Preparation of betaine injection and its therapeutic effect in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterised by elevated pulmonary pressure, right ventricular failure (RVF) and ultimately death. Aggressive treatment of RVF is considered an important therapeutic strategy to treat PAH. Previous studies have indicated that betaine may be may a promising therapeutic approach for PAH-induced RVF. Therefore, in this study, betaine solution for injection was prepared and characterised using various techniques. The therapeutic efficacy of three different methods of administration (intragastric, nebulised inhalation and intravenous injection) were comprehensively evaluated in terms of pharmacokinetics, tissue distribution and pharmacodynamics. The pharmacokinetic results demonstrated that betaine injection administered via nebulised inhalation significantly prolonged betaine's half-life and increased its internal circulation time compared to the intragastric and intravenous routes. Biodistribution experiments verified that the betaine formulation accumulated in the lung tissue when administered via inhalation. The results of the pharmacodynamic analysis further confirmed that right ventricular systolic pressure, mean pulmonary artery pressure and right ventricular hypertrophy index increased in the model group and that inhaled betaine suppressed these pathological changes to a level comparable to those observed in the control group. Taken together, these results indicate that betaine administered by inhalation is a promising strategy for the treatment of PAH-induced RVF.

Application of transcriptomics and proteomics in pulmonary arterial hypertension.

The onset and progression of pulmonary arterial hypertension (PAH), a malignant disease, are associated with environmental and epigenetic factors. Recent advancements in transcriptomics and proteomics technology have provided new insights into PAH and identified novel gene targets involved in the development of the disease. Transcriptomic analysis has led to the discovery of possible novel pathways, such as miR-483 targeting several PAH-related genes and a mechanistic link between the increase in HERV-K mRNA and protein. Proteomic analysis has revealed crucial details, including the loss of SIRT3 activity and the significance of the CLIC4/Arf6 pathway in PAH pathogenesis. Gene profiles and protein interaction networks of PAH have been analyzed, clarifying the roles of differentially expressed genes or proteins in the occurrence and development of PAH. This article discusses these recent advances.

Role of gut microbiota in postoperative complications and prognosis of gastrointestinal surgery: A narrative review.

Gastrointestinal surgery is often challenging because of unexpected postoperative complications such as pouchitis, malabsorption, anastomotic leak, diarrhea, inflammatory responses, and life-threatening infections. Moreover, the gut microbiota has been shown to be associated with the complications described above. Major intestinal reconstruction, such as Roux-en-Y gastric bypass (RYGB) and ileal pouch-anal anastomosis surgery, could result in altered gut microbiota, which might lead to some of the benefits of these procedures but could also contribute to the development of postsurgical complications. Moreover, postsurgical reestablishment of the gut microbiota population is still poorly understood. Here, we review evidence outlining the role of gut microbiota in complications of gastrointestinal surgery, especially malabsorption, anastomotic leak, pouchitis, and infections. In addition, this review will evaluate the risks and benefits of live biotherapeutics in the complications of gastrointestinal surgery.

Vasodilatory effects of betaine on isolated rat pulmonary artery rings.

The aim of this study was to investigate the vasodilatory effects of betaine, an alkaloid isolated from Lycium barbarum, on isolated pulmonary artery rings in rats and its possible mechanisms. Pulmonary vessels of normal Sprague-Dawley rats were isolated and pre-contracted using norepinephrine. Then, betaine was cumulatively added in differing concentrations (0.02-0.14 mg/mL), and the tension curve was observed and recorded. Changes in the tension of the pulmonary artery rings with an intact endothelium and a dissected endothelium were recorded. The interactions among betaine and NG-nitro-L-arginine methyl ester, indomethacin, 4-aminopyridine, barium chloride, and glibenclamide were evaluated. The experimental results show that betaine can relax the pulmonary artery rings pre-contracted by norepinephrine. Furthermore, pre-incubation with NG-nitro-L-arginine methyl ester and indomethacin did not inhibit betaine vasodilation, demonstrating that vasodilation by betaine is endothelium-dependent. Additionally, pretreatment of pulmonary artery rings with 4-aminopyridine and glibenclamide had no effect on betaine. However, pretreatment of pulmonary artery rings with barium chloride attenuated the effects of betaine. In conclusion, the vasodilatory effects of betaine on pulmonary artery rings is associated with inward rectifier potassium channels.

Betaine alleviates right ventricular failure via regulation of Rho A/ROCK signaling pathway in rats with pulmonary arterial hypertension.

Pulmonary vascular remodeling was shown to lead to pulmonary arterial hypertension (PAH), further trigger excessive apoptosis of cardiomyocytes, and ultimately cause right ventricular failure (RVF), which involves the activation of Rho A/ROCK signaling pathway. Betaine has been found efficacious for attenuating PAH through its anti-inflammatory effects in our previous research while its effects on RVF due to PAH remains inconclusive. Thus, we attempted to elucidate the protective effects of betaine on PAH, RVF due to PAH as well as the potential mechanisms. To this end, male Sprague Dawley rats received a single subcutaneous injection of monocrotaline (50 mg/kg) to imitate PAH and RVF, and subsequently oral administration of betaine (100, 200, and 400 mg/kg/day). Betaine treatment improved the hemodynamics and histomorphological parameters and echocardiographic changes. Moreover, betaine also alleviated the pulmonary vascular remodeling and cardiomyocyte apoptosis. The mechanisms study revealed that administration of betaine significantly increased the expression of Rho A, ROCK1, and ROCK2. Furthermore, betaine alleviated the changes of its downstream molecules P53, Bcl-2, Bax, phosphorylated MYPT1 (p-MYPT1), total MYPT1 (t-MYPT1), p27kip1, and Cleaved Caspase-3. According to what we observed, this study indicated that betaine treatment could protect RVF due to PAH, which may be achieved through an altered Rho A/ROCK signaling pathway.

Protective effects of 18ß-glycyrrhetinic acid on pulmonary arterial hypertension via regulation of Rho A/Rho kinsase pathway.

PURPOSE: Excessive proliferation, migration and anti-apoptosis of pulmonary artery smooth muscle cells (PASMCs) are the basis for the development of pulmonary vascular remodeling, and it is the driving force for pulmonary arterial hypertension (PAH). 18ß-glycyrrhetinic acid (18ß-GA) is the main active substance extracted from Chinese herbal medicine licorice, with outstanding anti-inflammatory, anti-oxidation and anti-proliferative effects. Our team found in previous studies that 18ß-GA has protective effects on monocrotaline-induced PAH in rats. However, the anti-angiogenic effect of 18ß-GA on PAH remains unclear. Therefore, in order to further investigate whether the beneficial effects of 18ß-GA on PAH are related to its antiproliferative effect, we conducted experiments in vivo and in vitro. METHODS AND RESULTS: In vivo, 18ß-GA relieved mean pulmonary arterial pressure, right ventricular systolic pressure, and right ventricular hypertrophy index, improving pulmonary remodeling. In vitro, 18ß-GA significantly inhibited PDGF-BB-induced proliferation and DNA synthesis of HPASMCs, blocking the progression of G0/G1 to S phase of the cell cycle. Furthermore, after treatment with 18ß-GA, the expression of Rho A, ROCK1, ROCK2 was decreased and ROCK activity was inhibited in HPASMC. In addition, 18ß-GA also attenuated PDGF-induced changes in p27kip1, Bax and Bcl-2. CONCLUSIONS: In summary, these results indicate that 18ß-GA regulates the activity of RhoA-ROCK signaling pathway, inhibits the proliferation of HPASMCs, and has potential value in the treatment of PAH.

Protective Effects of 18ß-Glycyrrhetinic Acid on Monocrotaline-Induced Pulmonary Arterial Hypertension in Rats.

Pulmonary arterial hypertension (PAH) is a destructive and rare disorder characterized by a progressive increase in pulmonary artery pressure and vasoconstriction, ultimately leading to right ventricular failure and death. 18ß-Glycyrrhetinic acid (18ß-GA) is an active ingredient in the commonly used Chinese herbal medicine radix glycyrrhizae, and it possesses antioxidant, anti-inflammatory, anti-tumor, and other pharmacological properties. This study aimed to determine whether 18ß-GA has protective effects against monocrotaline (MCT)-induced PAH and whether it is associated with oxidative stress. The PAH of rats was induced by MCT (60 mg/kg) and oral administration of 18ß-GA (100, 50, or 25 mg/kg/day), sildenafil (30 mg/kg), or saline for 21 consecutive days. The development of PAH was evaluated by hemodynamic parameters and right ventricular hypertrophy index. Hematoxylin and eosin staining, Masson trichrome staining, and electron microscopy were used to determine the degree of vascular remodeling and proliferation in lung tissue. Moreover, the antioxidant capacity and malondialdehyde levels in the lungs were measured according to the instructions provided by the test kits, and the expression levels of nicotinamide adenine dinucleotide phosphate oxidase-2 (Nox2) and Nox4 were detected through Western blot analysis. Results of our study indicated that 18ß-GA treatment significantly improved the hemodynamic and pathomorphological data of the rats, reduced the changes in oxidative stress biomarkers, and inhibited Nox2 and Nox4 expression. Our research indicated that 18ß-GA has a protective effect against MCT-induced PAH by inhibiting oxidative stress in rats.

Regulation of endothelial nitric oxide synthase and asymmetric dimethylarginine by matrine attenuates isoproterenol-induced acute myocardial injury in rats.

OBJECTIVES: This study was designed to investigate the cardioprotective effects of matrine on regulation of endothelial nitric oxide synthase (eNOS) and asymmetric dimethylarginine (ADMA) in isoproterenol-induced acute myocardial ischaemic rats. METHODS: Male Sprague-Dawley rats were pretreated with matrine (200, 100 and 50 mg/kg) orally for 10 days. Acute myocardial injury was induced in rats by subcutaneous injection of isoproterenol. Serum and haemodynamic parameters, histopathological variables and expression of protein levels were analysed. KEY FINDINGS: Oral administration of matrine (200, 100 and 50 mg/kg) significantly attenuated isoproterenol-induced cardiac necrosis and left ventricular dysfunction. Matrine treatment restored impaired ventricular Akt and eNOS protein expression with concomitant increased phosphorylation of Akt (Ser473) and eNOS (Ser1177), and also restored glycogen synthase kinase 3ß activity, as indicated by increased phosphorylation at Ser 9. Moreover, treatment with matrine had no effect on the isoproterenol-induced elevated protein arginine methyltransferase 1 protein expression, but could significantly normalize the reduced dimethylarginine dimethylaminohydrolase 2 expression and attenuate the increased serum level of ADMA. The expression of catechol-o-methyltransferase and monoamine oxidase did not differ among all groups (all P > 0.05). CONCLUSIONS: Our results suggested that matrine protects against isoproterenol-induced myocardial ischaemia via eNOS and ADMA pathway.

Rosuvastatin attenuates monocrotaline-induced pulmonary hypertension via regulation of Akt/eNOS signaling and asymmetric dimethylarginine metabolism.

This study was designed to investigate whether rosuvastatin could attenuate monocrotaline-induced pulmonary hypertension via regulation of Akt/eNOS signaling pathway and asymmetric dimethylarginine (ADMA) metabolism in rats. After a single-dose injection of monocrotaline (60 mg/kg), oral administration of rosuvastatin (5mg/kg) was started from day 1 to day 28 (preventive administration) or from day 15 to day 28 (therapeutic administration), or with vehicle as corresponding controls. 28 days after monocrotaline, significant pulmonary hypertension characterized by pulmonary arterial medial wall thickening, right ventricular hypertrophy and right heart failure was observed. Rosuvastatin (5mg/kg, for 14 days and 28 days) treatment significantly attenuated monocrotaline-induced pulmonary vascular remodeling, right ventricular hypertrophy and dysfunction, and normalized the down-regulated pulmonary Akt/p-Akt and eNOS/p-eNOS expressions, while increased DDAH2 expression accompanied by decreased serum level of ADMA. However expression of PRMT1 and GSK3ß/p-GSK3ß did not differ among all groups (all P>0.05). We concluded that rosuvastatin inhibits monocrotaline-induced pulmonary hypertension through normalization of Akt, eNOS and DDAH2 expressions, and decreasing the level of ADMA.

Clinical cellular cardiomyoplasty: technical considerations.

Three patients, all with a history of coronary heart disease, underwent coronary artery bypass grafting and implantation of autologous satellite cells. Satellite cells were isolated from muscle biopsies of the right vastus lateralis muscle after enzymatic treatment. While the heart was still under hypothermic cardioplegia, 4 mL of cell suspension divided into approximately 40 doses was injected into the ventricular wall of the ischemic area. Less than 5 minutes were required to complete the cell implantation. All patients survived the procedure, without obvious arrhythmia, had an uneventful recovery, and were discharged from the hospital. At 3 to 4 months follow-up examination, increased left ventricular ejection fraction, decreased left ventricular diastolic diameter, as well as improved ventricular wall thickness and perfusion at the satellite cell implantation sites were observed. Our experience indicated the safety and early benefit of cellular cardiomyoplasty using autologous satellite cells.