Recently, the significantly higher incidence of Alzheimer's disease (AD) in women than in men has been attributed to the loss of neuroprotective estrogen after menopause. Does phytoestrogen have the ability to protect against amyloid-β (Aβ) toxicity? The aim of this study was to evaluate hypothesis that β-ecdysterone (β-Ecd) protects SH-SY5Y cells from Aβ-induced apoptosis by separate signaling pathways involving protein kinase B (Akt) and c-Jun N-terminal kinase (JNK). Here, we demonstrate that phytoestrogen β-Ecd inhibits Aβ-triggered mitochondrial apoptotic pathway, as indicated by Bcl-2/Bax ratio elevation, cytochrome c (cyt c) release reduction, and caspase-9 inactivation. Interestingly, β-Ecd upregulates Bcl-2 expression in SH-SY5Y cells under both basal and Aβ-challenged conditions, but downregulates Bax expression only in Aβ-challenged conditions. Subsequently, Akt-dependent NF-κB activation is required for Bcl-2 upregulation, but not Bax downregulation, in response to β-Ecd, which was validated by the use of LY294002 and Bay11-7082. Notably, β-Ecd attenuates the Aβ-evoked reactive oxygen species (ROS) production, apoptosis signal-regulating kinase 1 (ASK1) phosphorylation and JNK activation without altering the basal ASK1 phosphorylation and JNK activation. ROS-scavenging by diphenyleneiodonium (DPI) abrogated the ability of β-Ecd to alter the activation of ASK1. Simultaneously, inhibition of JNK by SP600125 abolished β-Ecd-induced Bax downregulation in Aβ-challenged SH-SY5Y cells, whereas LY294002 failed to do so. Consequently, β-Ecd possesses neuroprotection by different and complementary pathways, which together promote a Bcl-2/Bax ratio. These data support our hypothesis and suggest that β-Ecd is a promising candidate for the treatment of AD.

The aim of this study was to evaluate the hypothesis that emodin inhibits extracellular matrix (ECM)-related gene expression in activated hepatic stellate cells (HSCs) by blocking canonical or/and noncanonical components of transforming growth factor β1 (TGFβ1) intracellular signaling. Here, we demonstrate that emodin suppressed the gene expression of HSCs activation markers type I collagen, fibronectin, and α-smooth muscle actin, as well as HSCs proliferation. Mechanistically, emodin suppresses TGFβ1, TGFβ receptor II, TGFβ receptor I, and Smad4 gene expression, as well as Smad luciferase activity. Simultaneously, emodin reduced p38 mitogen-activated protein kinase (p38 ) activity but not c-Jun N-terminal kinases and extracellular signal-regulated kinases 1 and 2 phosphorylation in HSC-T6 cells. Interestingly, deprivation of TGFβ using a neutralizing antibody abolished emodin-mediated inhibitions of the both Smad transcriptional activity and p38 phosphorylation. Furthermore, emodin-mediated inhibition of HSCs activation could be partially blocked by PD98059 inhibition of p38 or short hairpin RNA-imposed knockdown of Smad4. Conversely, simultaneous inhibition of Smad4 and p38 pathways completely reverses the effects of emodin, suggesting that Smad and p38 locate downstream of TGFβ1 and regulate collagen genes expression in HSCs. Collectively, these data suggest that emodin is a promising candidate for the treatment of hepatic fibrosis.

The pathogenesis of Parkinson's disease (PD) is multifactorial event. Combination therapies might be more effective in controlling the disease. Thus, the studies reported were designed to test the hypothesis that gastrodin (GAS)-induced de novo synthesis of nuclear factor E2-related factor 2 (Nrf2) and isorhynchophylline (IRN) inhibition of Nrf2 nuclear export contribute to their additive or synergistic neuroprotective effect. Here, we have demonstrated that the combination of GAS and IRN (GAS/IRN) protects SH-SY5Y cells against 1-methyl-4-phenylpyridinium (MPP) toxicity in a synergistic manner. Concomitantly, GAS/IRN led to a statistically significant reduction of oxidative stress, as assessed by reactive oxygen species (ROS) and lipid hydroperoxides (LPO), and enhancement of both glutathione (GSH) and thioredoxin (Trx) systems compared with treatment with either agent alone in MPP-challenged SH-SY5Y cells. Interestingly, GAS but not IRN activated extracellular signal-regulated kinases 1 and 2 (ERK1/2), leading to a increase in de novo synthesis of Nrf2 and nuclear import of Nrf2. Simultaneously, IRN but not GAS suppressed both constitutive glycogen synthase kinase (GSK)-3β and Fyn activation, which inhibited nuclear export of Nrf2. Importantly, simultaneous inhibition of GSK-3β pathway by IRN and activation of ERK1/2 pathway by GAS synergistically induced accumulation of Nrf2 in the nucleus in SH-SY5Y cells challenged with MPP. Furthermore, the activation of the ERK1/2 pathway and inhibition of GSK-3β pathway by GAS/IRN are mediated by independent mechanisms. Collectively, these novel findings suggest an in vitro model of synergism between IRN and GAS in the induction of neuroprotection warrant further investigations in vivo.

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Objectives: We aimed to conduct a systematic review and meta-analysis to assess the impact of chronic opioid exposure on esophageal motility in patients undergoing manometric evaluation. Methods: Multiple databases were searched through October 2022 for original studies comparing the manometric results of patients who have used chronic opioids (for >90 days) to those who do not. The primary outcomes were esophageal dysmotility disorders. Three high-resolution manometry parameters were conducted as secondary outcomes. A random effects model was applied to calculate the odds ratio (OR) and means difference (MD) along with a 95% confidence interval. Results: Nine studies were included in this meta-analysis. Opioid use was associated with higher esophageal dysmotility disorders, including distal esophageal spasm (pooled OR 4.84, 95% CI 1.60–14.63, P = 0.005, I2=96%), esophagogastric junction outflow obstruction (pooled OR 5.13, 95% CI 2.11–12.43, P = 0.0003, I2=93%), and type III achalasia (pooled OR 4.15, 95% CI 2.15–8.03, P < 0.0001, I2=64%). No significant differences were observed for hypercontractile esophagus, type I achalasia, or type II achalasia. The basal lower esophageal sphincter pressure (MD 3.02, 95% CI 1.55–4.50, P < 0.0001, I2=90%), integrated relaxation pressure (MD 2.51, 95%CI 1.56–3.46, P < 0.00001, I2=99%), and distal contractile integral (MD 640.29, 95% CI 469.56–811.03, P < 0.00001, I2=91%) significantly differed between the opioid use and nonopioid use group. However, opioid use was associated with a lower risk of ineffective esophageal motility (pooled OR 0.68, 95% CI 0.49–0.95, P = 0.02, I2=53%). Conclusion: Chronic opioid exposure is associated with an increased frequency esophageal dysmotility disorders. Our results revealed that opioid use is significantly associated with Type III achalasia but not with Type I and II achalasia. Therefore, opioid treatment should be taken into account as a potential underlying risk factors when diagnosing these major esophageal motor abnormalities.