Microbiota-derived acetate attenuates neuroinflammation in rostral ventrolateral medulla of spontaneously hypertensive rats.

BACKGROUND: Increased neuroinflammation in brain regions regulating sympathetic nerves is associated with hypertension. Emerging evidence from both human and animal studies suggests a link between hypertension and gut microbiota, as well as microbiota-derived metabolites short-chain fatty acids (SCFAs). However, the precise mechanisms underlying this gut-brain axis remain unclear. METHODS: The levels of microbiota-derived SCFAs in spontaneously hypertensive rats (SHRs) were determined by gas chromatography-mass spectrometry. To observe the effect of acetate on arterial blood pressure (ABP) in rats, sodium acetate was supplemented via drinking water for continuous 7 days. ABP was recorded by radio telemetry. The inflammatory factors, morphology of microglia and astrocytes in rostral ventrolateral medulla (RVLM) were detected. In addition, blood-brain barrier (BBB) permeability, composition and metabolomics of the gut microbiome, and intestinal pathological manifestations were also measured. RESULTS: The serum acetate levels in SHRs are lower than in normotensive control rats. Supplementation with acetate reduces ABP, inhibits sympathetic nerve activity in SHRs. Furthermore, acetate suppresses RVLM neuroinflammation in SHRs, increases microglia and astrocyte morphologic complexity, decreases BBB permeability, modulates intestinal flora, increases fecal flora metabolites, and inhibits intestinal fibrosis. CONCLUSIONS: Microbiota-derived acetate exerts antihypertensive effects by modulating microglia and astrocytes and inhibiting neuroinflammation and sympathetic output.

Duck STING mediates antiviral autophagy directing the interferon signaling pathway to inhibit duck plague virus infection.

Migratory birds are important vectors for virus transmission, how migratory birds recognize viruses and viruses are sustained in birds is still enigmatic. As an animal model for waterfowl among migratory birds, studying and dissecting the antiviral immunity and viral evasion in duck cells may pave a path to deciphering these puzzles. Here, we studied the mechanism of antiviral autophagy mediated by duck STING in DEF cells. The results collaborated that duck STING could significantly enhance LC3B-II/I turnover, LC3B-EGFP puncta formation, and mCherry/EGFP ratio, indicating that duck STING could induce autophagy. The autophagy induced by duck STING is not affected by shRNA knockdown of ATG5 expression, deletion of the C-terminal tail of STING, or TBK1 inhibitor BX795 treatment, indicating that duck STING activated non-classical selective autophagy is independent of interaction with TBK1, TBK1 phosphorylation, and interferon (IFN) signaling. The STING R235A mutant and Sar1A/B kinase mutant abolished duck STING induced autophagy, suggesting binding with cGAMP and COPII complex mediated transport are the critical prerequisite. Duck STING interacted with LC3B through LIR motifs to induce autophagy, the LIR 4/7 motif mutants of duck STING abolished the interaction with LC3B, and neither activated autophagy nor IFN expression, indicating that duck STING associates with LC3B directed autophagy and dictated innate immunity activation. Finally, we found that duck STING mediated autophagy significantly inhibited duck plague virus (DPV) infection via ubiquitously degraded viral proteins. Our study may shed light on one scenario about the control and evasion of diseases transmitted by migratory birds.

Ascorbic acid protects retinal pigment epithelial cells from high glucose by inhibiting the NF-κB signal pathway through MALAT1/IGF2BP3 axis.

BACKGROUND: Diabetic retinopathy (DR) is a common complication of diabetes with nocuous effects on patients' eye health, typically accompanies by excessive inflammation and oxidative stress. Insulin-like growth factor-2 messenger RNA-binding protein 3 (IGF2BP3) was engaged with inflammation, whereas its precise role in the DR process was unclear. And enhanced lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and decreased ascorbic acid (AA) were also found in DR. This study was to explore the regulatory role and mechanism of IGF2BP3, MALAT1 and AA in the high glucose (HG)-induced retinal pigment epithelial (RPE) cell injury. METHODS: ARPE-19 cells were treated with HG to establish the in vitro RPE cell injury model. The mRNA and protein levels of the gene were evaluated by qRT-PCR or Western blot. Immunofluorescence detected the translocation condition of the p65 protein. Inflammatory factor levels were detected by ELISA assays. Apoptosis was detected by flow cytometry. The binding interaction of IGF2BP3 and MALAT1 was validated by RIP-qPCR assays. RESULTS: In HG-induced RPE cell injury, IGF2BP3 expression, inflammatory response and apoptosis were enhanced. Next, the IGF2BP3 activated the NF-κB signalling to promote the RPE cell injury development. MALAT1 could directly bind with IGF2BP3 and up-regulate its expression. In addition, AA ameliorated the HG-induced RPE cell injury through the regulation of MALAT1. CONCLUSION: Ascorbic acid ameliorated HG-induced RPE cell injury by repressing the NF-κB signalling pathway via modulating the MALAT1/IGF2BP3 axis.

Chronic intermittent hypobaric hypoxia ameliorates vascular reactivity through upregulating adiponectin expression of PVAT in metabolic syndrome rats.

Cumulating evidence demonstrated that chronic intermittent hypobaric hypoxia (CIHH) had beneficial effects on the body. This study investigated the role of perivascular adipose tissue (PVAT) in ameliorating effect of CIHH on vascular reactivity by adiponectin in mesenteric artery of metabolic syndrome (MS) rats. Main methods: 6-week-old male Sprague-Dawley rats were randomly divided into four groups: control (CON), MS model, CIHH treatment, and MS + CIHH treatment group. The size of adipocytes in PVAT was measured by scanning electron microscopy. Serum adiponectin was measured. The microvessel recording technique was used to observe the effect of CIHH on contraction and relaxation in mesenteric artery rings. Also, the expressions of interleukin-1ß, tumor necrosis factor-α, adiponectin, AdipoR1, AdipoR2, APPL1, and endothelial nitric oxide synthase (eNOS) were assayed by Western blotting. Key findings: in MS rats, adipocyte size increased, serum adiponectin decreased, contraction reaction increased while relaxation reaction decreased, the expression of pro-inflammatory cytokines was upregulated, while adiponectin was downregulated in PVAT, and the expressions of AdipoR1, AdipoR2, APPL, and phosphorylated-eNOS were downregulated in mesenteric artery. All aforementioned abnormalities of MS were ameliorated in MS + CIHH rats. We concluded that CIHH treatment improves vascular reactivity through upregulating adiponectin expression and downregulating pro-inflammatory cytokine expression of PVAT in MS rats.

Novel Advances in the Study of IgG4-Related Disease in the Eye and Ocular Adnexa.

Immunoglobin G4 (IgG4)-related disease in the eye and ocular adnexa (IgG4-ROD) is a newly discovered autoimmune disease that histologically exhibits extensive lymphocyte and plasma cell infiltration, occlusive phlebitis, and mat or whorled fibrosis. The disease can affect multiple ocular tissues and organs, such as the lacrimal gland, extraocular muscles, orbital fat, and trigeminal nerve. The main clinical manifestations are chronic, painless swelling of the orbit or unilateral orbit and proptosis, which may be accompanied by peripheral lymphadenopathy. Usually, visual impairment is not apparent, but in severe cases, it can cause a loss of function of the tissues and organs involved and affect the daily lives of patients. The pathogenesis of IgG4-ROD is not clear. Based on existing literature, it is speculated that it may be related to factors such as autoantibody production, microbial infection, and genetic inheritance. For the treatment of IgG4-ROD, glucocorticoids, immunosuppressive agents, biological agents, and surgery are mainly used in clinical practice. Although these treatment methods can achieve a particular effect, they have limitations, such as high recurrence rates, serious side effects, and postoperative complications. With the increase in IgG4-ROD-related reports, some progress has been made in the current understanding and research of the disease.

Adenosine mono-phosphate-activated protein kinase-mammalian target of rapamycin signaling participates in the protective effect of chronic intermittent hypobaric hypoxia on vascular endothelium of metabolic syndrome rats.

Our previous study demonstrated that chronic intermittent hypobaric hypoxia (CIHH) protects vascular endothelium function through ameliorating autophagy in mesenteric arteries of metabolic syndrome (MS) rats. This study aimed to investigate the role of adenosine mono-phosphate-activated protein kinase-mammalian target of rapamycin (AMPK-mTOR) signaling in CIHH effect. Six-week-old male Sprague-Dawley rats were divided into control (CON), MS model, CIHH treatment (CIHH), and MS + CIHH groups. Serum pro-inflammatory cytokines were measured. The endothelium dependent relaxation (EDR), endothelial ultrastructure and autophagosomes were observed in mesenteric arteries. The expression of phosphor (p)-AMPKα, p-mTOR, autophagy-related and endoplasmic reticulum stress-related proteins, p-endothelial nitric oxide synthase, and cathepsin D were assayed. In MS rats, pro-inflammatory cytokines were increased, EDR was attenuated, and endothelial integrity was impaired. In addition, the expression level of p-AMPKα and cathepsin D was down-regulated, but the level of p-mTOR was up-regulated. While in MS + CIHH rats, all aforementioned abnormalities were ameliorated, and the beneficial effect of CIHH was cancelled by AMPKα inhibitor. In conclusion, AMPK-mTOR signaling pathway participates in the protection of CIHH on vascular endothelium of MS rats.

Contribution of retrotrapezoid nucleus neurons to CO2 -amplified cardiorespiratory activity in spontaneously hypertensive rats.

KEY POINTS: This study demonstrates that both CO2 -induced respiratory and cardiovascular responses are augmented in spontaneously hypertensive rats (SHRs). Genetic ablation of the retrotrapezoid nucleus (RTN) neurons depresses enhanced hypercapnic ventilatory response and eliminates CO2 -stimulated increase in arterial pressure and heart rate in SHRs. SHRs have a high protein level of pH-sensitive channels in the RTN, including the TASK-2 channel, Kv12.1 channel and acid-sensing ion channel 3. The inhibition of putative TASK-2 channel activity by clofilium diminishes amplified hypercapnic ventilatory and cardiovascular responses, and reduces the number of CO2 -activated RTN neurons in SHRs. These results indicate that RTN neurons contribute to enhanced CO2 -stimulated respiratory and cardiovascular responses in SHRs. ABSTRACT: The respiratory regulation of cardiovascular activity is essential for maintaining an efficient ventilation and perfusion ratio. Activation of central respiratory chemoreceptors not only elicits a ventilatory response but also regulates sympathetic nerve activity and arterial blood pressure (ABP). The retrotrapezoid nucleus (RTN) is the most completely characterized cluster of central respiratory chemoreceptors. We hypothesize that RTN neurons contribute to augmented CO2 -stimulated respiratory and cardiovascular responses in adult spontaneously hypertensive rats (SHRs). Our findings indicate that SHRs exhibit more enhanced hypercapnic cardiorespiratory responses than age-matched normotensive Wistar-Kyoto rats. Genetic ablation of RTN neurons notably depresses an enhanced hypercapnic ventilatory response (HCVR) and eliminates a CO2 -stimulated greater increase in ABP and heart rate in SHRs. In addition, SHRs have a higher protein level of pH-sensitive channels in the RTN, including TASK-2 channels, Kv12.1 channels and acid-sensing ion channel 3. Administration of clofilium (i.p.), an unselective inhibitor of TASK-2 channels, not only significantly reduces the enhanced HCVR but also inhibits CO2 -amplified increases in ABP and heart rate in SHRs. Moreover, clofilium significantly decreases the number of CO2 -activated RTN neurons in SHRs. Taken together, we suggest that RTN neurons play an important role in enhanced hypercapnic ventilatory and cardiovascular responses in SHRs and the putative mechanism involved is associated with TASK-2 channel activity in the RTN.

Chronic intermittent hypobaric hypoxia attenuates ischemic limb injury by promoting angiogenesis in mice.

This study aimed to evaluate the protective effect of chronic intermittent hypobaric hypoxia (CIHH) against limb ischemic injury. C57BL/6 mice were randomly divided into three groups: limb ischemic injury group (Ischemia, induced by ligation and excision of the left femoral artery), limb ischemia following CIHH pretreatment group (CIHH+Ischemia, simulated a 5000 m altitude hypoxia, 6 h per day for 28 days, before induction of hind-limb ischemia), and sham group (Sham). The blood flow in the mouse models of hind-limb ischemia was examined using laser doppler imaging. The functional and morphological performance of ischemic muscle was evaluated using contraction force and hematoxylin-eosin and Masson's trichrome staining. Angiogenesis was determined by immunohistochemistry staining of the endothelial markers CD31 and CD34. The protein expressions of angiogenesis-related genes were detected using Western blot assay. Chronic ischemia resulted in reduced blood perfusion, decreased contraction tension, and morphological destruction in gastrocnemius muscle. CIHH pretreatment increased the contractile force and muscle fiber diameter and decreased necrosis and fibrosis of the ischemic muscle. Also, CIHH significantly increased the density of CD31+ and CD34+ cells and promoted the expression of angiogenesis-related molecules in ischemic muscle. These data demonstrate that CIHH has a protective effect against chronic limb ischemia by promoting angiogenesis.

Circ_0055625 knockdown inhibits tumorigenesis and improves radiosensitivity by regulating miR-338-3p/MSI1 axis in colon cancer.

BACKGROUND: Radiotherapy is a main therapeutic method for cancers, including colon cancer. In the current study, we aim to explore the effects of circular RNA (circRNA) circ_0055625 in the progression and radiosensitivity of colon cancer and the underlying mechanism. METHODS: The expression of circ_0055625 and musashi homolog 1 (MSI1) mRNA was detected by quantitative real-time polymerase chain reaction (qRT-PCR). MSI1 protein expression was determined by Western blot. Cell proliferation was assessed by cell counting kit-8 (CCK-8) and colony formation assays. Cell survival fraction, apoptosis, and invasion were investigated by colony formation assay, flow cytometry analysis, and transwell invasion assay, respectively. Cell migration was detected by wound-healing and transwell migration assays. The binding relationship between microRNA-338-3p (miR-338-3p) and circ_0055625 or MSI1 was predicted by online databases and identified by Dual-Luciferase Reporter Assay. The effects of circ_0055625 silencing on the tumor formation and radiosensitivity of colon cancer in vivo were explored by in vivo tumor formation assay. RESULTS: Circ_0055625 and MSI1 were upregulated in colon cancer tissues and cells relative to control groups. Radiation treatment apparently increased the expression of circ_0055625 and MSI1 in colon cancer cells. Circ_0055625 knockdown or MSI1 silencing repressed cell proliferation, migration, and invasion and promoted cell apoptosis and radiosensitivity in colon cancer. Also, circ_0055625 silencing-mediated effects were attenuated by MSI1 overexpression. Additionally, circ_0055625 silencing reduced MSI1 expression, which could be attenuated by miR-338-3p inhibitor. Mechanically, circ_0055625 acted as a sponge for miR-338-3p to regulate MSI1. Furthermore, circ_0055625 knockdown hindered tumor growth and improved radiosensitivity in vivo. CONCLUSION: Circ_0055625 repression inhibited the progression and radioresistance of colon cancer by downregulating MSI1 through sponging miR-338-3p. This result might provide a theoretical basis for improving the therapy of colon cancer with radiation.

The Kv12 voltage-gated K+ channels are expressed in the Phox2b-expressing neurons in the nucleus tractus solitarii in mice.

Accumulating evidence demonstrates that the nucleus tractus solitarii (NTS) neurons serve as central respiratory chemoreceptors, but the underlying molecular mechanisms remain undefined. The present study investigated the expression of acid-sensitive ether-à-go-go-gene-like (Elk, Kv12) channels in the NTS of mice. Immunofluorescence staining was used to observe the distribution and cellular localization of the Kv12 channels in NTS neurons. Western blot and quantitative real-time PCR (qPCR) were used to evaluate protein and mRNA expression levels of Kv12 channels. The results showed that all of the three members (Kv12.1, Kv12.2, Kv12.3) of the Kv12 channel family were expressed in NTS neurons, and their expressions were co-localized with paired-like homeobox 2b gene (Phox2b) expression. The expression of Kv12.1 mRNA was the largest, whereas the expression of Kv12.3 was the least in the NTS. The results suggest Kv12 channels are expressed in Phox2b-expressing neurons in the NTS of mice, which provides molecular evidence for pH sensitivity in Phox2b-expressing NTS neurons.

Activation of Phox2b-Expressing Neurons in the Nucleus Tractus Solitarii Drives Breathing in Mice.

The nucleus tractus solitarii (NTS) is implicated in the control of breathing, but the neuronal phenotype and circuit mechanism involved in such a physiological function remain incompletely understood. This study focused on the respiratory role of paired-like homeobox 2b gene (Phox2b)-expressing NTS neurons and sought to determine whether selective stimulation of this set of neurons activates breathing in male mice. A Cre-dependent vector encoding a Gq-coupled human M3 muscarinic receptor (hM3Dq) was microinjected into the NTS of Phox2b-Cre transgenic mice. The hM3Dq-transduced neurons were pharmacologically activated in conscious mice while respiratory effects were measured by plethysmography. We demonstrate that chemogenetic stimulation of Phox2b-expressing NTS neurons significantly increased baseline minute volume via an increase in respiratory frequency rather than tidal volume. Chemogenetic stimulation also synergized with moderate CO2 stimulation to enhance pulmonary ventilatory response. Selective ablation of Phox2b-expressing NTS neurons notably attenuated a hypercapnic ventilatory response. Moreover, histological evidence revealed that stimulation of Phox2b-expressing NTS neurons increased neuronal activity of the preBötzinger complex. Finally, we presented the neuroanatomical evidence of direct projection of Phox2b-expressing NTS neurons to putative respiratory central pattern generator. Overall, these findings suggest that selective activation of Phox2b-expressing NTS neurons potentiates baseline pulmonary ventilation via an excitatory drive to respiratory central pattern generator and this group of neurons is also required for the hypercapnic ventilatory response.SIGNIFICANCE STATEMENT The nucleus tractus solitarii (NTS) has been implicated in the control of breathing. The paired-like homeobox 2b gene (Phox2b) is the disease-defining gene for congenital central hypoventilation syndrome and is restrictively present in brainstem nucleus, including the NTS. Using a chemogenetic approach, we demonstrate herein that selective stimulation of Phox2b-expressing NTS neurons vigorously potentiates baseline pulmonary ventilation via an excitatory drive to respiratory central pattern generator in rodents. Genetic ablation of these neurons attenuates the hypercapnic ventilatory response. We also suggest that a fraction of Phox2b-expressing neurons exhibit CO2 sensitivity and presumably function as central respiratory chemoreceptors. The methodology is expected to provide a future applicability to the patients with sleep-related hypoventilation or apnea.

Amplified cardiorespiratory activity by hypoxia in conscious spontaneously hypertensive rats.

Activation of peripheral respiratory chemoreceptors provokes respiratory and cardiovascular reflexes, providing a novel understanding of pathogenic mechanism of hypertension. Here we hypothesize that activation of peripheral respiratory chemoreceptors by hypoxia causes enhanced cardiorespiratory activity in conscious spontaneously hypertensive rats (SHRs). Using whole body plethysmography in combination with radio telemetry, pulmonary ventilation, arterial blood pressure and heart rate were examined in SHRs and Wistar-Kyoto (WKY) rats. We found that exposure to hypoxia induced greater increases in tidal volume and minute ventilation volume in SHRs compared to WKY rats. In addition, hypoxia caused a robust increase in arterial blood pressure and heart rate in SHRs relative to WKY counterparts. After carotid body denervation, the hypoxic ventilatory response was significantly decreased in both SHRs and WKY rats, but without significant difference between the two strains; moreover, the differences of arterial blood pressure and heart rate changes during hypoxic exposure were statistically insignificant between SHRs and WKY rats. It is concluded that hypoxia remarkably potentiates cardiorespiratory activity in the SHRs, suggesting an enhanced sensitivity of carotid bodies to hypoxia.

Limb remote ischemia per-conditioning protects the heart against ischemia-reperfusion injury through the opioid system in rats.

Remote ischemia per-conditioning (RPerC) has been demonstrated to have cardiac protection, but the underlying mechanism remains unclear. This study aimed to investigate the mechanism underlying cardiac protection of RPerC. Adult male Sprague-Dawley rats were used in this study. Cardiac ischemia/reperfusion (I/R) was induced by 30 min of occlusion and 3 h of reperfusion of the left anterior descending coronary artery. RPerC were performed by 5 min of occlusion of the right femoral artery followed by 5 min of reperfusion for three times during cardiac ischemia. The hemodynamics, left ventricular function, arrhythmia, and infarct area were measured. Protein expression levels of endothelial nitric oxide synthase (eNOS), inducible NOS (iNOS), protein kinase C-ε (PKCε), and PKCδ in the myocardium were assayed. During I/R, systolic artery pressure and left ventricular function were decreased, infarct area was increased, and arrhythmia score was increased (P < 0.05). However, changes of the above parameters were significantly attenuated in RPerC-treated rats compared with control rats (P < 0.05). The cardiac protective effects of RPerC were prevented by naloxone or glibenclamide. Also, RPerC increased the protein expression levels of eNOS, iNOS, PKCε, and PKCδ in the myocardium compared with control rats. These effects were blocked by naloxone, an opioid receptor antagonist, and glibenclamide, an ATP-sensitive K+ channel blocker (KATP). In summary, this study suggests that RPerC protects the heart against I/R injury through activation of opioid receptors and the NO-PKC-KATP channel signaling pathways.

Depressive Effects of Chronic Intermittent Hypobaric Hypoxia on Renal Vascular Hypertension through Enhancing Baroreflex.

Baroreflex function plays a critical role in the maintenance of cardiovascular homeostasis and is impaired in different types of hypertension in both human and animals. Chronic intermittent hypobaric hypoxia (CIHH) facilitates baroreflex in anesthetized rats. The aim of present study was to investigate the effect of CIHH on arterial blood pressure (ABP) and baroreflex function in renal vascular hypertension (RVH) rats. Adult male Sprague-Dawley rats were randomly divided into four groups: Sham-operated (SHAM), RVH, CIHH treatment (CIHH), and RVH plus CIHH (RVH+CIHH) groups. RVH was induced by 2-kidney-1-clip method. CIHH rats experienced 28-day (6 h per day) hypobaric hypoxia simulating 5,000 m altitude in hypobaric chamber. Renal sympathetic nerve activity (RSNA), ABP and heart rate (HR) were recorded. Baroreflex was elicited by intravenous infusion of phenylephrine (PE, 25 µg/kg) and sodium nitroprusside (SNP, 10 µg/KG), respectively. Baroreflex curves were plotted by using RSNA or HR v.s. mean arterial pressure (MAP). The systolic ABP measured by tail-cuff method was significantly higher in RVH rats compared with SHAM rats. Furthermore, RSNA-MAP baroreflex curves were shifted to the right and upward with a decrease in baroreflex gain (Gmax) in RVH rats. CIHH treatment significantly decreased systolic ABP in RVH rats to the level in SHAM rats and shifted RSNA-MAP baroreflex curves to the left and downward with a normalized Gmax. These data suggest that CIHH treatment produces an anti-hypertensive effect in RVH rats, likely due to facilitating baroreflex function. Thus, CIHH represents a novel potential therapeutics to treat hypertension.

Beneficial Effects of Hypoxic Preconditioning on Human Umbilical Cord Mesenchymal Stem Cells.

As human umbilical cord mesenchymal stem cells (hUC-MSCs) transplanation may be promising in heart failure treatment, it is important to know whether hypoxic preconditioning (HP) promote hUC-MSCs proliferation and differentiation and protect them against chemical hypoxic damages. This study aimed to investigate the effects of HP on proliferation and differentiation of human umbilical cord mesenchymal stem cells (hUC-MSCs). The study also aimed to confirm our hypothesis that HP could promote hUC-MSCs proliferation and differentiation to cardiomyocyte-like cells as well as effectively protecting hUC-MSCs and cardiomyocyte-like cells against chemical hypoxic damages. Isolated hUC-MSCs were cultured in hypoxia at 1%, 3% and 5% O2 for 72 hours. 5-azacytidine (5-AZA) induced differentiation of hUC-MSCs to cardiomyocyte-like cells was determined by streptavidin-perosidase (SP) immunohistochemical staining and the content of troponin (TnI). Flow cytometry was used to measure cell cycle in hUC-MSCs and cardiomyocyte-like cells. The mitochondrial membrane potential (ΔΨ(m)) and mitochondrial Ca²âº concentration ([Ca²âº](m)), were measured in hUC-MSCs and cardiomyocyte-like cells during chemical hypoxia induced by cobalt chloride (100 µmol/L). HP optimally promoted the proliferation of hUC-MSCs at 3% O2 and enhanced the differentiation of hUC-MSCs to cardiomyocyte-like cells by 5-AZA in a concentration-dependent manner. The cell cycle distribution of cardiomyocyte-like cells, but not hUC-MSCs, was clearly changed by HP. Chemical hypoxic damage, decreased ΔΨ(m) and increased [Ca²âº](m), were alleviated significantly in HP-treated cells compared with the normaxia-treated cells. The results demonstrate that HP promoted hUC-MSCs proliferation and differentiation to cardiomyocyte-like cells, and protected both cell types against chemical hypoxic damage.

Clinical observation on removal of small foreign bodies touching the optic nerve in the deep orbital region: a case series.

PURPOSE: Five patients presented to our institution with deep intraorbital foreign bodies adjacent to the optic nerve. We removed all foreign bodies by lateral orbitotomy to evaluate the treatment and the benefits of their extraction. METHODS: The clinical outcomes of the five patients were retrospectively analyzed. RESULTS: Radiology in all five patients revealed small foreign bodies touching the optic nerve in the deep orbital region. All patients also suffered from significant secondary psychological disturbances, these including anxiety and altered sleep patterns. They had become preoccupied with a strong desire to remove the intraorbital foreign bodies [IFB]. In this cohort, two had no light perception before surgery, another two had light perception, and one had hand motion perception as well as vitreous hemorrhage that had been plugged with silicone oil in other hospital. All foreign bodies were removed via lateral orbitotomy. Visual acuity improved after the operation in only three cases. However, the psychological well-being of all five patients improved. CONCLUSIONS: Consideration should be given to removal of intraorbital foreign bodies adjacent to the optic nerve, even where a significant degree of vision has already been lost. Furthermore some patients can achieved vision improvement and such surgery can frequently address the significant psychological disturbance that can be associated with such orbital foreign bodies.

[Clinical observation on removal of small foreign bodies touching the optic nerve in the deep orbital region].

OBJECTIVE: To evaluate the treatment and therapeutic efficacy of extraction of deep intra-orbital little foreign bodies touching the optic nerve. METHODS: In this retrospective study, the clinical data of 5 deep intra-orbital little foreign bodies cases were recorded from 2008 to 2012 in Eye Center, PLA 474th Hospital. The treatment and therapeutic effect were analyzed. RESULT: The properties of the foreigen bodies in these 5 cases weremetallic in 4 cases and nonmetallic in 1 cases. The preoperative visual acurity were no light perception in 3 cases, light perception in 1 case, and hand movement in 1 case. The complications included vitreous hemorrhage which had been temponaded with silicon oil in other hospital (1 case), traumatic cataract, retinal and choroid detachment (1 case), traumatic retinal detachment and vitreous hemorrhage (2 cases). In all the cases, computed tomography (CT) indicated deep orbital foreign bodies touching the optic nerve, and clinical manifestations showed optic nerve injuries. The Foreign bodies were extracted successfully in all the cases. The postoperative visual acuity improved in 3 cases, however 2 cases remained blind. CONCLUSIONS: Carefully positioned with CT preoperatively, Deep intra-orbital little foreign bodies touching the optic nerve could be exctracted by lateral orbitotomy and the vision could improve in some patients.

Acid-sensing ion channel 1 in nucleus tractus solitarii neurons contributes to the enhanced CO2-stimulated cardiorespiratory effect in spontaneously hypertensive rats.

AIMS: Activation of central respiratory chemoreceptors provides excitatory drive to both respiratory and sympathetic outputs. The enhanced respiratory-sympathetic coupling contributes to the onset and development of hypertension. However, the specific central targets and molecular mechanisms involved in this process remain elusive. This study aimed to investigate the role of acid-sensing ion channel 1 (ASIC1) in nucleus tractus solitarii (NTS) neurons in CO2-stimulated cardiorespiratory effects in spontaneously hypertensive rats (SHRs). MAIN METHODS: Respiration and blood pressure of conscious rats were recorded by whole-body plethysmography and telemetry, respectively. Western blot was used to detect the expression difference of ASIC1 protein in NTS region between Wistar-Kyoto (WKY) rats and SHRs. Excitability of NTS neurons were assessed by extracellular recordings. KEY FINDINGS: Compared to WKY rats, the enhanced CO2-stimulated cardiopulmonary effect and up-regulation of ASIC1 in the NTS were already observed in 4-week-old prehypertensive SHRs. Furthermore, specific blockade of ASIC1 effectively attenuated the CO2-stimulated increase in firing rate of NTS neurons in anesthetized adult SHRs. Intracerebroventricular injections of the ASIC1a blocker PcTx1 or knockdown Asic1 in NTS neurons significantly reduced the heightened CO2-stimulated ventilatory response, and diminished the CO2-stimulated increase in arterial pressure and heart rate in adult SHRs. SIGNIFICANCE: These findings showed that dysregulated ASIC1 signaling in the NTS contribute to the exaggerated CO2-stimulated cardiorespiratory effects observed in SHRs.

Exosomal Circ_FMN2 Derived from the Serum of Colorectal Cancer Patients Promotes Cancer Progression by miR-338-3p/MSI1 Axis.

BACKGROUND: Colorectal cancer (CRC) is a common malignancy of the gastrointestinal tract with high incidence and mortality. Exosomal circular RNA (circRNA) has been shown to be associated with the malignant progression of cancers, including CRC. Circ_0005100 (named as circ_FMN2) has been shown to promote CRC cell proliferation and migration. However, whether exosomal circ_FMN2 participated in CRC progression remains unclear. METHODS: Exosomes were isolated from the serum of CRC patients and then identified using transmission electron microscope. Western blot assay was used to test the protein levels of exosome markers, proliferation-related marker, metastasis-related markers and musashi-1 (MSI1). The expression levels of circ_FMN2, microRNA (miR)-338-3p and MSI1 were detected by qPCR. Flow cytometry, colony formation assay, MTT assay, and transwell assay were employed to measure cell cycle, apoptosis, colony formation ability, viability, migration and invasion. Dual-luciferase reporter assay was performed to assess the interaction between miR-338-3p and circ_FMN2 or MSI1. BALB/c nude mice was used to conduct animal experiments. RESULTS: Circ_FMN2 was overexpressed in the exosomes of CRC patient's serums and CRC cells. Overexpressed exosomal circ_FMN2 could promote CRC cell proliferation, metastasis, and suppress apoptosis. Circ_FMN2 acted as miR-338-3p sponge. MiR-338-3p overexpression reversed the promotion effect of circ_FMN2 on CRC progression. MSI1 was found to be a target of miR-338-3p, and its overexpression revoked the inhibitory effect of miR-338-3p on CRC progression. Furthermore, exosomal circ_FMN2 overexpression also could facilitate CRC tumor growth in vivo. CONCLUSION: Exosomal circ_FMN2 accelerated CRC progression through miR-338-3p/MSI1 axis, revealing that exosomal circ_FMN2 might be a target for CRC treatment.