Background Irritable bowel syndrome (IBS) is a common functional disease characterized by chronic abdominal pain and changes in bowel movements. Effective therapy for visceral hypersensitivity in IBS patients remains challenging. This study investigated the roles of brain‐derived neurotrophic factor (BDNF) and tyrosine kinase receptor B (TrkB) and the effect of ANA‐12 (a selective antagonist of TrkB) on chronic visceral hypersensitivity in an IBS‐like rat model. Methods An IBS‐like rat model was established through neonatal maternal separation (NMS), and visceral hypersensitivity was assessed by electromyographic (EMG) responses of the abdominal external oblique muscles to colorectal distention (CRD). Different doses of ANA‐12 were injected intrathecally to investigate the effect of that drug on visceral hypersensitivity, and the open field test was performed to determine whether ANA‐12 had side effects on movement. Thoracolumbar spinal BDNF, TrkB receptor and Protein kinase Mζ (PKMζ) expression were measured to investigate their roles in chronic visceral hypersensitivity. Whole‐cell recordings were made from thoracolumbar superficial dorsal horn (SDH) neurons of lamina II. Results The expression of BDNF and TrkB was enhanced in the thoracolumbar spinal cord of the NMS animals. ANA‐12 attenuated visceral hypersensitivity without side effects on motricity in NMS rats. PKMζ expression significantly decreased after the administration of ANA‐12. The frequency of spontaneous excitatory postsynaptic currents (sEPSCs) increased in the thoracolumbar SDH neurons of lamina II in NMS rats. The amplitude and frequency of sEPSCs were reduced after perfusion with ANA‐12 in NMS rats. Conclusions Neonatal maternal separation caused visceral hypersensitivity and increased synaptic activity by activating BDNF‐TrkB‐PKMζ signalling in the thoracolumbar spinal cord of adult rats. PKMζ was able to potentiate AMPA receptor (AMPAR)‐mediated sEPSCs in NMS rats. ANA‐12 attenuated visceral hypersensitivity and synaptic activity by blocking BDNF/TrkB signalling in NMS rats. Significance ANA‐12 attenuates visceral hypersensitivity via BDNF‐TrkB‐PKMζ signalling and reduces synaptic activity through AMPARs in NMS rats. This knowledge suggests that ANA‐12 could represent an interesting novel therapeutic medicine for chronic visceral hypersensitivity.
Fibrosis caused by the increase in extracellular matrix in cardiac fibroblasts plays an important role in the occurrence and development of atrial fibrillation (AF). The aim of this study was to investigate the role of hsa-miR-4443 in AF, human cardiac fibroblast (HCFB) proliferation, and extracellular matrix remodeling. TaqMan Stem-loop miRNA assay was used to measure hsa-miR-4443 expression in patients with persistent AF (n=123) and healthy controls (n=100). Patients with AF were confirmed to have atrial fibrosis by late gadolinium enhancement. At the cellular level, after hsa-miR-4443 mimic and inhibitor were transfected with HCFBs, proliferation, apoptosis, migration, and invasion were analyzed. Lastly, hsa-miR-4443-targeted gene and transforming growth factor (TGF)-β1/α-SMA/collagen pathway were evaluated by dual-luciferase reporter assay and western blot, respectively. In patients with AF, hsa-miR-4443 decreased significantly and collagen metabolism level increased significantly. Logistic regression analysis showed that low hsa-miR-4443 level was a risk factor of AF (P<0.001). The receiver operating characteristic curve revealed that hsa-miR-4443 was useful for predicting AF (area under the curve: 0.828, sensitivity: 0.71, specificity: 0.78, P<0.001). In HCFBs, hsa-miR-4443 targeted thrombospondin-1 (THBS1) and downregulated TGF-β1/α-SMA/collagen pathway. The inhibition of hsa-miR-4443 expression promoted HCFB proliferation, migration, invasion, myofibroblast differentiation, and collagen production. The significant reduction of hsa-miR-4443 can be used as a biomarker for AF. hsa-miR-4443 protected AF by targeting THBS1 and regulated TGF-β1/α-SMA/collagen pathway to inhibit HCFB proliferation and collagen synthesis.
Background Controlled studies and observational studies have shown that sodium-glucose cotransporter type 2 inhibitors (SGLT-2i) are beneficial for the survival of patients with heart failure (HF). However, it is unclear whether SGLT-2i can provide benefit in patients with other cardiovascular diseases. Here, we conducted a systematic review and meta-analysis to determine the outcomes of cardiovascular, renal, and safety outcomes of SGLT-2i administration in patients with cardiovascular diseases. Methods We searched PubMed, EMBASE, Cochrane Library, Web of Science databases, and ClinicalTrials.gov databases for randomised controlled trials written in English from inception until November 1, 2020. Two reviewers independently identified randomised controlled trials comparing the effects of SGLT-2i in patients with cardiovascular disease with or without diabetes. Primary outcomes were cardiovascular outcomes and renal outcomes. Secondary outcomes were safety outcomes, including adverse endocrine outcomes and adverse infection outcomes. The effects of SGLT-2i were evaluated using RevMan5.3 software. The Cochrane risk of bias tool was used to assess study quality. Results We identified 10 randomised controlled trials (25,108 patients in the SGLT-2i group and 18,574 patients in the placebo group). Meta-analysis revealed that SGLT-2i treatment significantly reduced all-cause mortality, cardiovascular mortality, and hospitalisation for heart failure (HHF) in patients with cardiovascular disease (all-cause mortality relative risk [RR]: 0.86; 95% confidence interval [CI] 0.81–0.91; P < 0.00001; I2 = 0%; cardiovascular mortality RR: 0.85; 95% CI 0.79–0.92; P < 0.0001; I2 = 26%; HHF RR: 0.69; 95% CI 0.64–0.81; P < 0.00001; I2 = 0%). In patients with HF, mortality and HHF after SGLT-2i treatment for HF with reduced ejection fraction were significantly reduced, whereas HF with preserved ejection fraction did not differ compared with placebo treatment. Moreover, SGLT-2i induced a lower incidence of renal damage and myocardial infarction than the placebo group; however, the risk of infection, amputation, volume depletion, and diabetic ketoacidosis was higher. Conclusions SGLT-2i had significant clinical effects on cardiovascular outcomes and significantly influenced acute kidney injury. The effects of SGLT-2i on cardiovascular disease were independent of diabetic status. Sotagliflozin could have advantages over other SGLT-2i in lowering HHF.
BackgroundThe pathogenesis of multiple chronic visceral pain syndromes, such as irritable bowel syndrome (IBS), is not well known, and as a result current therapies are ineffective. The objective of this study was to investigate the effect of spinal protein kinase M zeta (PKMζ) on visceral pain sensitivity in rats with IBS to better understand the pathogenesis and investigate the effect of zeta inhibitory peptide (ZIP) as a therapy for chronic visceral pain.MethodsVisceral hypersensitivity rats were produced by neonatal maternal separation (NMS). Visceral pain sensitivity was assessed by electromyographic (EMG) responses of abdominal muscles to colorectal distention (CRD). Spinal PKMζ and phosphorylated PKMζ (p-PKMζ) were detected by western blot. Varying doses of ZIP were intrathecally administered to investigate the role of spinal PKMζ in chronic visceral hypersensitivity. The open field test was used to determine if ZIP therapy causes spontaneous motor activity side effects.ResultsGraded CRD pressure significantly increased EMG responses in NMS rats compared to control rats (p < 0.05). p-PKMζ expression increased in the thoracolumbar and lumbosacral spinal cord in the IBS-like rats with notable concomitant chronic visceral pain compared to control rats (p < 0.05). EMG data revealed that intrathecal ZIP injection (1, 5, and 10 μg) dose-dependently attenuated visceral pain hypersensitivity in IBS-like rats.ConclusionsPhosphorylated PKMζ may be involved in the spinal central sensitization of chronic visceral hypersensitivity in IBS, and administration of ZIP could effectively treat chronic visceral pain with good outcomes in rat models.
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