Alcohol consumption and all-cause and cause-specific mortality among US adults: prospective cohort study.

BACKGROUND: Previous studies have shown inconsistent findings regarding the association of light to moderate alcohol consumption with cause-specific mortality. Therefore, this study sought to examine the prospective association of alcohol consumption with all-cause and cause-specific mortality in the US population. METHODS: This was a population-based cohort study of adults aged 18 years or older in the National Health Interview Survey (1997 to 2014) with linkage to the National Death Index records through December 31, 2019. Self-reported alcohol consumption was categorized into seven groups (lifetime abstainers; former infrequent or regular drinkers; and current infrequent, light, moderate, or heavy drinkers). The main outcome was all-cause and cause-specific mortality. RESULTS: During an average follow-up of 12.65 years, among the 918,529 participants (mean age 46.1 years; 48.0% male), 141,512 adults died from all causes, 43,979 from cardiovascular disease (CVD), 33,222 from cancer, 8246 from chronic lower respiratory tract diseases, 5572 from accidents (unintentional injuries), 4776 from Alzheimer's disease, 4845 from diabetes mellitus, 2815 from influenza and pneumonia, and 2692 from nephritis, nephrotic syndrome, or nephrosis. Compared with lifetime abstainers, current infrequent, light, or moderate drinkers were at a lower risk of mortality from all causes [infrequent-hazard ratio: 0.87; 95% confidence interval: 0.84 to 0.90; light: 0.77; 0.75 to 0.79; moderate 0.82; 0.80 to 0.85], CVD, chronic lower respiratory tract diseases, Alzheimer's disease, and influenza and pneumonia. Also, light or moderate drinkers were associated with lower risk of mortality from diabetes mellitus and nephritis, nephrotic syndrome, or nephrosis. In contrast, heavy drinkers had a significantly higher risk of mortality from all causes, cancer, and accidents (unintentional injuries). Furthermore, binge drinking ≥ 1 day/week was associated with a higher risk of mortality from all causes (1.15; 1.09 to 1.22), cancer (1.22; 1.10 to 1.35), and accidents (unintentional injuries) (1.39; 1.11 to 1.74). CONCLUSIONS: Infrequent, light, and moderate alcohol consumption were inversely associated with mortality from all causes, CVD, chronic lower respiratory tract diseases, Alzheimer's disease, and influenza and pneumonia. Light or moderate alcohol consumption might also have a beneficial effect on mortality from diabetes mellitus and nephritis, nephrotic syndrome, or nephrosis. However, heavy or binge had a higher risk of all-cause, cancer, and accidents (unintentional injuries) mortality.

The two sides of resistance-resilience relationship in both aboveground and belowground communities in the Eurasian steppe.

The ongoing nitrogen (N) deposition has led to profound changes in aboveground and belowground ecosystems. However, the stability of plant and soil microbial community toward N addition in terms of resistance and resilience is less understood. We established a long-running field trial (2008-2018) in a series of N applications in combination with a mowing and fencing (unmown) treatment in a semiarid steppe. We assessed the resistance via ongoing N treatment of one subplot and the resilience via discontinuing N treatment in another to promote natural recovery since 2014. Plant resistance was negatively correlated with N application rate, while microbial resistance was independent of N rate. Mowing significantly reduced plant resistance and resilience, reduced soil microbial resistance but improved its resilience. Generally, plants are more resilient but less resistant to N than soil microbes. The two sides of resistance-resilience relationship were revealed: trade-offs exist between resistance and resilience for both plants and microbes at the community level; and trade-offs between resistance and resilience cannot be scaled down to species/group level. This study provided an important theoretical basis for the recovery and conservation of semiarid steppe and new insight into resistance-resilience relationship.

Foxp2 regulates anatomical features that may be relevant for vocal behaviors and bipedal locomotion.

Fundamental human traits, such as language and bipedalism, are associated with a range of anatomical adaptations in craniofacial shaping and skeletal remodeling. However, it is unclear how such morphological features arose during hominin evolution. FOXP2 is a brain-expressed transcription factor implicated in a rare disorder involving speech apraxia and language impairments. Analysis of its evolutionary history suggests that this gene may have contributed to the emergence of proficient spoken language. In the present study, through analyses of skeleton-specific knockout mice, we identified roles of Foxp2 in skull shaping and bone remodeling. Selective ablation of Foxp2 in cartilage disrupted pup vocalizations in a similar way to that of global Foxp2 mutants, which may be due to pleiotropic effects on craniofacial morphogenesis. Our findings also indicate that Foxp2 helps to regulate strength and length of hind limbs and maintenance of joint cartilage and intervertebral discs, which are all anatomical features that are susceptible to adaptations for bipedal locomotion. In light of the known roles of Foxp2 in brain circuits that are important for motor skills and spoken language, we suggest that this gene may have been well placed to contribute to coevolution of neural and anatomical adaptations related to speech and bipedal locomotion.

Maize residue retention shapes soil microbial communities and co-occurrence networks upon freeze-thawing cycles.

Maize residue retention is an effective agricultural practice for improving soil fertility in black soil region, where suffered from long freezing-thawing periods and intense freeze-thawing (FT) cycles. However, very few studies have examined the influence of maize residue retention on soil microbial communities under FT cycles. We investigated the response of soil microbial communities and co-occurrence networks to maize residue retention at different FT intensities over 12 cycles using a microcosm experiment conditioned in a temperature incubator. Our results indicated that maize residue retention induced dramatic shifts in soil archaeal, bacterial and fungal communities towards copiotroph-dominated communities. Maize residue retention consistently reduced soil fungal richness across all cycles, but this effect was weaker for archaea and bacteria. Normalized stochastic ratio analysis revealed that maize residue retention significantly enhanced the deterministic process of archaeal, bacterial and fungal communities. Although FT intensity significantly impacted soil respiration, it did not induce profound changes in soil microbial diversity and community composition. Co-occurrence network analysis revealed that maize residue retention simplified prokaryotic network, while did not impact fungal network complexity. The network robustness index suggested that maize residue retention enhanced the fungal network stability, but reduced prokaryotic network stability. Moreover, the fungal network in severe FT treatment harbored the most abundant keystone taxa, mainly being cold-adapted fungi. By identifying modules in networks, we observed that prokaryotic Module #1 and fungal Module #3 were enhanced by maize residue retention and contributed greatly to soil quality. Together, our results showed that maize residue retention exerted stronger influence on soil microbial communities and co-occurrence network patterns than FT intensity and highlighted the potential of microbial interactions in improving soil functionality.

Core bacteria and fungi in response to residue retention and their contribution to soil multifunctionality in maize agroecosystem.

Core microbiome has been proven to play crucial roles in soil function. However, we still lack knowledge on how core microbiome responds to crop residue retention, and whether they contribute to this process. Consequently, we examined the effect of residue retention on soil core and non-core microbial communities in maize seedling, mature stage and freezing period based on a multi-site field experiment in Sanjiang Plain, Northeast China. Totally, 247 bacterial amplicon sequence variants (ASVs) and 109 fungal ASVs were identified as core microbiota. Both core and non-core bacterial/fungal community composition were significantly influenced by residue retention across all study sites. Especially, the core fungal community shifted towards a saprotroph-dominated community. Normalized stochastic ratio pattern revealed that that deterministic process dominated both core and non-core microbial community assembly processes. Residue retention enhanced the deterministic process of core microbial community assembly, while exhibited opposite effect on non-core microbial community. This study also revealed that soil fungi were more sensitive to residue retention than bacteria, with a larger proportion of core fungi were enriched or depleted by residue retention. In addition, residue retention complicated core bacterial co-occurrence network, while simplified fungal network. Our results pointed out both no reduction in microbial diversity or collapse in microbial network structure after repeated freezing-thawing cycles. The potential function of core microbiome was evaluated through random forest analysis and structural equation model, the results indicated core microbiome contributed more to multifunctionality than non-core microbiome. Overall, this study strengthened our understanding of soil core microbiome in response to residue retention, and highlighted their importance in maintaining soil multifunctionality.

Insight into N2O emission and denitrifier communities under different aeration intensities in composting of cattle manure from perspective of multi-factor interaction analysis.

Nitrous oxide (N2O) emission from composting is a significant contributor to greenhouse effect and ozone depletion, which poses a threat to environment. To address the challenge of mitigating N2O emission during composting, this study investigated the response of N2O emission and denitrifier communities (detected by metagenome sequencing) to aeration intensities of 6 L/min (C6), 12 L/min (C12), and 18 L/min (C18) in cattle manure composting using multi-factor interaction analysis. Results showed that N2O emission occurred mainly at mesophilic phase. Cumulative N2O emission (QN2O, 9.79 mg·kg-1 DW) and total nitrogen loss (TN loss, 16.40 %) in C12 composting treatment were significantly lower than those in the other two treatments. The lower activity of denitrifying enzymes and the more complex and balanced network of denitrifiers and environmental factors might be responsible for the lower N2O emission. Denitrification was confirmed to be the major pathway for N2O production. Moisture content (MC) and Luteimonas were the key factors affecting N2O emission, and nosZ-carrying denitrifier played a significant role in reducing N2O emission. Although relative abundance of nirS was lower than that of nirK significantly (P < 0.05), nirS was the key gene influencing N2O emission. Community composition of denitrifier varied significantly with different aeration treatments (R2 = 0.931, P = 0.001), and Achromobacter was unique to C12 at mesophilic phase. Physicochemical factors had higher effect on QN2O, whereas denitrifying genes, enzymes and NOX- had lower effect on QN2O in C12. The complex relationship between N2O emission and the related factors could be explained by multi-factor interaction analysis more comprehensively. This study provided a novel understanding of mechanism of N2O emission regulated by aeration intensity in composting.

Improving prediction of N2O emissions during composting using model-agnostic meta-learning.

Nitrous oxide (N2O) represents a significant environmental challenge as a harmful, long-lived greenhouse gas that contributes to the depletion of stratospheric ozone and exacerbates global anthropogenic greenhouse warming. Composting is considered a promising and economically feasible strategy for the treatment of organic waste. However, recent research indicates that composting is a source of N2O, contributing to atmospheric pollution and greenhouse effect. Consequently, there is a need for the development of effective, cost-efficient methodologies to quantify N2O emissions accurately. In this study, we employed the model-agnostic meta-learning (MAML) method to improve the performance of N2O emissions prediction during manure composting. The highest R2 and lowest root mean squared error (RMSE) values achieved were 0.939 and 18.42 mg d-1, respectively. Five machine learning methods including the backpropagation neural network, extreme learning machine, integrated machine learning method based on ELM and random forest, gradient boosting decision tree, and extreme gradient boosting were adopted for comparison to further demonstrate the effectiveness of the MAML prediction model. Feature analysis showed that moisture content of structure material and ammonium concentration during composting process were the two most significant features affecting N2O emissions. This study serves as proof of the application of MAML during N2O emissions prediction, further giving new insights into the effects of manure material properties and composting process data on N2O emissions. This approach helps determining the strategies for mitigating N2O emissions.

How do intellectual property demonstration cities contribute to low-carbon development? Evidence from China.

An intellectual property demonstration city (IPDC) not only promotes innovation, but also brings many unexpected gains, the most prominent of which is carbon reduction. Unfortunately, few scholars have included IPDC and carbon emissions in a unified research framework, ignoring the role of intellectual property protection in environmental governance. Therefore, this paper investigates the impact of IPDC on carbon emissions through a multi-period difference-in-difference (DID) model, a spatial DID model, and a mediating effect model with IPDC policy as a quasi-natural experiment. The research results are as follows: (1) IPDC policy has a significant inhibitory effect on carbon emissions. Compared to non-pilot cities, IPDC policy can reduce carbon emissions by about 20.6%. (2) There are temporal and regional heterogeneity of the IPDC policy on carbon emissions. More specifically, the carbon reduction effect of IPDC is more effective in large cities and cities with richer human capital, stricter environmental regulation, and higher financial development. Meanwhile, the policy effects in 2012 and 2015 are larger than those in 2018, while the policy effects in 2014, 2016, and 2019 are not significant. (3) IPDC policy reduces carbon emissions mainly by stimulating innovation and green innovation, and promoting R&D element agglomeration. (4) IPDC policy has obvious spatial spillover effects and leads to the surrounding cities becoming pollution havens. The above conclusions have implications for designing a better urbanization model to promote innovative development and reduce carbon emissions.

Cost-effectiveness analysis of serplulimab plus chemotherapy in the first-line treatment for PD-L1-positive esophageal squamous cell carcinoma in China.

Objective: The ASTRUM-007 trial (NCT03958890) demonstrated that serplulimab plus chemotherapy administered every 2-week significantly improved progression-free and overall survival in patients with previously untreated, programmed death-ligand 1 (PD-L1) positive advanced esophageal squamous-cell carcinoma (ESCC). This study was aimed to investigate the cost-effectiveness of serplulimab plus chemotherapy in the first-line treatment of PD-L1-positive advanced ESCC. Methods: A partitioned survival model with a 2-week cycle and a 10-year time horizon was constructed from the Chinese healthcare system perspective. The survival data, direct medical costs and utilities were derived from the ASTRUM-007 trial, YAOZHI database and published sources. Total costs, quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs) were calculated. Scenario, one-way and probabilistic sensitivity analyses were performed to assess the uncertainty around model parameters. Results: Compared with chemotherapy, serplulimab plus chemotherapy provided additional 0.27 QALYs with an incremental cost of $33,460.86, which had an ICER of $124,483.07 per QALY. The subgroup analyses revealed that the ICERs of serplulimab plus chemotherapy were $134,637.42 and $105,589.71 in advanced ESCC patients with 1 ≤ CPS < 10 and CPS ≥ 10, respectively. The price of serplulimab, patient weight, utility values and discount rate were the most influential parameters on base-case results. At a willingness-to-pay threshold of three times per capita GDP ($40,587.59) in 2022, the probability of serplulimab plus chemotherapy being cost-effective was 0% compared with chemotherapy. When the price of serplulimab decreased by 70%, the probabilities of serplulimab plus chemotherapy being cost-effective were 81.42%, 67.74% and 96.75% in advanced ESCC patients with PD-L1-positive, PD-L1 1≤CPS<10 and CPS≥10, respectively. Conclusion: Serplulimab plus chemotherapy in the first-line treatment for PD-L1-positive advanced ESCC might not be cost-effective in China.

Rearranged Homoadamantane-Type Polycyclic Polyprenylated Acylphloroglucinols from Hypericum pseudohenryi.

Hypseudohenones A-C (1-3), the first rearranged homoadamantane-type polycyclic polyprenylated acylphloroglucinols, were isolated from Hypericum pseudohenryi. Their structures with an unprecedented tricyclo[4.3.1.13,8]undecane-2,4,10-trione core were determined by spectroscopic analysis, quantum-chemical calculations, and X-ray crystallography. A method for determining the relative configuration at C-3 was established by the peak shape of H-28 or J-value of H-3/H-28. Moreover, 2-3 exhibited significant AChE inhibitory activity, and the interactions of 2-3 with AChE were evaluated by molecular docking.

Neuroimaging uncovers distinct relationships of glymphatic dysfunction and motor symptoms in Parkinson's disease.

BACKGROUND: Studies of glymphatic dysfunction in Parkinson's disease (PD) patients have attracted much attention in recent years. However, the relationships between glymphatic dysfunction and clinical symptoms remains unclear. OBJECTIVES: To determine whether the diffusion tensor image analysis along the perivascular space (DTI-ALPS) affect the severity and types of motor and non-motor symptoms in PD patients. METHODS: De novo PD patients and controls who performed both DTI and 123I-DaTscan single photon emission computed tomography (SPECT) scanning were retrieved from the international multicenter Parkinson's Progression Marker Initiative (PPMI) cohort. Glymphatic system was evaluated by the DTI-ALPS. Motor symptoms were assessed by Movement Disorders Society Unified Parkinson's Disease Rating Scale III (MDS-UPDRS-III). The influence of glymphatic activity on motor and non-motor symptoms was explored by multivariate linear regression models. RESULTS: A total of 153 PD patients (mean age 60.97 ± 9.47 years; 99 male) and 67 normal controls (mean age 60.10 ± 10.562 years; 43 male) were included. The DTI-ALPS index of PD patients was significantly lower than normal controls (Z = - 2.160, p = 0.031). MDS-UPDRS III score (r = - 0.213, p = 0.008) and subscore for rigidity (r = - 0.177, p = 0.029) were negatively correlated with DTI-ALPS index. The DTI-ALPS index was significantly associated with MDS-UPDRS-III score (ß = - 0.160, p = 0.048) and subscore for rigidity (ß = - 0.170, p = 0.041) after adjusting for putamen dopamine transporter availability and clinical factors. CONCLUSIONS: Our results showed distinct relationships between glymphatic dysfunction and the severity and types of PD motor symptoms, suggesting the potential of DTI-ALPS index as a biomarker for PD motor symptoms.

Caged polycyclic polyprenylated acylphloroglucinols as Cav3.2 low voltage-gated Ca2+ channel inhibitors from Hypericum curvisepalum.

Five caged polycyclic polyprenylated acylphloroglucinols including an unprecedented octahydro-2,5-methanoindene skeleton (1) were discovered from Hypericum curvisepalum. Biologically, 1 and 2 are potent Cav3.2 T-type Ca2+ channel inhibitors with negligible effect on the cardiovascular antitarget, the human ether-à-go-go-related gene potassium channel. Additionally, 2 indicates strong antinociception in the mouse acetic acid writhing test.

Trends in Abdominal Obesity and Central Adiposity Measures by Dual-Energy X-Ray Absorptiometry Among US Children: 2011-2018.

Objective: Previous studies that have reported trends on abdominal obesity among US children were usually based on anthropometric assessments. However, little is known about the recent trends in central adiposity measures by DXA and abdominal obesity since 2011-2012. Study Design: A serial cross-sectional analysis of US population-weighted data among children from NHANES 2011 to 2018 was conducted. Results: Between 2011-2012 and 2017-2018, there was a relatively stable trend among children aged 8-19 years in trunk fat and trunk fat percentage. During the same time periods, there were no significant changes in prevalence of abdominal obesity by waist circumference (18.6 vs. 21.1%) among those aged 2-19 years, and abdominal obesity by WHtR (34.1 vs. 36.2%) among those aged 6-19 years. However, a significant increase trend among boys aged 2-19 years was found in prevalence of abdominal obesity by waist circumference (16.1-22.7%; P = 0.004). For Mexican American youth and non-Hispanic Asian boys, there is a significant increase in mean trunk fat percentage and waist circumference. Conclusion: Between 2011-2012 and 2017-2018, there have been no significant changes in central adiposity measured by DXA and prevalence of abdominal obesity among US children. Our study further supports that there is an urgent need to improve their lifestyle to reduce abdominal obesity for US children, especially for Mexican American youth and non-Hispanic Asian boys.

Discovery of dearomatized isoprenylated acylphloroglucinols with colon tumor suppressive activities in mice via inhibiting NFκB-FAT1-PDCD4 signaling activation.

Dearomatized isoprenylated acylphloroglucinols (DIAPs) are specific natural products mainly distributed in the plants of genus Hypericum. In this study, guided by HPLC-UV screening, 46 DIAPs (approximately 70% of all DIAPs) including 20 new ones and an unprecedented architecture, were discovered from the roots of Hypericum henryi, which were elucidated by comprehensive spectroscopic, X-ray crystallography, and ECD methods. Compounds 1-7, 39, and 41-42 exhibited remarkable cytotoxicities (IC50 = 0.84-5.63 µM) in human colon cancer HCT116 cells, in which 2 and 6 possessed selective cytotoxicities towards colon cancer cells. The preliminary structure-activity relationships of these tested compounds were discussed. In addition, mechanistic investigations demonstrated that 2 and 6 could significantly suppress the expressions of NFκB, FAT1, and promoted novel tumor suppressor gene PDCD4 in HCT116 cells. Furthermore, in HCT116 colon xenograft-bearing mouse model, treatments with 2 and 6 reduced the growth of xenograft tumors in dose-dependent manner. Expressions of FAT1 in tumors were also decreased in mice treated with 2 and 6, suggesting their anti-tumor effects were via FAT1 signaling pathway. In conclusion, this is the first report on the mechanistic and in vivo studies of DIAP, indicating that these metabolites can be considered as a new type of anti-colon cancer lead agents for further drug development.

Disentangling the role of salinity-sodicity in shaping soil microbiome along a natural saline-sodic gradient.

Increasing salinity and sodicity have been recognized as threats to soil fertility and crop yield worldwide. In recent years, salt-affected soils have received great attentions due to the shortage of arable land. This study therefore aims to characterize soil bacterial community, assembly process and co-occurrence network along natural saline-sodic gradients across Songnen Plain, Northeast China. As revealed by Miseq sequencing, 8482 bacterial OTUs were annotated at 97% identity across 120 soil samples. Our results indicated that soil salinity-sodicity not only significantly decreased bacterial richness and but also impacted bacterial community composition. The dominant bacterial phyla included Proteobacteria (28.89%), Actinobacteria (19.96%) and Gemmatimonadetes (16.71%). By applying threshold indicator species analysis (TITAN), OTUs from Gemmatimonadetes were found to be the taxa with the most prevalent and strongest preference for high salinity-sodicity. Null model analysis revealed that the majority (76.4%) of ßNTI values were below -2 or above 2, indicating deterministic process was dominant across all samples. Notably, deterministic process contributed to a greater extent in higher saline-sodic soils. The bacterial co-occurrence network was more complex in slightly saline-sodic soils than in moderately and extremely saline-sodic soils, reflected by more nodes, more hubs and stronger connections, which was mainly driven by soil pH. These results provide strong evidence that salinity-sodicity was a key determinant in shaping soil bacterial community, assembly process and co-occurrence network pattern.

Gender Differences in Chronic Obstructive Pulmonary Disease Symptom Clusters.

Purpose: Previous research has indicated that female and male patients may experience different levels of symptoms. However, no studies of chronic obstructive pulmonary disease (COPD) patients have compared the number and types of symptom clusters identified in male and female patients. Therefore, the purpose of this study was to investigate gender differences in symptom clusters among COPD patients. Patients and Methods: A total of 371 eligible patients were enrolled in the study. We assessed nine COPD symptoms, namely, dyspnea, cough, sputum, chest tightness, sleep quality, fatigue, frailty, anxiety, and depression. Exploratory factor analyses were used to explore the underlying clusters of the COPD symptoms. Results: Underlying the nine symptoms, female patients had 2 clusters, and male patients had 3 clusters. Specifically, the three general symptoms poor sleep, fatigue, and frailty loaded on the same symptom cluster with anxiety and depression in female patients, while the same 3 general symptoms loaded on the same symptom cluster with chest tightness and dyspnea in male patients. Moreover, cough and sputum not only were more common in male patients but also loaded together on a separate symptom cluster. Conclusion: Our findings suggest that in order to improve fatigue, frailty, and poor sleep quality, symptom management strategies should more closely address anxiety and depression in female patients as well as chest tightness and dyspnea in male patients. Smoking cessation is particularly important in male COPD patients because they account for a much higher proportion of smokers and are more likely to have cough and sputum. These findings signify the importance of identifying and implementing gender-tailored symptom management strategies to relieve symptom burden in COPD patients to enhance their quality of life.

Novel Meroterpenoids from Hypericum patulum: Highly Potent Late Nav1.5 Sodium Current Inhibitors.

Hypulatones A and B (1 and 2), two racemic meroterpenoids possessing an unprecedented spiro[benzofuran-2,1'-cycloundecan]-4'-ene-4,6(5H)-dione core, were characterized from Hypericum patulum. Compound 2 was found to significantly inhibit the late current of Nav1.5 (late INa, IC50 = 0.2 µM). Importantly, 2 exhibited remarkable separation (>100-fold) of late INa relative to peak INa and notable selectivity over Cav3.1, Kv1.5, and hERG. 1 showed comparable inhibition on late INa compared to that of 2 with poorer selectivity.

Adipogenesis Inhibitory Activity of Hypersampsone P from Hypericum subsessile.

Adamantane polycyclic polyprenylated acylphloroglucinols (PPAPs) with caged architecture, a special class of hybrid natural products, is specifically rich in the plant family Guttiferae, especially Hypericum or Garcinia genus. Hypersampsone P is one of Adamantane PPAPs compounds extracted from Hypericum subsessile. Here we have chosen, screened ten PPAPs and identified one of them showed an activity in inhibiting of adipocytes differentiation. Particularly, the compound, hypersampsone P, blunted the adipocyte differentiation dose-dependently. Moreover, hypersampsone P down-regulated the expressions of several key regulators for adipogenesis, including PPARγ and FABP4. The treatment of cells at the early stage of adipogenesis by hypersampsone P induced the greatest blunting of adipocyte differentiation and the effect might be involved in the LKB1-AMPK signaling pathway.

Dearomatized Isoprenylated Acylphloroglucinol Derivatives with Potential Antitumor Activities from Hypericum henryi.

A series of dearomatized isoprenylated acylphloroglucinols derivatives, hyperhenols A-E (1-5), as well as seven known analogues (6-12), were characterized from Hypericum henryi. Their structures were determined by combination of NMR, ECD spectroscopy, and X-ray diffraction analysis. Compounds 1 and 6-8 were tested to exhibit potential antitumor properties, of which 6 and 7 inhibited cell growth through inducing apoptosis and cell cycle arrest. In addition, these compounds could induce autophagy and PINK1/Parkin-mediated mitophagy in cancer cell lines, as well as suppress lung cancer A549 cells metastasis in vitro.

Knockout of ASAP1 induces autophagy in papillary thyroid carcinoma by inhibiting the mTOR signaling pathway.

Due to lymph node metastasis and infiltration, surgery for PTC (papillary thyroid carcinoma) is a high-risk treatment strategy. Our work reports for the first time that ASAP1 (ArfGAP with SH3 Domain, Ankyrin Repeat and PH Domain 1) is highly expressed in PTC and that its high expression is related to autophagy. Autophagy and ASAP1 expression in 40 PTC tissues and normal tissues were detected by immunofluorescence. We used the lentiviral CRISPR/Cas9 nickase to generate stable cell lines. The difference in autophagy levels between the ASAP1 KO group and the control group was determined by Western blot and immunofluorescence analyses. We added chloroquine (CQ) to verify that ASAP1 increased the formation of autophagosomes rather than reducing their degradation. The expression of mTOR activity-related proteins (P-P70S6K, P-MTOR) was studied by Western blotting. ASAP1 was upregulated while autophagy was downregulated in PTC tissues compared to normal tissues. Knockout of ASAP1 induced autophagy in both MDA-T32 and MDA-T85 cells. Knockout of ASAP1 attenuated the activation of the mTOR signaling pathway. Our studies demonstrated that ASAP1 is upregulated while autophagy is reduced in PTC tissues. In addition, knockout of ASAP1 induces autophagy in PTC by inhibiting the mTOR signaling pathway.