Matrine alleviates hypoxia-induced inflammation and pulmonary vascular remodelling via RPS5/NF-κB signalling pathway.

Hypoxia-induced vasoconstriction and vascular remodelling are the main pathological features of hypoxic pulmonary arterial hypertension (HPAH), and inflammation is participated in the occurrence of pulmonary vascular remodelling (PVR). Matrine is an alkaloid with the effects of anti-inflammation, antifibrosis and antitumour. But, few studies have explored the role of matrine in regulating PVR, and the related mechanisms are still unknown. In this study, we found that hypoxia-induced pulmonary artery smooth muscle cells (PASMCs) proliferation and inhibited its apoptosis, reduced the expression of ribosomal protein s5 and activated the nuclear factor kappa-B (NF-κB) signalling. Matrine, sildenafil and NF-κB inhibitor Bay 11-7082 could reverse these changes and impel the cell cycle in phase S retardation, and reduced the expression of p50, p65, proliferating cell nuclear antigen (PCNA), Bcl-2. In addition, matrine could lower right ventricular systolic pressure and mean pulmonary artery pressure of rats, α-smooth muscle actin and PCNA expression in pulmonary artery media, the levels of tumor necrosis factor-α and interleuki-1ß, thus improved hypoxia-induced PVR. This study indicated that matrine could alleviate inflammation and improve PVR through reversing the imbalance of proliferation and apoptosis of PASMCs, thus it had a therapeutic effect on HPAH.

Association between two different lipid injectable emulsions and parenteral nutrition-associated cholestasis in very low birth weight infants: A retrospective cohort study.

BACKGROUND: Using soybean oil-based lipid emulsions (Intralipid), which contain higher amounts of ω-6 fatty acids and phytosterols in parenteral nutrition, is a risk factor for cholestasis (parenteral nutrition-associated cholestasis [PNAC]). An alternative form of a mixed lipid emulsion (SMOFlipid) has been developed to reduce the risk of PNAC, but significant benefits over Intralipid in very low birth weight (VLBW) infants have yet to be demonstrated. The aim of this study was to compare the differences in PNAC incidence in VLBW infants receiving SMOFlipid vs Intralipid. METHODS: The study was conducted in Sir Run Run Shaw Hospital of the Zhejiang University School of Medicine, Hangzhou, China, from January 2016 to March 2022. In total, 235 VLBW infants were administered SMOFlipid or Intralipid for ≥21 days and were included in the study. The primary outcome was the incidence of PNAC. Secondary outcomes included bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis, late-onset sepsis, length of stay, weight 28 days after birth, severity of PNAC, and the time to reversal of PNAC. RESULTS: Forty-four VLBW infants (35.5%) in the SMOFlipid group vs 41 (36.9%) in the Intralipid group achieved PNAC (P = 0.817). The subgroup analysis showed that the peak direct bilirubin level was lower (median [interquartile range] 55.6 [36.4] vs 118.4 [77.2] µmol/L; P < 0.001), and the time to reversal of PNAC was shorter (44 [49] vs 96 [61]; P < 0.001) in the SMOFlipid group than in the Intralipid group. CONCLUSION: SMOFlipid may represent a better alternative for VLBW infants who require prolonged parenteral nutrition.

Astragaloside IV protects cardiomyocytes from hypoxic injury by regulating endoplasmic reticulum stress via eIF2α/CHOP signaling pathway.

Endoplasmic reticulum stress (ER stress) is suggested to promote cardiomyocyte apoptosis and ultimately lead to ischemic injury. Inhibition of ER stress-induced apoptosis may be a therapeutic strategy for MI injury. Astragaloside-IV (AST) from Astragalus membranaceus (Fisch) Bge, was reported to have cardioprotective properties. In this study, we investigated the protective effect of AST on cardiomyocytes against hypoxia injury by regulating ER stress and inhibiting apoptosis. H9c2 cardiomyocytes were divided into three groups, normal group, hypoxia group and AST group. Cell viability was determined by CCK-8 assay. Intracellular reactive oxygen species (ROS) production was detected by DCFH-DA (2,7- dichloro-dihydrofluorescein diacetate) florescent staining. The study showed that AST treatment could significantly increase the cell viability of H9c2 cells exposed to hypoxia. Furthermore, AST could restrain cell apoptosis and decrease the production of ROS. Compared with normal group, the protein levels of Bax, caspase-3, caspase-9, GRP78, p-eIF2α, and CHOP were enhanced in the hypoxia group, whereas the protein level of Bcl-2 was dramatically reduced. Compared with hypoxia group, AST markedly inhibited the phosphorylation of eIF2α and the expression of caspase-3, caspase-9 and CHOP, and promoted the protein expression of Bcl-2. Thus, AST can inhibit the ER stress-mediated apoptosis, partly through the eIF2α/CHOP pathway suppression to inhibit ER stress.

Clinical effects of multi-oil versus pure soybean oil-based lipid emulsions for preterm infants: An observational study.

BACKGROUND AND OBJECTIVES: Conventional soybean oil-based intravenous lipid emulsions (SO-ILEs) have high polyunsaturated fatty acid (PUFA) contents and phytosterols that may have adverse effects in preterm infants. Recently, the multi-oil-based intravenous lipid emulsion (MO-ILE), SMOFlipid, has been widely utilized in the neonatal intensive care unit (NICU), but significant benefits over SO-ILEs in low gestational age neonates have yet to be demonstrated. This study was performed to compare the effects of the SO-ILE, Intralipid, and the MO-ILE, SMOFlipid, on neonatal health outcomes in preterm infants. METHODS AND STUDY DESIGN: We performed a retrospective review of preterm infants born at gestational week (GW) <32 receiving parenteral nutrition for longer durations (≥14 d) in the NICU between 2016 and 2021. The primary aim of this study was to investigate differences in morbidity between preterm infants receiving SMOFlipid and Intralipid. RESULTS: A total of 262 preterm infants were included in the analysis, with 126 receiving SMOFlipid and 136 receiving Intralipid. The SMOFlipid group had lower rates of ROP (23.8% vs 37.5%, respectively; p=0.017), although the rate of ROP was not different in multivariate regression analysis. The length of hospi-tal stay was significantly shorter in the SMOFlipid than SO-ILE group (median [IQR]=64.8 [37] vs 72.5 [49] days; p<0.001). CONCLUSIONS: The use of SMOFlipid as the lipid emulsion was associated with higher clinical efficacy than SO-ILE in preterm infants.

SIRT6 inhibits hypoxia-induced pulmonary arterial smooth muscle cells proliferation via HIF-1α/PDK4 signaling.

SIRT6 is an NAD+-dependent protein that plays a vital role in regulating the cell proliferation, differentiation and apoptosis. Abnormal proliferation of pulmonary artery smooth muscle cells (PASMCs) in peripheral vascular is one of the major pathological findings of pulmonary vascular remodeling in pulmonary arterial hypertension (PAH). However, whether SIRT6 is involved in hypoxia-induced proliferation of PASMCs and its possible mechanisms remain unknown. In the present study, we found that the expression of SIRT6 was decreased in both hypoxia-induced PAH rats model and HPASMCs. Hypoxia promoted the proliferation of HPASMCs in a time-dependent manner, inhibited the activity of caspase-3 and the production of PDH, increased the activity of LDH, ROS level, mitochondrial membrane potential(MMP) and the expression of HIF-1α and PDK4, which induced glycolysis. SIRT6 over-expression could inhibit the proliferation of HPASMCs and increase the apoptosis rate, impelled the retardation of cell cycle in phase G1. Meanwhile, SIRT6 over-expression reduced LDH activity, the levels of ROS and MMP, which simultaneously increased the production of PDH, the expression of HIF-1α, PDK4, Cyclin D1 and PCNA in hypoxia-induced HPASMCs. Moreover, SIRT6 over-expression inhibited the transcriptional activation of HIF-1α/PDK4 signaling. In addition, SIRT6 knockdown with SIRT6 siRNA exhibited the same effect as hypoxia. Together, our results indicated that SIRT6 was participant in regulating hypoxia-induced imbalance of proliferation and apoptosis of HPASMCs, which was associated with the activation of HIF-1α/PDK4 signaling pathway. Targeting at SIRT6 gene and regulating the downstream metabolism signaling pathway may be a novel strategy for the treatment of hypoxia-induced PAH.

Augmentation in patients with restless legs syndrome receiving pramipexole therapy: a retrospective study in a single center from China.

PURPOSE: Augmentation is a major complication of long-term pramipexole treatment of restless legs syndrome (RLS). However, there have been no studies on augmentation in Chinese patients with RLS. We therefore investigated the clinical characteristics of augmentation in RLS patients treated with pramipexole in a real-world Chinese setting. METHODS: This study was an observational, retrospective assessment of 103 patients with RLS, who had been continuously treated with pramipexole for at least one month between January 2016 and December 2018 in a tertiary hospital in East China. Demographic data and disease and drug treatment information were collected from electronic medical records and telephone interviews to analyze the rate and clinical features of augmentation. Augmentation was confirmed by Max Planck Institute criteria. Comparisons were made between patients with and without augmentation. RESULTS: Fifteen patients (15%) were classified as having augmentation. Compared to RLS patients without augmentation, more patients with augmentation switched from other dopaminergic drugs (P<0.05) and had a longer duration of RLS symptoms before pramipexole treatment (P<0.05). In addition, patients with augmentation had a longer duration (P<0.05) and higher dosage (P<0.05) of pramipexole than those without augmentation. Augmentation was possibly associated with pramipexole tolerance (P<0.01). CONCLUSION: The augmentation rate of the Chinese RLS patients in our study was 15%. Augmentation may be associated with switching from other dopaminergic drugs, long disease duration before pramipexole use, the dose and duration of pramipexole, and tolerance to pramipexole.

Efficacy and safety of sevoflurane vs propofol in combination with remifentanil for anesthesia maintenance during craniotomy: A meta-analysis.

BACKGROUND: The purpose of this study was to evaluate the efficacy and safety of sevoflurane-remifentanil (SR) vs propofol-remifentanil (PR) as inhalation anesthesia or total intravenous anesthesia in patients undergoing craniotomy, respectively. METHODS: Electronic databases included PubMed, ScienceDirect, Embase, Cochrane library, CNKI, and Wanfang data were searched using suitable search items. Randomized clinical controlled trials comparing the combination of SR and PR as anesthetics for neurosurgery were included. The outcomes included wake-up time, spontaneous respiration time, extubation time, and safety. RESULTS: Seventeen studies were included in this meta-analysis. There were no statistically significant differences in wake-up time (P = .25, standardized mean difference (SMD) = 0.29, 95% CI -0.20 to 0.77), extubation time (P = .1, SMD = 0.52, 95% CI -0.11 to 1.14) and spontaneous respiration time (P = .58, SMD = 0.43, 95% CI -1.07 to 1.93) when patients with SF and PF for anesthesia maintenance. Moreover, the changes of hemodynamic parameters are similar between the 2 groups. During anesthesia maintenance, SF could significantly increase the incidence of hypotension and brain edema than PF (P = .02, SMD = 1.68, 95% CI 1.07 to 2.62; P < .0001, SMD = 3.37, 95% CI 1.86 to 6.12), PF markedly promoted the incidence of hypertension (P = .001, SMD = 0.55, 95% CI 0.39 to 0.79). The postoperative adverse reactions were similar between the 2 groups (P > .05), but the incidence of postoperative nausea and vomiting proved to be higher in SF group (P < .0001, SMD = 2.12, 95% CI 1.47 to 3.07). CONCLUSIONS: SR and PR as anesthetics in patients underwent craniotomy had similar effects, but PR was superior to SR in terms of safety of intraoperation and postoperation.

Efficacy and safety of riociguat in the treatment of chronic thromboembolic pulmonary arterial hypertension: A meta-analysis.

BACKGROUND: Riociguat is a novel soluble guanylate cyclase stimulator, and has been widely used for the treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension (CTEPH). Some studies found that riociguat had better effects on CTEPH and proved to be safe, but the results were not utterly consistent. Therefore, the purpose of this study was to comprehensively evaluate the efficacy and safety of riociguat in the treatment of CTEPH. METHODS: Randomized controlled trials on riociguat for the treatment of CTEPH were searched through such electronic databases as PubMed, Embase, Cochrane Library, Web of Science, China national knowledge internet, and Wanfang. The outcomes included exercise capacity, pulmonary hemodynamics, and side effects. The fixed-effects or random-effects models were used to analyze the pooled data, and heterogeneity was assessed by the I2 test. RESULTS: Four studies involving 520 patients were included in this meta-analysis. Compared with the placebo group, riociguat significantly improved the hemodynamic indexes and increased 6-min walking distance (P < .0001, standardized mean difference (SMD) = -0.24, 95%CI -0.35 to -0.12; P < .00001, SMD = 0.52, 95%CI 0.33 to 0.71), and decreased the Borg dyspnea score (P = .002, SMD = -0.31, 95%CI -0.51 to -0.12). In addition, riociguat could also significantly reduce the living with pulmonary hypertension scores and increase the EQ-5D scores (P = .01, SMD=-0.23, 95%CI -0.42 to -0.05; P < .00001, SMD = 0.47, 95%CI 0.27 to 0.66), but there was no significant difference in the change level of N-terminal pro-hormone B-type natriuretic peptide in patients with riociguat (P = .20, SMD = -0.24, 95%CI -0.61 to -0.13). The common adverse events of riociguat were dyspepsia and peripheral edema, and no other serious adverse reactions were observed. CONCLUSIONS: We confirmed that riociguat had better therapeutic effects in improving the hemodynamic parameters and exercise capacity in patients with CTEPH without inducing serious adverse events. This will provide a reasonable medication regimen for the treatment of CTEPH.

Efficacy and safety of dapagliflozin plus saxagliptin vs monotherapy as added to metformin in patients with type 2 diabetes: A meta-analysis.

BACKGROUND: This study aim at evaluating the efficacy and safety of dapagliflozin plus saxagliptin vs monotherapy as added to metformin in patients with type 2 diabetes mellitus (T2DM). METHOD: PubMed, Cochrane library, Embase, CNKI and Wanfang databases were searched up to 31 December 2019. Randomized controlled trials (RCTs) applicable in dapagliflozin plus saxagliptin vs monotherapy as added to metformin in the treatment of T2DM were included. The outcomes included changes in HbA1c, FPG, body weight, SBP, DBP and adverse reactions. Fixed or random effects model were used to assess these outcomes. RESULTS: In this study, 8 RCTs involved 7346 patients were included. Compared with dapagliflozin plus metformin(DM) group, patients treated with dapagliflozin plus saxagliptin add on to metformin(DSM) could significantly increase the adjusted mean change levels of HbA1c, FPG, SBP and DBP(P < .00001, SMD = -4.88, 95%CI = -6.93∼-2.83; P < .00001, SMD = -6.50, 95%CI = -8.55∼-4.45; P < .00001, SMD = -0.97, 95%CI = -1.15∼-0.78; P < .00001, SMD = -2.00, 95%CI = -2.20∼-1.80), but no major difference in body weight loss showed(P = .12, SMD = 0.92, 95%CI = -0.22∼2.06). Furthermore, DSM therapy displayed better effects than saxagliptin plus metformin(SM) in the adjusted mean change levels of HbA1c, FPG, body weight and SBP(P < .00001, SMD = -7.75, 95%CI = -8.84∼-6.66; P < .00001, SMD = -7.75, 95%CI = -8.84∼-6.66; P = .04, SMD = -3.40, 95%CI = -6.64∼-0.17; P = .04, SMD = -7.75, 95%CI = -8.84∼-6.66), whereas no obvious difference in lowering DBP(P = .18, SMD = -16.35, 95%CI = -40.12∼7.41). Additionally, compared with DM and SM groups, there were no remarkable difference in the incidence of nausea, influenza, headache, diarrhea, urinary tract infection and renal failure for patients taking DSM, but the incidence of genital infection and hypoglycemia were higher in DSM group. CONCLUSIONS: Patients taking the DSM therapy had better effects in reducing the level of HbA1c, FPG, body weight, SBP and DBP than the DM and SM therapy. However, patients treated with DSM therapy are more likely to have hypoglycemia and genital infection. Dapagliflozin plus saxagliptin may be a suitable therapy strategy for patients with T2DM inadequately controlled with metformin, and this will provide a clinical reference for the treatment of T2DM.

Cysteinyl Leukotriene Receptor 2 is Involved in Inflammation and Neuronal Damage by Mediating Microglia M1/M2 Polarization through NF-κB Pathway.

Microglia activation plays a key role in regulating inflammatory and immune reaction during cerebral ischemia and it exerts pro-inflammatory or anti-inflammatory effect depending on M1/M2 polarization phenotype. Cysteinyl leukotriene 2 receptor (CysLT2R) is a potent inflammatory mediator receptor, and involved in cerebral ischemic injury, but the mechanism of CysLT2R regulating inflammation and neuron damage remains unclear. Here, we found that LPS and CysLT2R agonist NMLTC4 significantly increased microglia proliferation and phagocytosis, up-regulated the mRNA expression of M1 polarization markers (IL-1ß, TNF-α, IFN-γ, CD86 and iNOS), down-regulated the expression of M2 polarization markers (Arg-1, CD206, TGF-ß, IL-10, Ym-1) and increased the release of IL-1ß and TNF-α. CysLT2R selective antagonist HAMI3379 could antagonize these effects. IL-4 significantly up-regulated the mRNA expression of M2 polarization markers, and HAMI3379 further increased IL-4-induced up-regulation of M2 polarization markers expression. Additionally, LPS and NMLTC4 stimulated NF-κB p50 and p65 proteins expression, and promoted p50 transfer to the nucleus. Pre-treatment with HAMI3379 and NF-κB signaling inhibitor Bay 11-7082 could reverse the up-regulation of p50 and p65 proteins expression, and inhibited p50 transfer to the nucleus. The conditional medium of BV-2 cells contained HAMI3379 could inhibit SH-SY5Y cells apoptosis induced by LPS and NMLTC4. These results were further confirmed in primary microglia. The findings indicate that CysLT2R was involved in inflammation and neuronal damage by inducing the activation of microglia M1 polarization and NF-κB pathway, inhibiting microglia M1 polarization and promoting microglia polarization toward M2 phenotype which may exerts neuroprotective effects, and targeting CysLT2R may be a new therapeutic strategy against cerebral ischemia stroke.

Lifestyle interventions to alleviate side effects on prostate cancer patients receiving androgen deprivation therapy: a meta-analysis.

BACKGROUND: Prostate cancer (PCa) patients receiving androgen deprivation therapy (ADT) are prone to suffer a series of potential side effects, including metabolic change, declining physical strength and worsening fatigue. Recent studies found that the change of lifestyle interventions can help to alleviate some adverse reactions, but the results were controversial. Therefore, the aim of this review was to comprehensively evaluate the effects of these lifestyle interventions on the side effects on PCa patients who received ADT. METHODS: We searched several electronic databases, including ScienceDirect, PubMed, Cochrane library, CNKI and Wanfang database, without language restrictions. Among the literature, such lifestyle interventions as dietary advice, exercise and physical activities were carried out in the way of randomized controlled trials (RCTs) on PCa patients taking ADT. Pooled estimates were performed using fixed-effects or random-effects model. RESULTS: Eleven RCTs involving 905 participants were included in this review. Compared with usual care group, exercise intervention could significantly improve the quality of life (QoL) of PCa patients undergoing ADT (P = 0.05, SMD = 0.17, 95% CI -0.00 to 0.34), but exercise plus dietary advice could not significantly improve the QoL (P = 0.15, SMD = 0.45, 95% CI -0.17 to 1.08). Moreover, lifestyle intervention could significantly change body composition (P = 0.03, SMD = -0.1, 95% CI -0.19 to -0.01). However, there showed no obvious difference in mitigating fatigue and depression (P = 0.46, SMD = 0.11, 95% CI -0.18 to 0.39; P = 0.31, SMD = -0.18, 95% CI -0.54 to 0.17). CONCLUSIONS: The results of this meta-analysis from present study indicated that exercise interventions can better improve the QoL and alleviate treatment-related side effects on prostate cancer patients taking ADT, and better therapeutic regimens for PCa patients are likely to emerge in the process.

Efficacy and safety of liraglutide versus sitagliptin both in combination with metformin in patients with type 2 diabetes: A systematic review and meta-analysis.

BACKGROUND: The aim of this systematic review was to evaluate the efficacy and safety of liraglutide versus sitagliptin both in combination with metformin in patients with type 2 diabetes and provide reference basis for rational use of clinical drugs. METHODS: Several databases were searched, including Web of science, PubMed, Cochrane library, CNKI, and Wanfang database. Only randomized controlled trials (RCTs) of liraglutide versus sitagliptin both in combination with metformin up to 31 August 2016 were included. Data were extracted independently by 2 reviewers, and a fixed or random effects model were used to analyze outcomes that were expressed as odds ratio (OR) or mean difference (MD) and 95% confidence intervals (95% CIs) for different situations. RESULTS: Five RCTs involving 1440 participants were included. Compared with sitagliptin combination with metformin group, participants' treatment with 1.2 mg and 1.8 mg liraglutide with metformin could significantly lower the level of glycosylated hemoglobin (HbA1c) (P < .00001, MD = -0.35, 95% CI -0.51 to -0.20). Moreover, patients with 1.8 mg liraglutide group had significant body weight loss (P < .00001, MD = -1.12, 95% CI -1.54 to -0.70). However, there were no obvious differences in cutting down the systolic blood pressure and diastolic blood pressure between liraglutide-metformin and sitagliptin-metformin groups. The incidence of gastrointestinal problems was significantly higher than sitagliptin with metformin groups. CONCLUSION: The results of this meta-analysis indicated that Liraglutide added on to metformin therapy could significantly lower the level of HbA1c and increase body weight loss. Meanwhile, the adverse reactions such as gastrointestinal problems were common in the liraglutide treatment group. Thus, this will provide an important reference for the treatment of patients with type 2 diabetes.