (SCI) triggers a complex cascade of events, including myelin loss, neuronal damage, neuroinflammation, and the accumulation of damaged cells and debris at the injury site. Infiltrating bone marrow derived macrophages (BMDMϕ) migrate to the epicenter of the SCI lesion, where they engulf cell debris including abundant myelin debris to become pro-inflammatory foamy macrophages (foamy Mϕ), participate neuroinflammation, and facilitate the progression of SCI. This study aimed to elucidate the cellular and molecular mechanisms underlying the functional changes in foamy Mϕ and their potential implications for SCI. Contusion at T10 level of the spinal cord was induced using a New York University (NYU) impactor (5 g rod from a height of 6.25 mm) in male mice. ABCA1, an ATP-binding cassette transporter expressed by Mϕ, plays a crucial role in lipid efflux from foamy cells. We observed that foamy Mϕ lacking ABCA1 exhibited increased lipid accumulation and a higher presence of lipid-accumulated foamy Mϕ as well as elevated pro-inflammatory response in vitro and in injured spinal cord. We also found that both genetic and pharmacological enhancement of ABCA1 expression accelerated lipid efflux from foamy Mϕ, reduced lipid accumulation and inhibited the pro-inflammatory response of foamy Mϕ, and accelerated clearance of cell debris and necrotic cells, which resulted in functional recovery. Our study highlights the importance of understanding the pathologic role of foamy Mϕ in SCI progression and the potential of ABCA1 as a therapeutic target for modulating the inflammatory response, promoting lipid metabolism, and facilitating functional recovery in SCI.

Effects of Microplastics on Soil Carbon Mineralization: The Crucial Role of Oxygen Dynamics and Electron Transfer.

Although our understanding of the effects of microplastics on the dynamics of soil organic matter (SOM) has considerably advanced in recent years, the fundamental mechanisms remain unclear. In this study, we examine the effects of polyethylene and poly(lactic acid) microplastics on SOM processes via mineralization incubation. Accordingly, we evaluated the changes in carbon dioxide (CO2) and methane (CH4) production. An O2 planar optical sensor was used to detect the temporal behavior of dissolved O2 during incubation to determine the microscale oxygen heterogeneity caused by microplastics. Additionally, the changes in soil dissolved organic matter (DOM) were evaluated using a combination of spectroscopic approaches and ultrahigh-resolution mass spectrometry. Microplastics increased cumulative CO2 emissions by 160-613%, whereas CH4 emissions dropped by 45-503%, which may be attributed to the oxygenated porous habitats surrounding microplastics. Conventional and biodegradable microplastics changed the quantities of soil dissolved organic carbon. In the microplastic treatments, DOM with more polar groups was detected, suggesting a higher level of electron transport. In addition, there was a positive correlation between the carbon concentration, electron-donating ability, and CO2 emission. These findings suggest that microplastics may facilitate the mineralization of SOM by modifying O2 microenvironments, DOM concentration, and DOM electron transport capability. Accordingly, this study provides new insights into the impact of microplastics on soil carbon dynamics.

Autophagy Suppresses Ferroptosis by Degrading TFR1 to Alleviate Cognitive Dysfunction in Mice with SAE.

Sepsis-associated encephalopathy (SAE) is a serious complication of sepsis that is characterized by long-term cognitive impairment, which imposes a heavy burden on families and society. However, its pathological mechanism has not been elucidated. Ferroptosis is a novel form of programmed cell death that is involved in multiple neurodegenerative diseases. In the current study, we found that ferroptosis also participated in the pathological process of cognitive dysfunction in SAE, while Liproxstatin-1 (Lip-1) effectively inhibited ferroptosis and alleviated cognitive impairment. Additionally, since an increasing number of studies have suggested the crosstalk between autophagy and ferroptosis, we further proved the essential role of autophagy in this process and demonstrated the key molecular mechanism of the autophagy-ferroptosis interaction. Currently, we showed that autophagy in the hippocampus was downregulated within 3 days of lipopolysaccharide injection into the lateral ventricle. Moreover, enhancing autophagy ameliorated cognitive dysfunction. Importantly, we found that autophagy suppressed ferroptosis by downregulating transferrin receptor 1 (TFR1) in the hippocampus, thereby alleviating cognitive impairment in mice with SAE. In conclusion, our findings indicated that hippocampal neuronal ferroptosis is associated with cognitive impairment. In addition, enhancing autophagy can inhibit ferroptosis via degradation of TFR1 to ameliorate cognitive impairment in SAE, which shed new light on the prevention and therapy for SAE.

Chaperone-mediated autophagy (CMA) alleviates cognitive impairment by reducing neuronal death in sepsis-associated encephalopathy (SAE).

Sepsis-associated encephalopathy (SAE) is a common and severe complication of sepsis, which causes long-term neurological deficits, such as cognitive impairment. Despite extensive research, there is still lack of specific treatments for SAE. Chaperone-mediated autophagy (CMA), a selective type of autophagy, has been reported to be related to cognitive dysfunctions in many neurodegenerative diseases. The aim of this study was to investigate the alteration of CMA activity in the hippocampus of SAE mice and explore the neuroprotective effect of enhanced CMA. Cecal ligation and puncture (CLP) was conducted to induce SAE. In the contextual fear conditioning test, the ratio of freezing time of CLP mice significantly decreased compared with that of the mice in the Sham group, indicating cognitive impairment in SAE mice. The expression of lysosome-associated membrane protein type 2A (Lamp2a) and chaperone heat shock cognate 71 kDa protein (Hsc70), positive markers for CMA activity, decreased in hippocampal neurons of SAE mice. Although overexpression of Lamp2a in neurons via adeno-associated virus injection in the hippocampus had little effect on the mortality of septic mice, this intervention significantly alleviated the memory impairments in contextual fear conditioning test, Y-maze test and novel objective recognition test, and attenuated the neural death observed in SAE mice. We further demonstrated that the overexpression of Lamp2a in the hippocampus increased the expression of phosphorylated cyclic-AMP response element binding protein (p-CREB), brain-derived neurotrophic factor (BDNF) and B-cell lymphoma-2 (Bcl-2), and suppressed the expression of cleaved caspase-3. Taken together, our study results suggested that the upregulation of CMA activity ameliorated cognitive impairments and neuron loss in SAE mice partially through the p-CREB-BDNF/Bcl-2 signaling pathways, providing a potential therapeutic target for SAE.

Hydralazine plays an immunomodulation role of pro-regeneration in a mouse model of spinal cord injury.

Spinal cord injury (SCI) results in severe motor and sensory dysfunction with no effective therapy. Spinal cord debris (sp) from injured spinal cord evokes secondary SCI continuously. We and other researchers have previously clarified that it is mainly bone marrow derived macrophages (BMDMs) infiltrating in the lesion epicenter to clear sp, rather than local microglia. Unfortunately, the pro-inflammatory phenotype of these infiltrating BMDMs is predominant which impairs wound healing. Hydralazine, as a potent vasodilator and scavenger of acrolein, has protective effects in many diseases. Hydralazine is also confirmed to promote motor function and hypersensitivity in SCI rats through scavenging acrolein. However, few studies have explored the effects of hydralazine on immunomodulation, as well as spontaneous pain and emotional response, the important syndromes in clinical patients. It remains unclear whether hydralazine affects infiltrating BMDMs after SCI. In this study, we targeted BMDMs to explore the influence of hydralazine on immune cells in a mouse model of SCI, and also investigated the contribution of polarized BMDMs to hydralazine-induced neurological function recovery after SCI in male mice. The adult male mice underwent T10 spinal cord compression. The results showed that in addition to improving motor function and hypersensitivity, hydralazine relieved SCI-induced spontaneous pain and emotional response, which is a newly discovered function of hydralazine. Hydralazine inhibited the recruitments of pro-inflammatory BMDMs and educated infiltrated BMDMs to a more reparative phenotype involving in multiple biological processes associated with SCI pathology, including immune/inflammation response, neurogenesis, lipid metabolism, oxidative stress, fibrosis formation, and angiogenesis, etc. As an overall effect, hydralazine-treated BMDMs loaden with sp partially rescued neurological function after SCI. It is concluded that hydralazine plays an immunomodulation role of educating pro-inflammatory BMDMs to a more reparative phenotype; and hydralazine-educated BMDMs contribute to hydralazine-induced improvement of neurological function in SCI mice, which provides support for drug and cell treatment options for SCI therapy.

Microbes drive metabolism, community diversity, and interactions in response to microplastic-induced nutrient imbalance.

The impact of conventional and biodegradable microplastics on soil nutrients (carbon and nitrogen) has been widely examined, and the alteration of nutrient conditions further influences microbial biosynthesis processes. Nonetheless, the influence of microplastic-induced nutrient imbalances on soil microorganisms (from metabolism to community interactions) is still not well understood. We hypothesized that conventional and biodegradable microplastic could alter soil nutrients and microbial processes. To fill this knowledge gap, we conducted soil microcosms with polyethylene (PE, new and aged) and polylactic acid (PLA, new and aged) microplastics to evaluate their effects on the soil enzymatic stoichiometry, co-occurrence interactions, and success patterns of soil bacterial communities. New and aged PLA induced soil N immobilization, which decreased soil mineral N by 91-141 %. The biodegradation of PLA led to a higher bioavailable C and wider bioavailable C:N ratio, which further filtered out specific microbial species. Both new and aged PLA had a higher abundance of copiotrophic members (Proteobacteria, 35-51 % in PLA, 26-34 % in CK/PE treatments) and rrn copy number. The addition of PLA resulted in a lower alpha diversity and reduced network complexity. Conversely, because of the chemically stable hydrocarbon structure of PE polymers, the new and aged PE microplastics had a minor effect on soil mineral N, bacterial community composition, and network complexity, but led to microbial C limitation. Collectively, all microplastics increased soil C-, N-, and P -acquiring enzyme activities and reduced the number of keystone species and the robustness of the co-occurrence network. The PLA treatment enhanced nitrogen fixation and ureolysis, whereas the PE treatment increased the degradation of recalcitrant carbon. Overall, the alteration of soil nutrient conditions by microplastics affected the microbial metabolism and community interactions, although the effects of PE and PLA microplastics were distinct.

The Role of Ferroptosis in Nervous System Disorders.

Ferroptosis is distinct from other apoptotic forms of programmed cell death and is characterized by the accumulation of iron and lipid peroxidation. Iron plays a crucial role in the oxidation of lipids via the Fenton reaction with oxygen. Hence, iron accumulation causes phospholipid peroxidation which induces ferroptosis. Moreover, detoxification by glutathione is disrupted during ferroptosis. A growing number of studies have implicated ferroptosis in nervous system disorders such as depression, neurodegenerative disease, stroke, traumatic brain injury, and sepsis-associated encephalopathy. This review summarizes the pathogenesis of ferroptosis and its relationship with various nervous system disorders.

Selective activation of cholinergic neurotransmission from the medial septal nucleus to hippocampal pyramidal neurones improves sepsis-induced cognitive deficits in mice.

BACKGROUND: Sepsis-associated encephalopathy is characterised by cognitive dysfunction, and might be mediated by deficits in neurotransmission. Reduced cholinergic neurotransmission in the hippocampus impairs memory function. We assessed real-time alterations of acetylcholine neurotransmission from the medial septal nucleus to the hippocampus, and explored whether sepsis-induced cognitive deficits can be relieved by activating upstream cholinergic projections. METHOD: Lipopolysaccharide (LPS) injection or caecal ligation and puncture (CLP) was used to induce sepsis and associated neuroinflammation in wild-type and mutant mice. Adeno-associated viruses for calcium and acetylcholine imaging, and for optogenetic and chemogenetic modulation of cholinergic neurones were injected into the hippocampus or medial septum, and a 200-µm-diameter optical fibre was implanted to collect acetylcholine and calcium signals. Cholinergic activity of the medial septum was manipulated and combined with cognitive assessment after LPS injection or CLP. RESULTS: Intracerebroventricular LPS injection reduced postsynaptic acetylcholine (from 0.146 [0.001] to 0.0047 [0.0005]; p=0.004) and calcium (from 0.0236 [0.0075] to 0.0054 [0.0026]; p=0.0388) signals in hippocampal Vglut2-positive glutamatergic neurones, whereas optogenetic activation of cholinergic neurones in the medial septum reversed LPS-induced reductions in these two signals. Intraperitoneal LPS injection decreased acetylcholine concentration in the hippocampus (476 [20] pg ml-1 to 382 [14] pg ml-1; p=0.0001). Reduction in long-term potentiation (238 [23] % to 150 [12] %; p=0.0082) and enhancement of hippocampal pyramidal neurone action potential frequency (5.8 [1.5] Hz to 8.2 [1.8] Hz; p=0.0343) were relieved, and neurocognitive performance was improved by chemogenetic activation of cholinergic innervation of the hippocampus 3 days after LPS injection in septic mice. CONCLUSIONS: Systemic or local LPS reduced cholinergic neurotransmission from the medial septum to hippocampal pyramidal neurones, and their selective activation alleviated defects in hippocampal neuronal function and synaptic plasticity and ameliorated memory deficits in sepsis model mice through enhanced cholinergic neurotransmission. This provides a basis for targeting cholinergic signalling to the hippocampus in sepsis-induced encephalopathy.

[Rapamycin alleviates cognitive impairment in mice with sepses-associated encephalopathy by promoting autophagy].

Objective To investigate the role of rapamycin in alleviating cognitive dysfunction by promoting autophagy in mice with sepsis-associated encephalopathy (SAE). Methods The model of SAE mice was established by caecal ligation and perforation (CLP). Murine sepsis score (MSS) was used to evaluate the severity of sepsis in SAE mice. And the cognitive function was tested by the contextual fear conditioning test. The expression levels of microtubule-associated protein 1 light chain 3 (LC3) and P62 in the hippocampus of the SAE mice were detected by Western blot analysis. Furthermore, the expression and distribution of LC3 in the hippocampal neurons were observed by immunofluorescence. Results The mortality of CLP-induced mice reached 41.7% with 14 days after the procedure, and significant cognitive dysfunction was detected in the surviving mice. Meanwhile, autophagy in the hippocampal tissue was impaired 14 days after CLP. The cognitive dysfunction of SAE mice was alleviated by promoting autophagy via rapamycin. Conclusion Rapamycin alleviated the cognitive dysfunction of SAE mice by promoting autophagy in the hippocampal neurons.

Neuronal MD2 induces long-term mental impairments in septic mice by facilitating necroptosis and apoptosis.

Sepsis-associated encephalopathy (SAE) is a complication of sepsis with high morbidity rates. Long-lasting mental health issues in patients with SAE result in a substantial decrease in quality of life. However, its underlying mechanism is unclear, and effective treatments are not available. In the current study, we explored the role of apoptosis and necroptosis related to mental dysfunction in sepsis. In a mouse model of sepsis constructed by cecal ligation and puncture (CLP), altered behavior was detected by the open field, elevated-plus maze and forced swimming tests on the fourteenth day. Moreover, apoptosis- and necroptosis-associated proteins and morphological changes were examined in the hippocampus of septic mice. Long-lasting depression-like behaviors were detected in the CLP mice, as well as significant increases in neuronal apoptosis and necroptosis. Importantly, we found that apoptosis and necroptosis were related according to Ramsay's rule in the brains of the septic mice. Inhibiting myeloid differentiation factor 2 (MD2), the crosstalk mediator of apoptosis and necroptosis, in neurons effectively reduced neuronal loss and alleviated depression-like behaviors in the septic mice. These results suggest that neuronal death in the hippocampus contributes to the mental impairments in SAE and that inhibiting neuronal MD2 is a new strategy for treating mental health issues in sepsis by inhibiting necroptosis and apoptosis.

[Recent progress of antimicrobial peptides in sepsis treatment].

Sepsis is a life-threatening organ dysfunction due to the dysregulation of host responses during infection. Severe systemic inflammatory response syndrome (SIRS) is the primary pathophysiological feature. Despite the classical antibiotic therapies play an important role in sepsis, the emergence of multi-resistant bacteria makes a greater challenge in clinical. Antimicrobial peptides (AMP) which consist of small cationic peptides, can be found in most organisms. As a result of their board-spectrum antibacterial activities and immunoregulatory functions, AMPs may have an excellent effect on the treatment of sepsis. In this review, we will discuss the basic role of AMPs in sepsis treatment and their application prospect and the challenges which need to be resolved in order to provide ideas for clinical application of AMPs.

An MD2-perturbing peptide has therapeutic effects in rodent and rhesus monkey models of stroke.

Studies have failed to translate more than 1000 experimental treatments from bench to bedside, leaving stroke as the second leading cause of death in the world. Thrombolysis within 4.5 hours is the recommended therapy for stroke and cannot be performed until neuroimaging is used to distinguish ischemic stroke from hemorrhagic stroke. Therefore, finding a common and critical therapeutic target for both ischemic and hemorrhagic stroke is appealing. Here, we report that the expression of myeloid differentiation protein 2 (MD2), which is traditionally regarded to be expressed only in microglia in the normal brain, was markedly increased in cortical neurons after stroke. We synthesized a small peptide, Trans-trans-activating (Tat)-cold-inducible RNA binding protein (Tat-CIRP), which perturbed the function of MD2 and strongly protected neurons against excitotoxic injury in vitro. In addition, systemic administration of Tat-CIRP or genetic deletion of MD2 induced robust neuroprotection against ischemic and hemorrhagic stroke in mice. Tat-CIRP reduced the brain infarct volume and preserved neurological function in rhesus monkeys 30 days after ischemic stroke. Tat-CIRP efficiently crossed the blood-brain barrier and showed a wide therapeutic index for stroke because no toxicity was detected when high doses were administered to the mice. Furthermore, we demonstrated that MD2 elicited neuronal apoptosis and necroptosis via a TLR4-independent, Sam68-related cascade. In summary, Tat-CIRP provides robust neuroprotection against stroke in rodents and gyrencephalic nonhuman primates. Further efforts should be made to translate these findings to treat both ischemic and hemorrhagic stroke in patients.

Microglia: A Potential Therapeutic Target for Sepsis-Associated Encephalopathy and Sepsis-Associated Chronic Pain.

Neurological dysfunction, one of the severe manifestations of sepsis in patients, is closely related to increased mortality and long-term complications in intensive care units, including sepsis-associated encephalopathy (SAE) and chronic pain. The underlying mechanisms of these sepsis-induced neurological dysfunctions are elusive. However, it has been well established that microglia, the dominant resident immune cell in the central nervous system, play essential roles in the initiation and development of SAE and chronic pain. Microglia can be activated by inflammatory mediators, adjacent cells and neurotransmitters in the acute phase of sepsis and then induce neuronal dysfunction in the brain. With the spotlight focused on the relationship between microglia and sepsis, a deeper understanding of microglia in SAE and chronic pain can be achieved. More importantly, clarifying the mechanisms of sepsis-associated signaling pathways in microglia would shed new light on treatment strategies for SAE and chronic pain.

Aspirin-Triggered Lipoxin Protects Lipopolysaccharide-Induced Acute Kidney Injury via the TLR4/MyD88/NF-κB Pathway.

The protective effect of aspirin-triggered lipoxin (ATL) on lipopolysaccharide (LPS)-induced acute kidney injury (AKI) and its possible mechanisms were explored. To induce acute renal injury, mice were treated with LPS. Concentration of serum creatinine (SCr) and blood urea nitrogen (BUN) was detected, and inflammatory cytokines and AKI biomarkers were determined by ELISA. The relative protein expression levels of TLR4/myeloid differentiation factor 88 (MyD88)/NF-κB signal pathway was assessed by Western blot. Mice subjected to LPS (4 mg/kg) treatment exhibited AKI demonstrated by markedly increased SCr and BUN levels compared with controls (P <0.01). Treatment with ATL decreased SCr and BUN levels after LPS injection (P <0.01). AKI biomarkers, such as urine NGAL, KIM-1, netrin-1, and L-FABP levels, increased by LPS and were inhibited by ATL (P <0.01). ATL also reduced LPS-induced secretion of inflammatory cytokines such as tumor necrosis factor-alpha, interleukin (IL)-1ß, IL-6, and IL-8 (P <0.01). Furthermore, mice pretreated with ATL before exposure to LPS showed a reduction in TLR, MyD88, and p65 phosphorylation (P <0.01), which are the key factors of the TLR/MyD88/NF-κB signaling pathway. These results indicated that ATL had protective effects on renal function and showed amelioration of LPS-induced kidney injury. The mechanisms underlying the protective effects of ATL can be considered are related to attenuation of the TLR4/MyD88/NF-κB signaling pathway.

Circular RNA expression profiles in neonatal rats following hypoxic-ischemic brain damage.

Circular RNAs (circRNAs) have been studied in a number of diseases. However, the roles of circRNAs in hypoxic­ischemic brain damage (HIBD) remains unknown. In the present study, high throughput sequencing was used to profile altered circRNAs in HIBD rats. A total of 66 circRNAs were identified to be differentially expressed (fold­change >2 and P­value <0.05) in HIBD rats compared with the control group, including 20 upregulated and 46 downregulated circRNAs. Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis indicated that numerous mRNAs transcribed from the host genes of altered circRNAs were involved in brain damage and neural regeneration. The interaction of circRNA/microRNA was predicted based on TargetScan and miRanda. The results of this study demonstrated an altered circRNA expression pattern in HIBD rats and suggests important roles in HIBD physiological and pathological processes. These findings suggest a novel focus for future studies investigating the molecular mechanism underlying HIBD and possibilities for the treatment of HIBD through modulating circRNAs.

High-throughput sequencing analysis of lncRNAs in hippocampus tissues with hypoxic-ischemic brain damage.

LncRNAs abundantly expressed in the brain have vital and wide-ranging functions in different biological processes. However, little is currently known regarding the influence of lncRNAs in developing brains after hypoxic-ischemic brain damage (HIBD). In this study, to investigate the lncRNAs expression signatures and the co-expression network of lncRNAs and mRNAs in the brain after HIBD, we established a neonatal rat HIBD model and detected the expression profiles of lncRNAs in the HIBD brain and a sham control using high-throughput sequencing. Further, highly differentially expressed lncRNAs were selected and validated by qRT-PCR. Finally, the biological functions of the selected lncRNAs were investigated by over-expressing or silencing the target genes through lentivirus transfection in hippocampal neuron cells. Our results revealed that the expression profile of lncRNAs was dramatically different between the HIBD brains and the sham control, showing as the aberrant expression of 617 lncRNA transcripts and 441 mRNA transcripts at 24 hours after HIBD. GO and KEGG analyses indicated that the differentially expressed mRNAs were mostly involved in the apoptosis signaling pathway. After validating the expression of 8 randomly selected lncRNA transcripts by qRT-PCR, we found that the TNFRSF17 gene (ID: ENSRNOG00000021987) was down-regulated in HI brains. After stable over-expression and silencing of TNFRSF17, the apoptosis rate of hippocampal neuron cells exhibited obvious changes under hypoxia or normaxia. The over-expression of TNFRSF17 could significantly up-regulate Bcl-2 but down-regulate Bax, caspase-3, and caspase-9 at the mRNA and protein levels, while the silencing of TNFRSF17 led to just the opposite phenomenon. Notably, the regulation effects of TNFRSF17 on apoptotic related genes and proteins under hypoxia were more obvious than those under normaxia. Moreover, the over-expression of TNFRSF17 reduced the apoptotic rate, but the loss of TNFRSF17 led to a high rate of apoptosis under hypoxia. Taken together, the silencing of TNFRSF17 exacerbated, while over-expression attenuated, neuron apoptosis induced by HI injury, suggesting that TNFRSF17 may be a target for the prognosis, diagnosis, and treatment of HIBD.

MicroRNA­106b regulates skeletal muscle insulin sensitivity and glucose homeostasis by targeting mitofusion­2.

MicroRNA­106b (miR­106b) is reported to be closely associated with skeletal muscle insulin resistance. The present study further investigated the role of miR­106b in skeletal muscle insulin sensitivity and glucose homeostasis in vivo. Mice were randomly divided into 4 groups and infected with lentivirus expressing miR­106b (miR­106b mice), miR­106b sponge (miR­106b inhibition mice) or the corresponding empty vectors. Mitofusion­2 (Mfn2) protein expression levels and glucose transporter (Glut)­4 protein translocation were significantly reduced in the muscle of miR­106b mice, whereas they were unaffected in miR­106b inhibition mice. miR­106b mice had significantly increased blood glucose levels following 12 h of fasting and impaired glucose tolerance, whereas miR­106b inhibition mice had no significant alterations in fasting blood glucose levels and glucose tolerance. In vitro, the suppressive effect of miR­106b on glucose uptake and Glut4 translocation was completely inhibited in C2C12 myotubes infected with Mfn2 plasmids. Following treatment of C2C12 myotubes with Mfn2 small interfering RNA, miR­106b inhibition consistently increased Mfn2 protein levels and improved glucose uptake and Glut4 translocation. These results indicated that miR­106b targeted Mfn2 and regulated skeletal muscle insulin sensitivity and glucose tolerance. Therefore, increased miR­106b expression may be a potential mechanism underlying insulin resistance and type 2 diabetes.

Silencing miR-106b improves palmitic acid-induced mitochondrial dysfunction and insulin resistance in skeletal myocytes.

MicroRNA­106b (miR­106b) is reported to correlate closely with skeletal muscle insulin resistance. In the current study the effect of miR­106b on palmitic acid (PA)­induced mitochondrial dysfunction and insulin resistance was investigated in C2C12 myotubes via the silencing of miR­106b. MiR­106b expression was increased under PA treatment, while miR­106b loss of function improved insulin sensitivity by upregulating its target mitofusin­2 (Mfn2) in C2C12 myocytes. Furthermore, miR­106b loss of function partly improved mitochondrial morphological lesions and increased the levels of mitochondial DNA and intracellular adenosine triphosphate that had been impaired by PA exposure in C2C12 myocytes. MiR­106b loss of function attenuated the levels of intracellular reactive oxygen species (ROS), and upregulated the expression levels of the estrogen­related receptor (ERR)­α/peroxisome proliferative activated receptor γ coactivator (PGC)­1α/Mfn2 axis under PA exposure. In addition, miR­106b negatively regulated skeletal muscle mitochondrial function and insulin sensitivity under PA­induced insulin resistance by targeting Mfn2, which may be associated with reduced ROS and upregulation of the ERR­α/PGC­1α/Mfn2 axis.

MicroRNA-106b induces mitochondrial dysfunction and insulin resistance in C2C12 myotubes by targeting mitofusin-2.

MicroRNA-106b (miR-106b) is reported to correlate closely with skeletal muscle insulin resistance and type 2 diabetes. The aim of this study was to identify an mRNA targeted by miR-106b which regulates skeletal muscle insulin sensitivity. MiR-106b was found to target the 3' untranslated region (3' UTR) of mitofusin-2 (Mfn2) through miR-106b binding sites and to downregulate Mfn2 protein abundance at the post-transcriptional level by luciferase activity assay combined with mutational analysis and immunoblotting. Overexpression of miR-106b resulted in mitochondrial dysfunction and insulin resistance in C2C12 myotubes. MiR-106b was increased in insulin-resistant cultured C2C12 myotubes induced by TNF-α, and accompanied by increasing Mfn2 level, miR-106b loss of function improved mitochondrial function and insulin sensitivity impaired by TNF-α in C2C12 myotubes. In addition, both overexpression and downregulation of miR-106b upregulated peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α and estrogen-related receptor (ERR)-α expression. MiR-106b targeted Mfn2 and regulated skeletal muscle mitochondrial function and insulin sensitivity. Therefor, Inhibition of miR-106b may be a potential new strategy for treating insulin resistance and type 2 diabetes.