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 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.

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.

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Introduction Controversies remain regarding the safety of tocilizumab in the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In this study, we seek to describe the infectious complications after tocilizumab in COVID patients and determine the related risk factors. Methods A single-center retrospective observational study was conducted among adult patients with SARS-CoV-2 infection admitted between 06/01/2020 and 12/31/2021 who received tocilizumab at our institution. Baseline demographics and laboratory values are obtained through reviewing electronic medical records. Risk factors of infectious complications after tocilizumab are identified through regression analysis. Statistics are performed using SPSS. P-value <0.05 is considered statistically significant. Results Out of the 52 patients identified, infectious complications after tocilizumab were documented in 30 patients (57.7%). The most common infections include pneumonia, urinary tract infections, and bacteremia of unknown sources. Overall mortality was 42.3%. Through multivariate regression analysis, age more than 65, hyperglycemia on admission, and tocilizumab administration more than 2 days after hospital admission are independent risk factors associated with developing infections. Conclusions In real-world experience, infectious complications are not uncommon in COVID patients who receive tocilizumab. Early use of tocilizumab may be of benefit. More rigorous patient selection and monitoring should be explored in future studies.

AimsThe coronavirus disease 2019 (COVID‐19) pandemic has resulted in more than six million deaths worldwide. Studies on the impact of obesity on patients hospitalized with COVID‐19 pneumonia have been conflicting, with some studies describing worse outcomes in patients with obesity, while other studies reporting no difference in outcomes. Previous studies on obesity and critical illness have described improved outcomes in patients with obesity, termed the “obesity paradox”. The study assessed the impact of obesity on the outcomes of COVID‐19 hospitalizations, using a nationally representative database.Materials and MethodsICD‐10 code U071 was used to identify all hospitalizations with the principal diagnosis of COVID‐19 infection in the National Inpatient Database (NIS) 2020. ICD‐10 codes were used to identify outcomes and comorbidities. Hospitalizations were grouped based on body mass index (BMI). Multivariable logistic regression was used to adjust for demographic characteristics and comorbidities.ResultsA total of 56,033 hospitalizations were identified. 48% were male, 49% were white and 22% were black. Patients hospitalized with COVID‐19 pneumonia in the setting of obesity and clinically severe obesity were often younger. Adjusted for differences in comorbidities, there was a significant increase in mortality, incidence of mechanical ventilation, shock, and sepsis with increased BMI. The mortality was highest amongst hospitalizations with BMI >= 60, with an adjusted odds ratio of 2.66 (95% CI 2.18 to 3.24) compared to hospitalizations with normal BMI. There was increased odds of mechanical ventilation across all BMI groups above normal, with the odds of mechanical ventilation increasing with increasing BMI.ConclusionThe results show that obesity is independently associated with worse patient outcomes in COVID‐19 hospitalizations and is associated with higher in‐patient mortality and higher rates of mechanical ventilation. The underlying mechanism of this is unclear, and further studies are needed to investigate the cause of this.This article is protected by copyright. All rights reserved.

Background: Early-stage gastrointestinal neoplasms are frequently treated with conventional endoscopic mucosal resection (C-EMR). However, C-EMR frequently leads to incomplete resection of large colorectal lesions. Tip-in endoscopic mucosal resection (EMR), which was recently introduced for en bloc resection of colorectal neoplasms, minimizes slippage during the procedure. Methods: We conducted a systematic review and meta-analysis of published studies that compared Tip-in EMR with conventional EMR. We searched several electronic databases and included studies that reported on the primary outcomes of en bloc resection rate and complete resection rate, as well as secondary outcomes such as procedure time and procedure-related complications (including perforation and delayed bleeding rate). We used a random effects model to calculate odds ratios (ORs) with 95% CIs for dichotomous data and weighted mean differences with 95% CIs for continuous data. We also conducted several sensitivity analyses to assess the robustness of our findings. Results: A total of 11 studies involving 1244 lesions (684 in the Tip-in EMR group and 560 in C-EMR group) were included in the meta-analysis. Our meta-analysis showed that compared with conventional EMR, Tip-in EMR significantly increased the en bloc resection rate in patients with colorectal neoplasia (OR=3.61; 95% CI, 2.09-6.23; P<0.00001; I 2=0%) and had a higher complete resection rate (OR=2.49; 95% CI, 1.65-3.76; P<0.0001; I 2=0%). However, the procedure time and rates of procedure-related complications did not differ significantly between the 2 groups. Conclusions: Tip-in EMR outperformed C-EMR for both the en bloc and complete resection of colorectal lesions with similar rates of procedural complications.

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.