Diabetic cardiomyopathy (DCM) is a common diabetic complication characterized by diastolic relaxation abnormalities, myocardial fibrosis and chronic heart failure. Although TGF‐β/Smad3 signalling has ...been shown to play a critical role in chronic heart disease, the role and mechanisms of Smad3 in DCM remain unclear. We reported here the potential role of Smad3 in the development of DCM by genetically deleting the Smad3 gene from db/db mice. At the age of 32 weeks, Smad3WT‐db/db mice developed moderate to severe DCM as demonstrated by a marked increase in the left ventricular (LV) mass, a significant fall in the LV ejection fraction (EF) and LV fractional shortening (FS), and progressive myocardial fibrosis and inflammation. In contrast, db/db mice lacking Smad3 (Smad3KO‐db/db) were protected against the development of DCM with normal cardiac function and undetectable myocardial inflammation and fibrosis. Interestingly, db/db mice with deleting one copy of Smad3 (Smad3 ± db/db) did not show any cardioprotective effects. Mechanistically, we found that deletion of Smad3 from db/db mice largely protected cardiac Smad7 from Smurf2‐mediated ubiquitin proteasome degradation, thereby inducing IBα to suppress NF‐kB‐driven cardiac inflammation. In addition, deletion of Smad3 also altered Smad3‐dependent miRNAs by up‐regulating cardiac miR‐29b while suppressing miR‐21 to exhibit the cardioprotective effect on Smad3KO‐db/db mice. In conclusion, results from this study reveal that Smad3 is a key mediator in the pathogenesis of DCM. Targeting Smad3 may be a novel therapy for DCM.
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•Compound 1 displays a single excitation double emission in aqueous suspensions.•The luminescence properties of 1 was exploited as a multi-responsive luminescence sensor of nitrofuran ...antibiotics and triazine pesticides.•1 has been successfully used in the field of antibiotic and pesticide detection of dual-function test strips.
In recent years, there has been an increasing concern for health and food safety due to the severe environmental pollution caused by the overuse of antibiotics and pesticides. Effective and accurate detection of these species is of great importance in many fields. In this paper, a two-dimensional lanthanide organic framework Tb(dobpdc)1.5(DEA)2n (1) was synthesized using 4,4′-dihydroxy-3,3′-biphenyl dicarboxylic acid ligand (H2L) with Tb(III) ion in the atmosphere of N,N'-diethylacetamide (DEA) and deionized water as solvents by solvothermal method. Compound 1 displays a single excitation double emission in aqueous suspensions. The luminescence properties of 1 were exploited as a multi-responsive luminescence sensor for nitrofuran antibiotics (nitrofurazone, nitrofurantoin) and triazine pesticides (metamitron) with a low detection limit and high selectivity via dual emission “turn-off” luminescence quenching. 1 has also been successfully applied to the construction of portable test strips for the detection of antibiotics and pesticides. In addition, the mechanism of fluorescence quenching has also been further discussed.
Neonatal hypoxic-ischemic (HI) injury derived from asphyxia during perinatal period, is a serious complication of neonatal asphyxia and the main cause of neonatal acute death and chronic neurological ...injury. Aberrant autophagy occurs in many nervous system diseases, but its role and underlying mechanism in HI injury is largely unknown. Here, we successfully constructed a newborn rat model of HI brain injury, and the knockout-miR-127-3p (KO-miR-127-3p) rats were structured by using CRISPR/Cas9. Subsequently, the in vitro functional experiments, in vivo zea-longa scores, as well as bioinformatics analyses and biological experiments were applied. The expression of autophagy-related proteins, including ATG12, P62, Beclin-1, LC3II in HI cortex with miR-127-3p knockout was significantly decreased, and autophagic vacuoles were disappeared. Moreover, miR-127-3p has a specific regulatory effect on CISD1 expression, another crucial molecule in autophagy process. Accordingly, the overexpression of CISD1 effectively inhibited the autophagic cell death and physiological dysfunction in the brain of HI injury, whereas si-CISD1 reversed the neuroprotective effects of KO-miR-127-3p. Our findings explained the underlying mechanism for HI injury, and miR-127-3p targeting CISD1 signal could be supposed as a new treatment strategy to prevent and treat HI injury.
Neonatal hypoxic–ischaemic (HI) injury is a serious complication of neonatal asphyxia and the leading cause of neonatal acute death and chronic neurological injury, and the effective therapeutic ...method is lacking to improve patients' outcomes. We reported in this study that panax notoginseng saponin (PNS) may provide a treatment option for HI. HI model was established using neonatal Sprague–Dawley rats and then intraperitoneally injected with different dosage of PNS, once a day for 7 days. Histological staining and behavioural evaluations were performed to elucidate the pathological changes and neurobehavioural variation after PNS treatment. We found PNS administration significantly reduced the infarct volume of brain tissues and improved the autonomous activities of neonatal rats, especially with higher dosage. PNS treatment at 40 mg/kg reduced neuronal damage, suppressed neuronal apoptosis and depressed astroglial reactive response. Moreover, the long‐term cognitive and motor functions were also improved after PNS treatment at 40 mg/kg. Importantly, PNS treatment elevated the levels of BDNF and TrkB but decreased the expression of p75NTR both in the cortex and hippocampus of HI rats. The therapeutic efficacy of PNS might be correlated with PNS‐activated BDNF/TrkB signalling and inactivation of p75NTR expression, providing a novel potential therapy for alleviating HI injury.
PNS ameliorated the acute cerebral injury induced by HI in neonatal rats. PNS treatment suppressed the neuronal apoptosis in neonatal HI rats and alleviated GFAP‐mediated inflammatory response. The long‐term neurological dysfunctions in neonatal HI rats were relieved after PNS treatment.
Brain-derived neurotrophic factor (BDNF) regulates many neurological functions and plays a vital role during the recovery from central nervous system injuries. However, the changes in BDNF expression ...and associated factors following hypoxia-ischemia induced neonatal brain damage, and the significance of these changes are not fully understood. In the present study, a rat model of hypoxic-ischemic brain damage was established through the occlusion of the right common carotid artery, followed by 2 hours in a hypoxic-ischemic environment. Rats with hypoxic-ischemic brain damage presented deficits in both sensory and motor functions, and obvious pathological changes could be detected in brain tissues. The mRNA expression levels of BDNF and its processing enzymes and receptors (Furin, matrix metallopeptidase 9, tissue-type plasminogen activator, tyrosine Kinase receptor B, plasminogen activator inhibitor-1, and Sortilin) were upregulated in the ipsilateral hippocampus and cerebral cortex 6 hours after injury; however, the expression levels of these mRNAs were found to be downregulated in the contralateral hippocampus and cerebral cortex. These findings suggest that BDNF and its processing enzymes and receptors may play important roles in the pathogenesis and recovery from neonatal hypoxic-ischemic brain damage. This study was approved by the Animal Ethics Committee of the University of South Australia (approval No. U12-18) on July 30, 2018.
Poor β cell proliferation is one of the detrimental factors hindering islet cell replacement therapy for patients with diabetes. Smad3 is an important transcriptional factor of TGF-β signaling and ...has been shown to promote diabetes by inhibiting β cell proliferation. Therefore, we hypothesize that Smad3-deficient islets may be a novel cell replacement therapy for diabetes.
We examined this hypothesis in streptozocin-induced type-1 diabetic mice and type-2 diabetic db/db mice by transplanting Smad3 knockout (KO) and wild type (WT) islets under the renal capsule, respectively. The effects of Smad3KO versus WT islet replacement therapy on diabetes and diabetic kidney injury were examined. In addition, RNA-seq was applied to identify the downstream target gene underlying Smad3-regulated β cell proliferation in Smad3KO-db/db versus Smad3WT-db/db mouse islets.
Compared to Smad3WT islet therapy, treatment with Smad3KO islets produced a much better therapeutic effect on both type-1 and type-2 diabetes by significantly lowering serum levels of blood glucose and HbA1c and protected against diabetic kidney injuries by preventing an increase in serum creatinine and the development of proteinuria, mesangial matrix expansion, and fibrosis. These were associated with a significant increase in grafted β cell proliferation and blood insulin levels, resulting in improved glucose intolerance. Mechanistically, RNA-seq revealed that compared with Smad3WT-db/db mouse islets, deletion of Smad3 from db/db mouse islets markedly upregulated
, a pivotal regulator of cell cycle G1/S entry. Further studies found that Smad3 could bind to the promoter of
, and thus inhibit β cell proliferation
an E2F3-dependent mechanism as silencing
abrogated the proliferative effect on Smad3KO β cells.
Smad3-deficient islet replacement therapy can significantly improve both type-1 and type-2 diabetes and protect against diabetic kidney injury, which is mediated by a novel mechanism of E2F3-dependent β cell proliferation.
Transforming growth factor β (TGF-β)/Smad3 plays a vital role in hypertensive cardiac fibrosis. The long non-coding RNA (lncRNA) Erbb4-IR is a novel Smad3-dependent lncRNA that mediates kidney ...fibrosis. However, the role of Erbb4-IR in hypertensive heart disease remains unexplored and was investigated in the present study by ultrasound-microbubble-mediated silencing of cardiac Erbb4-IR in hypertensive mice induced by angiotensin II. We found that chronic angiotensin II infusion induced hypertension and upregulated cardiac Erbb4-IR, which was associated with cardiac dysfunction, including a decrease in left ventricle ejection fraction (LVEF) and LV fractional shortening (LVFS) and an increase in LV mass. Knockdown of cardiac Erbb4-IR by Erbb4-IR short hairpin RNA (shRNA) gene transfer effectively improved the angiotensin II-induced deterioration of cardiac function, although blood pressure was not altered. Furthermore, silencing cardiac Erbb4-IR also inhibited angiotensin II-induced progressive cardiac fibrosis, as evidenced by reduced collagen I and III, alpha-smooth muscle actin (α-SMA), and fibronectin accumulation. Mechanistically, improved hypertensive cardiac injury by specifically silencing cardiac Erbb4-IR was associated with increased myocardial Smad7 and miR-29b, revealing that Erbb4-IR may target Smad7 and miR-29b to mediate angiotensin II-induced hypertensive cardiac fibrosis. In conclusion, Erbb4-IR is pathogenic in angiotensin II (Ang II)-induced cardiac remodeling, and targeting Erbb4-IR may be a novel therapy for hypertensive cardiovascular diseases.
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Lan and colleagues find that lncRNA Erbb4-IR is a Smad3-dependent lncRNA and mediates angiotensin II-induced hypertensive cardiac fibrosis by suppressing cardiac Smad7 and miR-29b. Targeting cardiac Erbb4-IR can effectively attenuate cardiac fibrosis in a mouse model of hypertension.
Cardiac arrhythmia remains a major public health problem worldwide. Combinations of traditional medicine (TM) and conventional medicine (CM) have been used for arrhythmia treatment, yet the ...effectiveness and safety of many TM preparations can be controversial. We analyzed the safety and effectiveness of Zhigancao decoction (ZGCD) combined with metoprolol for arrhythmia treatment.
Systematic searches for randomized clinical trials (RCTs) were conducted in eight databases (January 2010-September 2020) without language restrictions. According to the Cochrane system evaluation method, the overall effectiveness and safety were evaluated by meta-analysis using Review Manager software (version 5.3), and publication bias was qualitatively analyzed using STATA 12.0.
A total of 39 RCTs were incorporated, including 4,260 patients with arrhythmia, with 2,133 patients in the experimental group (ZGCD + metoprolol, ZGCD + BB) and 2,127 patients in the control group (metoprolol only, BB). Meta-analysis revealed that compared with BB, ZGCD + BB could significantly increase the total efficacy (OR = 4.74, 95% CI: 3.78-5.94,
< 0.01) and lower the incidences of arrhythmia (MD = -3.39, 95% CI: -4.09 to -2.68,
< 0.01). Moreover, mean HR reductions were reported in patients receiving ZGCD + BB the ZGCD + BB group (MD = -8.48, 95% CI: -10.98 to -5.97,
< 0.01) and a decrease in TCM symptoms were reported also (MD = -2.92, 95% CI: -3.08 to -2.76,
< 0.01). The incidence of adverse events was lower in patients treated with ZGCD + BB (RR = 0.36, 95% CI: 0.26-0.51,
< 0.01). These results appeared consistent across common arrhythmias. Nevertheless, the majority of included studies were unable to be formally assessed for bias, and funnel-plot analysis implied a moderate risk of publication bias.
ZGCD + BB appeared to demonstrate good efficacy and fewer adverse reactions compared to BB in the treatment of arrhythmia, and this may represent a useful complementary therapy. However, our findings must be cautiously evaluated because of the small sample size and low quality of the clinic trials cited in the review. Rigorous and large-scale RCTs are warranted in the future to confirm these results.
https://inplasy.com/inplasy-2021-10-0045/.
Cardiovascular disease (CVD), including heart failure, myocardial fibrosis and myocardial infarction, etc, remains one of the leading causes of mortality worldwide. Evidence shows that miRNA plays an ...important role in the pathogenesis of CVD. miR-29 family is one of miRNA, and over the past decades, many studies have demonstrated that miR-29 is involved in maintaining the integrity of arteries and in the regulation of atherosclerosis, especially in the process of myocardial fibrosis. Besides, heart failure, myocardial fibrosis and myocardial infarction are inseparable from the regulatory role of miR-29. Here, we comprehensively review recent studies regarding miR-29 and CVD, illustrate the possibility of miR-29 as a potential marker for prevention, treatment and prognostic observation.
•miR-29 plays an important role in cardiovascular disease, and its regulatory function is almost omni-directional.•The role of miR-29 in myocardial fibrosis is currently a hot topic and he influence of the miR-29 family on fibrocyte activation and extracellular matrix overproduction have been studied in depth.•Both circulating miR-29 and miR-29 in tissues or cells are associated with the occurrence and development of cardiovascular diseases.•The therapeutic effect of miR-29 has been extensively studied, but its role in prevention and prognosis of disease remains to be proved.
Interleukin 10 (IL-10) is a synthetic inhibitor of human cytokines with immunomodulatory and anti-inflammatory effects. This study was designed to investigate the expression variation of IL-10 in the ...multiple sites including cortex, hippocampus, and lung tissues of neonatal hypoxic-ischemic (HI) rats and explore the crucial role of IL-10 in alleviating HI brain damage. In this study, neonatal Sprague-Dawley rats were subjected to the right common carotid artery ligation, followed by 2 h of hypoxia. The expression of IL-10 in the cortex, hippocampus, and lung tissues was measured with immunohistochemistry, real-time quantitative polymerase chain reaction (RT-qPCR), and western blot (WB). Immunofluorescence double staining was performed to observe the localization of IL-10 in neurons and astrocytes. Moreover, not-targeting and targeting IL-10 siRNA lentivirus vectors were injected into the rats of the negative control (NC) and IL-10 group, respectively, and the mRNA levels of B-cell lymphoma 2 (Bcl-2) and endoplasmic reticulum protein 29 (ERp29) were detected by RT-qPCR following IL-10 silence. The results demonstrated that the IL-10 expression was markedly increased after HI and IL-10 were colocalized with neurons and astrocytes which were badly injured by HI insult. In addition, Bcl-2 and ERp29 were remarkably decreased following IL-10 mRNA interference compared with the NC group. Our findings revealed that IL-10 exerted its antiapoptotic and neuroprotective effects by regulating the expression of Bcl-2 and ERp29, indicating that IL-10 may be a promising molecule target for HIE treatment.
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