Gastrodin provides neuroprotection in models of traumatic brain injury via Nrf2 signaling pathway

Gastrodin is one of the main active components of Gastrodia elata and has significant therapeutic value for various nervous system diseases. Its medicinal properties include smooth muscle relaxation, anti-necrosis, anti-aging, and anti-apoptosis effects. However, its possible effects on traumatic brain injury (TBI) are still unclear. In this study, the effects of gastroditin on TBI rats were investigated. The results proved that gastrodin had neuroprotective effect on TBI through alleviating brain deficits, decreasing brain water content, inhibiting neuronal apoptosis, and suppressing oxidative stress in brain tissues of TBI rats. Mechanically, gastrodin upregulated the expression of Nrf2 downstream proteins, suggesting the activation of Nrf2 pathway in brain tissues of TBI rats. In conclusion, gastrodin provided neuroprotection in TBI rats via Nrf2 pathway.

EFFICACY OF INTERFERENTIAL THERAPY ON SELECTED CARDIOPULMONARY PARAMETERS OF ASTHMATIC PATIENTS WITH POST COVID19 EXPOSURE: STUDY PROTOCOL

Background: Interferential therapy (IFT) is the application of two medium frequency currents to the skin to stimulate and activate different systems in the body using specific frequencies and frequency ranges. IFT in the thoracic region aims to reduce myalgia in the chest and upper back, reduce muscular fatigue and induce mucus expectoration. This study is designed to test the efficacy of IFT on asthma patients recently exposed to SARS-CoV-2 virus.Methods: IFT will be administered as an intervention to 28 asthma patients with and without a history of COVID-19 exposure for 20 minutes. Six continuous outcome variables at different points will be utilized as an outcome measure. Selected Baseline Pulmonary Function Test (PFT) and Cardiopulmonary Variables (CVS) will be assessed on entry into the study, Quality of life and asthma control will be evaluated every two (2) weeks of the study. Data obtained will be analyzed using descriptive and inferential statistics of repeated ANOVA; P<0.05. Discussion: The study outcome will compare the efficacy of IFT on Bronchial Asthma patients with Post COVID-19 exposure, identify the relationship between the Intervention on Asthma patients with or without COVID-19 exposure.Contribution of Paper: Asthma control in the SARS-CoV-2 virus is still unclear, this study aims to evaluate the effect of airway smooth muscle relaxation induced by IFT on the possible long-term manifestations of SARS-CoV-2 virus on asthma control, and quality of life of asthma patients. This study will add to the existing knowledge on the management of the severe acute respiratory syndrome.

The decrease of MYPT1 is critical for impairment of NO-mediated vosodilation in mesenteric artery of the older spontaneously hypertensive rats

Nitric oxide (NO) mediated vasodilatation is a fundamental response of vasculature, however, the regulation of NO signaling pathway on resistance vessels in the elderly hypertension is still unclear. The 16-weeks-spontaneously hypertensive rats (SHR), the 18-months-SHR (OldSHR), and the age matched Wistar-Kyoto rats were used to study the changes of mesenteric resistance artery dilatation caused by sodium nitroprusside (SNP). After pre-vasoconstriction by Norepinephrine (NE), the response of endothelium-denuded mesenteric artery ring to SNP was observed, and the changes in vascular response after pharmacological interventions of key nodes in the NO/sGC/cGMP/PKG1α signaling pathway were observed as well. RNA sequencing and functional enrichment analyses were used to provide information for conducting validation experiments. Vasodilation of NO in OldSHR was decreased, which significantly correlated with the reduction of PKG-mediated effect. Functional enrichment analysis of RNA sequencing showed that genes encoding important proteins such as sGC and MYPT1 (protein phosphatase 1 regulatory subunit 12A) were downregulated in OldSHR. Molecular biology validation results showed that mRNA expression of both α and β subunits of sGC were reduced, while mRNA and protein expression of PKG1α were reduced in OldSHR. More importantly, the expression of MYPT1 and p S668-MYPT1 was significantly reduced in OldSHR, even under the treatment of SNP. The experiment also revealed an enhanced cAMP system in vasodilatory in hypertension, while this function completely lost in the elderly hypertension. Therefore, a NO-mediated decrease in vascular smooth muscle relaxation was found in the elderly hypertension. The dysfunction in cGMP-PKG signaling, in particular, the decreased p S668-MYPT1 was mechanistically involved.

Effects of Pentoxifylline in a Rat Model of Manganism: Evaluation of the Possible Toxicity

Objective. Manganese (Mn) has been reported, through dietary and occupational overexposure, to induce neurotoxicity named manganism. Pentoxifylline (PTX) administration attracts much attention considering the beneficial properties of PTX, as an anti-inflammatory and smooth muscle relaxation agent. This in vivo study aims to evaluate the effect of PTX on manganism in rat model. Materials and Methods. Thirty adult male Sprague Dawley rats received MnCl2 (100 mg/kg, i.p. on days 1, 3, and 7) during a week alone or in combination with PTX (300 mg/kg, i.p. every day for 8 consecutive days on manganism rat model). Several locomotor activity indices, as well as biomarkers of oxidative stress, were monitored in the brain tissue of Mn-exposed animals. Results. It was found that PTX supplementation (300 mg/kg, i.p.) deteriorated the Mn-induced locomotor deficit. This drug also increased the Mn brain accumulation as well as reactive oxygen species (ROS) and lipid peroxidation products in the manganism rat model. Moreover, the levels of total antioxidant capacity (TAC) and glutathione (GSH) were shown to be reduced significantly compared to the control group. Conclusion. The results of this study revealed that PTX at a high dose (300 mg/kg) might increase manganism complications. PTX lowers the blood viscosity, improves the tissue perfusion, and increases the Mn levels in the brain.

Nitric Oxide: From Gastric Motility to Gastric Dysmotility

It is known that nitric oxide (NO) plays a key physiological role in the control of gastrointestinal (GI) motor phenomena. In this respect, NO is considered as the main non-adrenergic, non-cholinergic (NANC) inhibitory neurotransmitter responsible for smooth muscle relaxation. Moreover, many substances (including hormones) have been reported to modulate NO production leading to changes in motor responses, further underlying the importance of this molecule in the control of GI motility. An impaired NO production/release has indeed been reported to be implicated in some GI dysmotility. In this article we wanted to focus on the influence of NO on gastric motility by summarizing knowledge regarding its role in both physiological and pathological conditions. The main role of NO on regulating gastric smooth muscle motor responses, with particular reference to NO synthases expression and signaling pathways, is discussed. A deeper knowledge of nitrergic mechanisms is important for a better understanding of their involvement in gastric pathophysiological conditions of hypo- or hyper-motility states and for future therapeutic approaches. A possible role of substances which, by interfering with NO production, could prove useful in managing such motor disorders has been advanced.

VIP/PACAP Signaling as an Alternative Target During Hyperoxic Exposure in Preterm Newborns

The use of oxygen therapy (high doses of oxygen - hyperoxia) in the treatment of premature infants results in their survival. However, it also results in a high incidence of chronic lung disease known as bronchopulmonary dysplasia, a disease in which airway hyper-responsiveness and pulmonary hypertension are well known as consequences. In our previous studies, we have shown that hyperoxia causes airway hyper-reactivity, characterized by an increased constrictive and impaired airway smooth muscle relaxation due to a reduced release of relaxant molecules such as nitric oxide, measured under in vivo and in vitro conditions (extra- and intrapulmonary) airways. In addition, the relaxation pathway of the vasoactive intestinal peptide (VIP) and/or pituitary adenylate cyclase activating peptide (PACAP) is another part of this system that plays an important role in the airway caliber. Peptide, which activates VIP cyclase and pituitary adenylate cyclase, has prolonged airway smooth muscle activity. It has long been known that VIP inhibits airway smooth muscle cell proliferation in a mouse model of asthma, but there is no data about its role in the regulation of airway and tracheal smooth muscle contractility during hyperoxic exposure of preterm newborns.

Effects of Small-Dose S-Ketamine On Anesthesia-Induced Atelectasis In Patients Undergoing General Anesthesia Accessed By Lung Ultrasound: Study Protocol For A Randomized, Double-Blinded Controlled Trial

Background: Aelectasis after anesthesia induction in most patients undergoing general anesthesia may lead to postoperative pulmonary complications (PPCs) and affect postoperative outcomes. However, there is still no existing effective method used for the prevention of perioperative atelectasis. S-ketamine may prevent atelectasis due to airway smooth muscle relaxation and anti-inflammatory effects. Lung ultrasound is a portable and reliable bedside imaging technology for diagnosing anesthesia-induced atelectasis. In this study, we aim to assess whether a small dose of S-ketamine can reduce the incidence of atelectasis after intubation under general anesthesia using lung ultrasound, in order to prevent the early formation of perioperative atelectasis and PPCs.Methods: This is a single-institution, prospective, randomized controlled, parallel grouping, and double-blind study. From October 2020 to March 2022, 100 patients (18-60 years old) scheduled for elective surgery will be recruited from Beijing Tiantan Hospital, Capital Medical University, and randomly assigned to the S-ketamine group (Group S) and the normal saline group (Group N) at a ratio of 1:1. The label-masked agents will be administered 5 min before induction, and all patients will undergo a standardized general anesthesia protocol. Related data will be collected at three-time points: after radial artery puncture (T1), 15 min after tracheal intubation (T2), and before extubation (T3). The primary outcome will be the total lung ultrasound scores (LUS) at T2. Secondary outcomes will include LUS in six chest regions at T2, total LUS at T3, arterial blood-gas analysis results (PaCO2, PaO2) and PaO2/FiO2 at T2 and T3, plateau pressure(Pplat) and dynamic lung compliance (Cdyn) at T2 and T3. The incidence of postoperative complications associated with S-ketamine and PPCs at 2 h and 24 h after surgery will be recorded.Discussion: This trial aims to explore whether a simple and feasible application of S-ketamine before the induction of general anesthesia can prevent atelectasis. The results of this study may provide new ideas and direct clinical evidence for the prevention and treatment of perioperative pulmonary complications during anesthesia.Trial registration: ClinicalTrials.gov identifier: NCT04745286.

Concentration-dependent alpha1-Adrenoceptor Antagonism and Inhibition of Neurogenic Smooth Muscle Contraction by Mirabegron in the Human Prostate

Introduction: Mirabegron is available for treatment of storage symptoms in overactive bladder, which may be improved by β3-adrenoceptor-induced bladder smooth muscle relaxation. In addition to storage symptoms, lower urinary tract symptoms in men include obstructive symptoms attributed to benign prostatic hyperplasia, caused by increased prostate smooth muscle tone and prostate enlargement. In contrast to the bladder and storage symptoms, effects of mirabegron on prostate smooth muscle contraction and obstructive symptoms are poorly understood. Evidence from non-human smooth muscle suggested antagonism of α1-adrenoceptors as an important off-target effect of mirabegron. As α1-adrenergic contraction is crucial in pathophysiology and medical treatment of obstructive symptoms, we here examined effects of mirabegron on contractions of human prostate tissues and on proliferation of prostate stromal cells.Methods: Contractions were induced in an organ bath. Effects of mirabegron on proliferation, viability, and cAMP levels in cultured stromal cells were examined by EdU assays, CCK-8 assays and enzyme-linked immunosorbent assay.Results: Mirabegron in concentrations of 5 and 10 μM, but not 1 µM inhibited electric field stimulation-induced contractions of human prostate tissues. Mirabegron in concentrations of 5 and 10 µM shifted concentration response curves for noradrenaline-, methoxamine- and phenylephrine-induced contractions to the right, including recovery of contractions at high concentrations of α1-adrenergic agonists, increased EC50 values, but unchanged Emax values. Rightshifts of noradrenaline concentration response curves and inhibition of EFS-induced contractions were resistant to L-748,337, l-NAME, and BPIPP. 1 µM mirabegron was without effect on α1-adrenergic contractions. Endothelin-1- and U46619-induced contractions were not affected or only inhibited to neglectable extent. Effects of mirabegron (0.5–10 µM) on proliferation and viability of stromal cells were neglectable or small, reaching maximum decreases of 8% in proliferation assays and 17% in viability assays. Mirabegron did not induce detectable increases of cAMP levels in cultured stromal cells.Conclusion: Mirabegron inhibits neurogenic and α1-adrenergic human prostate smooth muscle contractions. This inhibition may be based on antagonism of α1-adrenoceptors by mirabegron, and does not include activation of β3-adrenoceptors and requires concentrations ranging 50-100fold higher than plasma concentrations reported from normal dosing. Non-adrenergic contractions and proliferation of prostate stromal cells are not inhibited by mirabegron.