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1.
Int J Mol Sci ; 22(17)2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34502202

RESUMO

Postmenopausal women with ovary hormone deficiency (OHD) are subject to overactive bladder (OAB) symptoms. The present study attempted to elucidate whether low-intensity extracorporeal shock wave therapy (LiESWT) alters bladder angiogenesis, decreases inflammatory response, and ameliorates bladder hyperactivity to influence bladder function in OHD-induced OAB in human clinical trial and rat model. The ovariectomized (OVX) for 12 months Sprague-Dawley rat model mimicking the physiological condition of menopause was utilized to induce OAB and assess the potential therapeutic mechanism of LiESWT (0.12 mJ/mm2, 300 pulses, and 3 pulses/second). The randomized, single-blinded clinical trial was enrolled 58 participants to investigate the therapeutic efficacy of LiESWT (0.25 mJ/mm2, 3000 pulses, 3 pulses/second) on postmenopausal women with OAB. The results revealed that 8 weeks' LiESWT inhibited interstitial fibrosis, promoted cell proliferation, enhanced angiogenesis protein expression, and elevated the protein phosphorylation of ErK1/2, P38, and Akt, leading to decreased urinary frequency, nocturia, urgency, urgency incontinence, and post-voided residual urine volume, but increased voided urine volume and the maximal flow rate of postmenopausal participants. In conclusion, LiESWT attenuated inflammatory responses, increased angiogenesis, and promoted proliferation and differentiation, thereby improved OAB symptoms, thereafter promoting social activity and the quality of life of postmenopausal participants.


Assuntos
Modelos Animais de Doenças , Tratamento por Ondas de Choque Extracorpóreas/métodos , Insuficiência Ovariana Primária/complicações , Qualidade de Vida , Regeneração , Bexiga Urinária Hiperativa/terapia , Bexiga Urinária/citologia , Adulto , Idoso , Animais , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Ratos , Ratos Sprague-Dawley , Método Simples-Cego , Bexiga Urinária Hiperativa/etiologia , Bexiga Urinária Hiperativa/patologia
2.
Medicina (Kaunas) ; 57(9)2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34577869

RESUMO

Background and Objectives: To evaluate the effects of low intensity extracorporeal shock wave therapy (LiESWT) on stress urinary incontinence (SUI). Materials and Methods: This investigation was a multicenter, single-blind, randomized-controlled trial study. Sixty female SUI patients were randomly assigned to receive LiESWT with 0.25 mJ/mm2 intensity, 3000 pulses, and 3 pulses/s, once weekly for a 4-week (W4) and 8-week (W8) period, or an identical sham LiESWT treatment without energy transmission. The primary endpoint was the changes in urine leakage as measured by a pad test and validated standardized questionnaires, while the secondary endpoint was the changes in a 3-day urinary diary among the baseline (W0), the W4 and W8 of LiESWT, and 1-month (F1), 3-month (F3), and 6-month (F6) follow-up after LiESWT. Results: The results showed that 4 weeks of LiESWT could significantly decrease urine leakage based on the pad test and validated standardized questionnaire scores, as compared to the sham group. Moreover, 8 weeks of LiESWT could significantly reduce urine leakage but increase urine volume and attenuate urgency symptoms, which showed meaningful and persistent improvement at W8, F1, F3, and F6. Furthermore, validated standardized questionnaire scores were significantly improved at W8, F1, F3, and F6 as compared to the baseline (W0). Conclusions: Eight weeks of LiESWT attenuated SUI symptoms upon physical activity, reduced urine leakage, and ameliorated overactive bladder symptoms, which implied that LiESWT significantly improved the quality of life. Our findings suggested that LiESWT could serve as a potentially novel and non-invasive treatment for SUI.


Assuntos
Tratamento por Ondas de Choque Extracorpóreas , Bexiga Urinária Hiperativa , Incontinência Urinária por Estresse , Feminino , Humanos , Qualidade de Vida , Método Simples-Cego , Resultado do Tratamento , Bexiga Urinária Hiperativa/terapia , Incontinência Urinária por Estresse/terapia
3.
Phytomedicine ; 92: 153734, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34536822

RESUMO

BACKGROUND: Neuropathic pain has been shown to be modulated by the activation of the chemokine C-X-C motif ligand 12 (CXCL12)/chemokine CXC receptor 4 (CXCR4) dependent nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome. Loganin, an iridoid glycoside, was proven to prevent neuropathic pain, but its underlying mechanisms related to NLRP3 activation are still unknown. PURPOSE: This study investigated the underlying mechanisms of loganin's effect on chronic constriction injury (CCI)-induced NLRP3 inflammasome activation in the spinal cord. METHODS: Sprague-Dawley rats were randomly divided into four groups: sham, CCI, sham + loganin, and CCI + loganin. Loganin (5 mg/kg/day) was administered intraperitoneally starting the day after surgery. Paw withdrawal threshold (PWT) and latency (PWL) were assessed before CCI and on days 1, 3, 7 and 14 after CCI. Spinal cords were collected for western blots and immunofluorescence studies. RESULTS: Loganin prevented CCI-attenuated PWT and PWL, suggesting improved mechanical allodynia and thermal hyperalgesia. The expression of CXCL12, CXCR4, thioredoxin-interacting protein (TXNIP), NLRP3 inflammasome (NLRP3, ASC, and caspase-1), IL-1ß, and IL-18 were enhanced on day 7 after CCI, and all were reduced after loganin treatment. Dual immunofluorescence also showed that increased CXCL12, CXCR4, and NLRP3 were colocalized with NeuN (neuronal marker), GFAP (astrocyte marker), and Iba1 (microglial marker) on day 7 in the ipsilateral spinal dorsal horn (SDH). These immunoreactivities were attenuated in loganin-treated rats. Moreover, loganin decreased the assembly of NLRP3/ASC inflammasome after CCI in the ipsilateral SDH. Loganin appears to attenuate CCI-induced neuropathic pain by suppressing CXCL12/CXCR4-mediated NLRP3 inflammasome. CONCLUSION: Our findings suggest that loganin might be a suitable candidate for managing CCI-provoked neuropathic pain.

4.
Int J Mol Sci ; 22(11)2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-34198942

RESUMO

Empagliflozin (EMPA) is a sodium-glucose transporter 2 (SGLT2) inhibitor that functions as a new-generation glucose-lowering agent and has been proven to be beneficial for patients with cardiovascular diseases. However, the possible benefits and mechanisms of its antiarrhythmic effects in cardiac tissue have not yet been reported. In this study, we elucidated the possible antiarrhythmic effects and mechanisms of EMPA treatment in cardiac tissues of metabolic syndrome (MS) mice. A total of 20 C57BL/6J mice (age: 8 weeks) were divided into four groups: (1) control group, mice fed a standard chow for 16 weeks; (2) MS group, mice fed a high-fat diet for 16 weeks; (3) EMPA group, mice fed a high-fat diet for 12 weeks and administered EMPA at 10 mg/kg daily for the following 4 weeks; and (4) glibenclamide (GLI) group, mice fed a high-fat diet for 12 weeks and administered GLI at 0.6 mg/kg daily for the following 4 weeks. All mice were sacrificed after 16 weeks of feeding. The parameters of electrocardiography (ECG), echocardiography, and the effective refractory period (ERP) of the left ventricle were recorded. The histological characteristics of cardiac tissue, including connexin (Cx) expression and fibrotic areas, were also evaluated. Compared with the MS group, the ECG QT interval in the EMPA group was significantly shorter (57.06 ± 3.43 ms vs. 50.00 ± 2.62 ms, p = 0.011). The ERP of the left ventricle was also significantly shorter in the EMPA group than that in the GLI group (20.00 ± 10.00 ms vs. 60.00 ± 10.00 ms, p = 0.001). The expression of Cx40 and Cx43 in ventricular tissue was significantly lower in the MS group than in the control group. However, the downregulation of Cx40 and Cx43 was significantly attenuated in the EMPA group compared with the MS and GLI groups. The fibrotic areas of ventricular tissue were also fewer in the EMPA group than that in the MS group. In this study, the ECG QT interval in the EMPA group was shorter than that in the MS group. Compared with the MS group, the EMPA group exhibited significant attenuation of downregulated connexin expression and significantly fewer fibrotic areas in ventricles. These results may provide evidence of possible antiarrhythmic effects of EMPA.


Assuntos
Compostos Benzidrílicos/farmacologia , Doenças Cardiovasculares/tratamento farmacológico , Conexina 43/genética , Conexinas/genética , Glucosídeos/farmacologia , Transportador 2 de Glucose-Sódio/genética , Animais , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/patologia , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Ecocardiografia , Eletrocardiografia , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Glibureto/farmacologia , Humanos , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/genética , Camundongos , Transportador 2 de Glucose-Sódio/efeitos dos fármacos
5.
Cells ; 10(4)2021 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-33923953

RESUMO

This study explored whether KMUP-1 improved chronic constriction injury (CCI)-induced BKCa current inhibition in dorsal root ganglion (DRG) neurons. Rats were randomly assigned to four groups: sham, sham + KMUP-1, CCI, and CCI + KMUP-1 (5 mg/kg/day, i.p.). DRG neuronal cells (L4-L6) were isolated on day 7 after CCI surgery. Perforated patch-clamp and inside-out recordings were used to monitor BKCa currents and channel activities, respectively, in the DRG neurons. Additionally, DRG neurons were immunostained with anti-NeuN, anti-NF200 and anti-BKCa. Real-time PCR was used to measure BKCa mRNA levels. In perforated patch-clamp recordings, CCI-mediated nerve injury inhibited BKCa currents in DRG neurons compared with the sham group, whereas KMUP-1 prevented this effect. CCI also decreased BKCa channel activity, which was recovered by KMUP-1 administration. Immunofluorescent staining further demonstrated that CCI reduced BKCa-channel proteins, and KMUP-1 reversed this. KMUP-1 also changed CCI-reduced BKCa mRNA levels. KMUP-1 prevented CCI-induced neuropathic pain and BKCa current inhibition in a peripheral nerve injury model, suggesting that KMUP-1 could be a potential agent for controlling neuropathic pain.

6.
J Pharm Pharmacol ; 73(6): 835-845, 2021 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-33779726

RESUMO

OBJECTIVES: Eugenosedin-A (Eu-A), an adrenergic and serotonergic antagonist, is known to have anti-metabolic syndrome effects. In this study, we evaluated its protective effects against diabetes mellitus (DM) in spontaneous hypertensive rats (SHR) and compared it with two anti-diabetes medications, glibenclamide (Gli) and pioglitazone (Pio). METHODS: We divided 10-week-old SHRs into five groups: a control group fed a normal diet; an untreated DM group induced by injecting the SHRs with STZ/NA and feeding them a high-fat diet (HFD); and three treated groups (after giving STZ/NA and HFD) gavage given with Eu-A, Gli or Pio (5 mg/kg per day) for 4 weeks. KEY FINDINGS: The untreated DM group weighed less and had hyperglycaemia, hypoinsulinemia and hyperlipidemia. They were also found to have aberrant glucose-dependent insulin pathways, glucose metabolism and lipid synthesis proteins, while the controls did not. Eu-A, Gli and Pio ameliorated the above biochemical parameters in the treatment groups. Eu-A and Pio, but not Gli, improved hypertension and tachycardia. CONCLUSIONS: Taken together, Eu-A ameliorated DM, hypertension and tachycardia by improving glucose, lipid homeostasis and anti-adrenergic, serotonergic activities. We concluded that Eu-A could be used in the development of an effective agent for controlling DM and its complications.

7.
Int J Med Sci ; 17(16): 2594-2602, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33029102

RESUMO

Pulmonary hypertension (PH) is a lethal and rapidly progressing disorder if left untreated, but there is still no definitive therapy. An imbalance between vasoconstriction and vasodilation has been proposed as the mechanism underlying PH. Among the vasomediators of the pulmonary circulation is the renin-angiotensin system (RAS), the involvement of which in the development of PH has been proposed. Within the RAS, angiotensin-converting enzyme 2 (ACE2), which converts angiotensin (Ang) II into Ang-(1-7), is an important regulator of blood pressure, and has been implicated in cardiovascular disease and PH. In this study, we investigated the effects of the ACE2 activator diminazene aceturate (DIZE) on the development of PH secondary to left ventricular dysfunction. A model of PH secondary to left ventricular dysfunction was established in 6-week-old Wistar rats by ascending aortic banding for 42 days. The hemodynamics and pulmonary expression of ACE, Ang II, ACE2, Ang-(1-7), and the Ang-(1-7) MAS receptor were investigated in the early treatment group, which was administered DIZE (15 mg/kg/day) from days 1 to 42, and in the late treatment group, administered DIZE (15 mg/kg/day) from days 29 to 42. Sham-operated rats served as controls. DIZE ameliorated mean pulmonary artery pressure, pulmonary arteriolar remodeling, and plasma brain natriuretic peptide levels, in addition to reversing the overexpression of ACE and up-regulation of both Ang-(1-7) and MAS, in the early and late treatment groups. DIZE has therapeutic potential for preventing the development of PH secondary to left ventricular dysfunction through ACEII activation and the positive feedback of ANG-(1-7) on the MAS receptor. A translational study in humans is needed to substantiate these findings.

8.
Antioxidants (Basel) ; 9(10)2020 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-33036258

RESUMO

Vascular calcification (VC) is highly prevalent in patients with atherosclerosis, chronic kidney disease, diabetes mellitus, and hypertension. In blood vessels, VC is associated with major adverse cardiovascular events. Xanthohumol (XN), a main prenylated chalcone found in hops, has antioxidant effects to inhibit VC. This study aimed to investigate whether XN attenuates VC through in vivo study. A rat VC model was established by four weeks oral administration of vitamin D3 plus nicotine in Sprague Dawley (SD) rats. In brief, 30 male SD rats were randomly divided into three groups: control, 25 mg/kg nicotine in 5 mL corn oil and 3 × 105 IU/kg vitamin D3 administration (VDN), and combination of VDN with 20 mg/L in 0.1% ethanol of XN (treatment group). Physiological variables such as body and heart weight and drinking consumption were weekly observed, and treatment with XN caused no differences among the groups. In comparison with the control group, calcium content and alkaline phosphatase (ALP) activity were increased in calcified arteries, and XN treatment reduced these levels. Dihydroethidium (DHE) and 2',7'-dichloroflurescin diacetate (DCFH-DA) staining to identify Superoxide and reactive oxygen species generation from aorta tissue showed increased production in VDN group compared with the control and treatment groups. Hematoxylin eosin (HE) and Alizarin Red S staining were determined to show medial vascular thickness and calcification of vessel wall. Administration of VDN resulted in VC, and XN treatment showed improvement in vascular structure. Moreover, overexpression of osteogenic transcription factors bone morphogenetic protein 2 (BMP-2) and runt-related transcription factor 2 (Runx2) were significantly suppressed by XN treatment in VC. Moreover, downregulation of vascular phenotypic markers alpha-smooth muscle actin (α-SMA) and smooth muscle 22 alpha (SM22α) were increased by XN treatment in VC. Furthermore, XN treatment in VC upregulated nuclear translocation of nuclear factor-E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) expressions. Otherwise, Kelch-like ECH-associated protein 1 (Keap1) was alleviated by XN treatment in VC. In conclusion, our findings suggested that XN enhances antioxidant capacity to improve VC by regulating the Nrf2/Keap1/HO-1 pathway. Therefore, XN may have potential effects to decrease cardiovascular risk by reducing VC.

9.
Cells ; 9(9)2020 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-32842536

RESUMO

Diabetic peripheral neuropathy (DPN) is caused by hyperglycemia, which induces oxidative stress and inflammatory responses that damage nerve tissue. Excessive generation of reactive oxygen species (ROS) and NOD-like receptor protein 3 (NLRP3) inflammasome activation trigger the inflammation and pyroptosis in diabetes. Schwann cell dysfunction further promotes DPN progression. Loganin has been shown to have antioxidant and anti-inflammatory neuroprotective activities. This study evaluated the neuroprotective effect of loganin on high-glucose (25 mM)-induced rat Schwann cell line RSC96 injury, a recognized in vitro cell model of DPN. RSC96 cells were pretreated with loganin (0.1, 1, 10, 25, 50 µM) before exposure to high glucose. Loganin's effects were examined by CCK-8 assay, ROS assay, cell death assay, immunofluorescence staining, quantitative RT-PCR and western blot. High-glucose-treated RSC96 cells sustained cell viability loss, ROS generation, NF-κB nuclear translocation, P2 × 7 purinergic receptor and TXNIP (thioredoxin-interacting protein) expression, NLRP3 inflammasome (NLRP3, ASC, caspase-1) activation, IL-1ß and IL-18 maturation and gasdermin D cleavage. Those effects were reduced by loganin pretreatment. In conclusion, we found that loganin's antioxidant effects prevent RSC96 Schwann cell pyroptosis by inhibiting ROS generation and suppressing NLRP3 inflammasome activation.


Assuntos
Glucose/efeitos adversos , Inflamassomos/metabolismo , Iridoides/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Piroptose/efeitos dos fármacos , Células de Schwann/metabolismo , Animais , Humanos , Ratos
10.
Molecules ; 25(16)2020 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-32784369

RESUMO

Sodium-glucose transporter 2 (SGLT2) inhibitors were shown to decrease mortality from cardiovascular diseases in the EMPA-REG trial. However, the effects of empagliflozin (EMPA) for cardiac arrhythmia are not yet clarified. A total of 20 C57BL/6J mice were divided into four groups: (1) The control group were fed standard chow, (2) the metabolic syndrome (MS) group were fed a high-fat diet, (3) the empagliflozin (EMPA) group were fed a high-fat diet and empagliflozin 10 mg/kg daily, and (4) the glibenclamide (GLI) group were fed a high-fat diet and glibenclamide 0.6 mg/kg daily. All mice were sacrificed after 16 weeks of feeding. H9c2 cells were treated with adipocytokines from the pericardial and peripheral fat from the study groups. The delayed-rectifier potassium current (IK) and L-type calcium channel current (ICa,L) were measured by the whole-cell patch clamp techniques. Adipocytokines from the peripheral and pericardial fat tissues of mice with MS could decrease the IK and increase the ICa,L of cardiomyocytes. After treating adipocytokines from pericardial fat, the IK in the EMPA and GLI groups were significantly higher than that in the MS group. The IK of the EMPA group was also significantly higher than the GLI group. The ICa,L of the EMPA and GLI groups were significantly decreased overload compared with that of the MS group. However, there was no significant difference of IK and ICa,L among study groups after treating adipocytokines from peripheral fat. Adipocytokines from pericardial fat but not peripheral fat tissues after EMPA therapy attenuated the effects of IK decreasing and ICa,L increasing in the MS cardiomyocytes, which may contribute to anti-arrhythmic mechanisms of sodium-glucose transporter 2 (SGLT2) inhibitors.


Assuntos
Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Adipocinas/metabolismo , Animais , Compostos Benzidrílicos/farmacologia , Peso Corporal/efeitos dos fármacos , Linhagem Celular , Glucosídeos/farmacologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL
11.
J Tradit Complement Med ; 10(4): 378-388, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32695655

RESUMO

Background and aim: Centella asiatica, Justicia gendarussa and Imperata cylindrica decoction (CJID) is efficacious for hypertension. NADPH (nicotinamide adenine dinucleotide phosphate) oxidase (NOX)-induced reactive oxygen species (ROS) generation modulates nuclear factor kappa B (NF-κB) activation and thus mediates hypertension-induced vascular remodeling. This research aims to investigate the anti-remodeling effect of CJID through the mechanism of NOXs-ROS-NF-κB pathway in spontaneously hypertensive rats (SHRs). Experimental procedure: CJID was orally administered once a day for five weeks in SHRs and normotensive-WKY (Wistar Kyoto) rats. All rats were sacrificed at the end of study and different assays were performed to determine whether CJID ameliorates vascular remodeling in SHRs, such as histological examination; lactate dehydrogenase (LDH), nitric oxide (NO), malondialdehyde (MDA) and superoxide dismutase (SOD) assays; superoxide and hydrogen peroxide (H2O2) generation assays, immunohistochemistry and immunofluorescence assays. . Changes in levels of inducible nitric oxide synthase (iNOS), NF-κB-p65, NF-κB inhibitor alpha/IκBα (inhibitory kappa B- alpha), phosphorylation of IκBα (p-IκBα) and NOX1, NOX2, NOX4 in the thoracic aorta were determined. Results: Vascular remodeling indicators, media thickness, collagen and elastic accumulation in the thoracic aorta, of SHRs-treated CJID were attenuated. Redox homeostasis, aortic superoxide and hydrogen peroxide generation were decreased in SHRs-treated group. Aortic iNOS, p-IκBα, NF-κB-p65 and NOX1, NOX2, NOX4 expressions were suppressed. Conclusions: CJI treatment diminishes oxidative stress response in the thoracic aorta of SHRs via regulation of NOXs-ROS-NF-κB signaling pathway. These findings indicate that CJI possess protective effect against hypertension-induced vascular remodeling in SHRs.

12.
Sci Rep ; 10(1): 5771, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32238829

RESUMO

Household air pollution has adverse effects on cardiovascular health. One of the major sources of household air pollutants is the combustion of cooking oils during cooking. Trans, trans-2,4-decadienal (tt-DDE) is a type of dienaldehyde that is present in a wide range of food and food products. It is a byproduct of the peroxidation of linoleic acid following the heating of oil during cooking. The mechanisms of the associations between household air pollution and cardiac arrhythmias are currently unclear. The purpose of this study was to determine effects of tt-DDE on the ion currents in H9c2 cells. The IK and ICa,L in H9c2 cells treated with and without tt-DDE were measured using the whole-cell patch clamp method. Expressions of Kv2.1 and Cav1.2 in H9c2 cells treated with and without tt-DDE were measured by western blot analysis. After the H9c2 cells had been exposed to tt-DDE, the IK and ICa,L were significantly decreased. The expression of Kv2.1, unlike that of Cav1.2, was also significantly decreased in these cells. These changes in IK and ICa,L that were induced by tt-DDE may help to explain the association between cardiac arrhythmogenesis and cooking-oil fumes.


Assuntos
Poluição do Ar em Ambientes Fechados/efeitos adversos , Aldeídos/efeitos adversos , Miócitos Cardíacos/efeitos dos fármacos , Óleos/efeitos adversos , Poluentes Atmosféricos/efeitos adversos , Animais , Arritmias Cardíacas/etiologia , Arritmias Cardíacas/metabolismo , Canais de Cálcio Tipo L/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Culinária , Humanos , Transporte de Íons/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Ratos , Canais de Potássio Shab/metabolismo
13.
Sci Rep ; 10(1): 5818, 2020 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-32242035

RESUMO

This study aimed to evaluate the therapeutic effects of Low intensity extracorporeal low energy shock wave therapy (LiESWT) on stress urinary incontinence (SUI). The investigation was a single-arm, open-label, multicentre study conducted in Taiwan. 50 female patients with SUI received LiESWT-treated with 0.25 mJ/mm2 intensity, 3000 pulses, and 3 pulses/second, once weekly for 4-weeks (W4) and 8-weeks (W8). The pad test, uroflowmetry, life quality questionnaires, and 3-day urinary diary measurement were performed before and after LiESWT intervention. The results revealed that 8-week of LiESWT treatment meaningfully improved urine leakage (pad test), maximum flow rate, post-voided residual urine, average urine volume, functional bladder capacity, urinary frequency, urgency symptom, and nocturia, which also persisted to show significant improvements at 1-month follow up (F1). Moreover, bothersome questionnaires scores were significantly improved at W4, W8, and F1 as compared to the baseline (W0). These results indicated that 8 weeks of LiESWT attenuated SUI symptoms on physical activity, reduced bladder leaks and overactive bladder (OAB), implying that LiESWT brought significant improvement in the quality of life. (ClinicalTrials.gov number, NCT04059133).


Assuntos
Incontinência Urinária por Estresse/terapia , Adulto , Idoso , Tratamento por Ondas de Choque Extracorpóreas/métodos , Feminino , Humanos , Pessoa de Meia-Idade , Noctúria/fisiopatologia , Qualidade de Vida , Inquéritos e Questionários , Taiwan , Resultado do Tratamento , Bexiga Urinária/fisiopatologia , Bexiga Urinária Hiperativa/fisiopatologia , Incontinência Urinária por Estresse/fisiopatologia , Adulto Jovem
14.
Phytomedicine ; 67: 153166, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31955133

RESUMO

BACKGROUND: Peripheral nerve injury can produce chronic and ultimately neuropathic pain. The chronic constriction injury (CCI) model has provided a deeper understanding of nociception and chronic pain. Loganin is a well-known herbal medicine with glucose-lowering action and neuroprotective activity. PURPOSE: This study investigated the molecular mechanisms by which loganin reduced CCI-induced neuropathic pain. METHODS: Sprague-Dawley rats were randomly divided into four groups: sham, sham+loganin, CCI and CCI+loganin. Loganin (1 or 5 mg/kg/day) was injected intraperitoneally once daily for 14 days, starting the day after CCI. For behavioral testing, mechanical and thermal responses were assessed before surgery and on d1, d3, d7 and d14 after surgery. Sciatic nerves (SNs) were collected to measure proinflammatory cytokines. Proximal and distal SNs were collected separately for Western blotting and immunofluorescence studies. RESULTS: Thermal hyperalgesia and mechanical allodynia were reduced in the loganin-treated group as compared to the CCI group. Loganin (5 mg/kg/day) prevented CCI from inducing proinflammatory cytokines (TNF-α, IL-1ß), inflammatory proteins (TNF-α, IL-1ß, pNFκB, pIκB/IκB, iNOS) and receptor (TNFR1, IL-1R), adaptor protein (TRAF2) of TNF-α, and Schwann cell demyelination and axonal damage. Loganin also blocked IκB phosphorylation (p-IκB). Double immunofluorescent staining further demonstrated that pNFκB/pIκB protein was reduced by loganin in Schwann cells on d7 after CCI. In the distal stumps of injured SN, Schwann cell demyelination was correlated with pain behaviors in CCI rats. CONCLUSION: Our findings indicate that loganin improves CCI-induced neuroinflammation and pain behavior by downregulating TNF-α/IL-1ß-dependent NF-κB activation.


Assuntos
Analgésicos não Narcóticos/farmacologia , Iridoides/farmacologia , NF-kappa B/metabolismo , Neuralgia/tratamento farmacológico , Células de Schwann/efeitos dos fármacos , Animais , Dor Crônica/tratamento farmacológico , Dor Crônica/metabolismo , Dor Crônica/patologia , Constrição , Citocinas/metabolismo , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Hiperalgesia/patologia , Interleucina-1beta/metabolismo , Masculino , Neuralgia/metabolismo , Neuralgia/patologia , Ratos Sprague-Dawley , Células de Schwann/metabolismo , Células de Schwann/patologia , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
15.
J Clin Med ; 8(6)2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31226824

RESUMO

Individuals with metabolic syndrome (MetS) are at high risk for atrial myopathy and atrial fibrillation. Very low-density lipoproteins (VLDLs) of MetS (MetS-VLDLs) are cytotoxic to atrial myocytes in vivo and in vitro. The calcineurin-nuclear factor of activated T-cells (NFAT) pathway, which is regulated by stromal interaction molecule 1 (STIM1)/ calcium release-activated calcium channel protein 1 (Orai1)-mediated store-operated Ca2+ entry (SOCE), is a pivotal mediator of adaptive cardiac hypertrophy. We hypothesized that MetS-VLDLs could affect SOCE and the calcineurin-NFAT pathway. Normal-VLDL and MetS-VLDL samples were isolated from the peripheral blood of healthy volunteers and individuals with MetS. VLDLs were applied to HL-1 atrial myocytes for 18 h and were also injected into wild-type C57BL/6 male mouse tails three times per week for six weeks. After the sarcoplasmic reticulum (SR) Ca2+ store was depleted, SOCE was triggered upon reperfusion with 1.8 mM of Ca2+. SOCE was attenuated by MetS-VLDLs, along with reduced transcriptional and membranous expression of STIM1 (P = 0.025), and enhanced modification of O-GlcNAcylation on STIM1 protein, while Orai1 was unaltered. The nuclear translocation and activity of calcineurin were both reduced (P < 0.05), along with the alteration of myofilament proteins in atrial tissues. These changes were absent in normal-VLDL-treated cells. Our results demonstrated that MetS-VLDLs suppressed SOCE by modulating STIM1 at the transcriptional, translational, and post-translational levels, resulting in the inhibition of the calcineurin-NFAT pathway, which resulted in the alteration of myofilament protein expression and sarcomere derangement in atrial tissues. These findings may help explain atrial myopathy in MetS. We suggest a therapeutic target on VLDLs to prevent atrial fibrillation, especially for individuals with MetS.

16.
Molecules ; 24(7)2019 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-30965668

RESUMO

To test whether KMUP-1 (7-[2-[4-(2-chlorophenyl) piperazinyl]ethyl]-1,3-dimethylxanthine) prevents myocardial ischemia-induced apoptosis, we examined KMUP-1-treated H9c2 cells culture. Recent attention has focused on the activation of nitric oxide (NO)-guanosine 3', 5'cyclic monophosphate (cGMP)-protein kinase G (PKG) signaling pathway triggered by mitogen-activated protein kinase (MAPK) family, including extracellular-signal regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), and p38 in the mechanism of cardiac protection during ischemia-induced cell-death. We propose that KMUP-1 inhibits ischemia-induced apoptosis in H9c2 cells culture through these pathways. Cell viability was assessed using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and apoptotic evaluation was conducted using DNA ladder assay and Hoechst 33342 staining. The level of intracellular calcium was detected using - Fura2-acetoxymethyl (Fura2-AM) staining, and mitochondrial calcium with Rhod 2-acetoxymethyl (Rhod 2-AM) staining under fluorescence microscopic observation. The expression of endothelium NO synthase (eNOS), inducible NO synthase (iNOS), soluble guanylate cyclase α1 (sGCα1), PKG, Bcl-2/Bax ratio, ERK1/2, p38, and JNK proteins were measured by Western blotting assay. KMUP-1 pretreatment improved cell viability and inhibited ischemia-induced apoptosis of H9c2 cells. Calcium overload both in the intracellular and mitochondrial sites was attenuated by KMUP-1 pretreatment. Moreover, KMUP-1 reduced intracellular reactive oxygen species (ROS), increased plasma NOx (nitrite and nitrate) level, and the expression of eNOS. Otherwise, the iNOS expression was downregulated. KMUP-1 pretreatment upregulated the expression of sGCα1 and PKG protein. The ratio of Bcl-2/Bax expression was increased by the elevated level of Bcl2 and decreased level of Bax. In comparison with the ischemia group, KMUP-1 pretreatment groups reduced the expression of phosphorylated extracellular signal-regulated kinases ERK1/2, p-p38, and p-JNK as well. Therefore, KMUP-1 inhibits myocardial ischemia-induced apoptosis by restoration of cellular calcium influx through the mechanism of NO-cGMP-MAPK pathways.


Assuntos
Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Isquemia Miocárdica/metabolismo , Miócitos Cardíacos/citologia , Piperidinas/farmacologia , Xantinas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Cálcio/metabolismo , Linhagem Celular , GMP Cíclico/metabolismo , Mitocôndrias/metabolismo , Modelos Biológicos , Isquemia Miocárdica/tratamento farmacológico , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Óxido Nítrico/metabolismo , Ratos
17.
Int J Med Sci ; 16(3): 443-449, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30911278

RESUMO

Background: Hypoxia plays an important role in the vascular tone of pulmonary circulation via the vasculature and parenchymal tissue. Endothelin-1 (ET-1), a potent vasoconstrictive peptide, plays a role in inflammation in mononuclear cells. Nitric oxide synthase (NOS), which generates nitric oxide (NO)/cyclic 3', 5'-monophosphate (cGMP), is coexpressed with ET-1 in many cell types. The aim of this study was to assess whether hypoxia induces the production of ET-1 and associated expression of NOS, NO/cGMP and chemokines in rat alveolar macrophages (AMs). Methods: NR8383 cells were cultured under hypoxic (1% oxygen) conditions for 0, 2, 4, 8 and 12 hours. Levels of ET-1, inducible NOS (iNOS), phosphorylated iNOS (p-iNOS), nitrite/nitrate (NOx), cGMP and monocyte chemoattractant protein-1 (MCP-1) were measured. Results: ET-1, p-iNOS, NOx, and cGMP increased significantly in AMs after 4 hours of hypoxia (p < 0.05). ET-1 and MCP-1 mRNA increased after 8 hours (p < 0.05). The protein expression of ET-1, MCP-1, and p-iNOS increased in a time-dependent manner, while iNOS expression decreased with time. Conclusions: The changes in ET-1, p-iNOS, and the NO/cGMP pathway in AMs may help elucidate the mechanisms in the hypoxic lung. Understanding changes in the endothelin axis in hypoxic AMs is a crucial first step to unravel its role in pulmonary circulation.


Assuntos
GMP Cíclico/metabolismo , Endotelina-1/metabolismo , Macrófagos Alveolares/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Animais , Hipóxia Celular , Células Cultivadas , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Endotelina-1/genética , Regulação da Expressão Gênica , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Ratos Sprague-Dawley
18.
Sci Rep ; 8(1): 16457, 2018 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-30405207

RESUMO

Valproate (VPA) is a well-known drug for treating epilepsy and mania, but its action in neuropathic pain is unclear. We used a chronic constriction injury (CCI) model to explore whether VPA prevents neuropathic pain-mediated inflammation and neuronal death. Rats were treated with or without VPA. CCI + VPA rats were intraperitoneally injected with VPA (300 mg/kg/day) from postoperative day (POD) 1 to 14. We measured paw withdrawal latency (PWL) and paw withdrawal threshold (PWT) 1 day before surgery and 1, 3, 7, 14 days after CCI and harvested the sciatic nerves (SN), spinal cord (SC) and dorsal root ganglia (DRG) on POD 3, 7, and 14. PWL and PWT were reduced in CCI rats, but increased in CCI + VPA rats on POD 7 and POD 14. VPA lowered CCI-induced inflammatory proteins (pNFκB, iNOS and COX-2), pro-apoptotic proteins (pAKT/AKT and pGSK-3ß/GSK-3ß), proinflammatory cytokines (TNF-α and IL-1ß) and nuclear pNFκB activation in the SN, DRG and SC in CCI rats. COX-2 and pGSK-3 proteins were decreased by VPA on immunofluorescence analysis. VPA attenuated CCI-induced thermal and mechanical pain behaviors in rats in correlation with anti-neuroinflammation action involving reduction of pNFκB/iNOS/COX-2 activation and inhibition of pAKT/pGSK-3ß-mediated neuronal death from injury to peripheral nerves.


Assuntos
Anti-Inflamatórios/farmacologia , Neuralgia/fisiopatologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Ácido Valproico/farmacologia , Animais , Biomarcadores , Morte Celular/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Glicogênio Sintase Quinase 3 beta/metabolismo , Mediadores da Inflamação/metabolismo , NF-kappa B/metabolismo , Neuralgia/tratamento farmacológico , Neuralgia/etiologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos
19.
Molecules ; 23(10)2018 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-30249030

RESUMO

Xanthine-based KMUP-1 was shown to inhibit phosphodiesterases (PDEs) and modulate G-protein coupled receptors (GPCRs) to lower hyperlipidemia and body weight. This study further investigated whether KMUP-1 affects adipogenesis and lipolysis in 3T3-L1 preadipocytes. KMUP-1 (1⁻40 µM) concentration-dependently attenuated Oil Red O (ORO) staining and decreased triglyceride (TG) accumulation, indicating adipogenesis inhibition in 3T3-L1 cells. In contrast, the ß-agonist ractopamine increased ORO staining and TG accumulation and adipogenesis. KMUP-1 (1⁻40 µM) also reduced MAPKs/Akt/PPARγ expression, PPARγ1/PPARγ2 mRNA, and p-ERK immunoreactivity at the adipogenesis stage, but enhanced hormone sensitive lipase (HSL) immunoreactivity at the lipolysis stage. Addition of protein kinase A (PKA) or protein kinase G (PKG) antagonist (KT5720 or KT5728) to adipocytes did not affect HSL immunoreactivity. However, KMUP-1 did increase HSL immunoreactivity and the effect was reduced by PKA or PKG antagonist. Simvastatin, theophylline, caffeine, and sildenafil, like KMUP-1, also enhanced HSL immunoreactivity. Phosphorylated HSL (p-HSL) was enhanced by KMUP-1, indicating increased lipolysis in mature 3T3-L1 adipocytes. Decreases of MAPKs/Akt/PPARγ during adipogenesis contributed to inhibition of adipocyte differentiation, and increases of PKA/PKG at lipolysis contributed to HSL activation and TG hydrolysis. Taken together, the data suggest that KMUP-1 can inhibit hyperadiposity in 3T3-L1 adipocytes.


Assuntos
Adipócitos/citologia , Adipogenia/efeitos dos fármacos , Piperidinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Triglicerídeos/metabolismo , Xantinas/farmacologia , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Animais , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Lipólise/efeitos dos fármacos , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , PPAR gama/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Esterol Esterase/metabolismo
20.
Clin Sci (Lond) ; 132(18): 2045-2058, 2018 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-30219798

RESUMO

The physiologic process of postnatal ductus arteriosus (DA) closure consists of vasoconstriction followed by vascular remodeling. We have recently reported that B-type natriuretic peptide (BNP), a potent vasodilator, also has anti-remodeling effects in pulmonary vasculature. However, its effects on DA have not been elucidated. We investigated whether BNP can prevent DA closure, and if so, the underlying mechanisms. Using in vivo studies, we examined effects of BNP (10 mg/kg, ip at birth) on DA closure in neonatal rats within 4 h after birth. We found that in control rats, the DA spontaneously closed at 4 h with a decreased DA diameter, enhanced intimal thickening, and luminal occlusion. BNP prevented DA closure at 4 h with a preserved DA diameter, attenuated intimal thickening, and preserved luminal patency. Ex vivo, BNP attenuated oxygen-induced vasoconstriction of isolated DA rings of newborn rats. These vasodilating effects were blunted by Rp-8-Br-PET-cGMPS, a cGMP inhibitor. In vitro, BNP inhibited angiotensin II (Ang II)-induced proliferation and migration of DA smooth muscle cells (DASMCs). BNP inhibited Ang II-induced mitochondrial reactive oxygen species (ROS) production and calcium overload in DASMCs. Finally, BNP inhibited Ang II-induced ERK1/2 activation. These in vitro effects were antagonized by Rp-8-Br-PET-cGMPS. In conclusion, BNP prevents postnatal DA closure by both vasodilation and anti-remodeling through the cGMP pathway. The mechanisms underlying anti-remodeling effects include anti-poliferation and anti-migration, with attenuation of mitochondrial ROS production and intracellular calcium and ERK1/2 signaling. Therefore, the BNP/cGMP pathway can be a promising therapeutic target for clinical management of DA patency.


Assuntos
Canal Arterial/efeitos dos fármacos , Peptídeo Natriurético Encefálico/farmacologia , Remodelação Vascular/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Angiotensina II/farmacologia , Animais , Animais Recém-Nascidos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , GMP Cíclico/análogos & derivados , GMP Cíclico/farmacologia , Canal Arterial/citologia , Canal Arterial/fisiologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/fisiologia , Ratos Wistar , Tionucleotídeos/farmacologia , Fatores de Tempo , Remodelação Vascular/fisiologia , Vasodilatação/fisiologia
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