Advances of pathogenesis and drug development in amyotrophic lateral sclerosis / 中国药理学通报

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting both upper and lower motor neurons. ALS patients develop progressive muscle atrophy, muscle weak and paralysis, finally died of respiratory failure. ALS is characterized by fast aggression and high mortality. What' s more, the disease is highly heterogeneous with unclear pathogenesis and lacks effective drugs for therapy. In this review, we summarize the main pathological mechanisms and the current drugs under development for ALS, which may provide a reference for the drug discovery in the future.

Erratum: Author correction to "Tumor-microenvironment activated duplex genome-editing nanoprodrug for sensitized near-infrared titania phototherapy" Acta Pharm Sin B (2022) 4224-4234

[This corrects the article DOI: 10.1016/j.apsb.2022.06.016.].

Logic-gated tumor-microenvironment nanoamplifier enables targeted delivery of CRISPR/Cas9 for multimodal cancer therapy

Recent innovations in nanomaterials inspire abundant novel tumor-targeting CRISPR-based gene therapies. However, the therapeutic efficiency of traditional targeted nanotherapeutic strategies is limited by that the biomarkers vary in a spatiotemporal-dependent manner with tumor progression. Here, we propose a self-amplifying logic-gated gene editing strategy for gene/H2O2-mediated/starvation multimodal cancer therapy. In this approach, a hypoxia-degradable covalent-organic framework (COF) is synthesized to coat a-ZIF-8 in which glucose oxidase (GOx) and CRISPR system are packaged. To intensify intracellular redox dyshomeostasis, DNAzymes which can cleave catalase mRNA are loaded as well. When the nanosystem gets into the tumor, the weakly acidic and hypoxic microenvironment degrades the ZIF-8@COF to activate GOx, which amplifies intracellular H+ and hypoxia, accelerating the nanocarrier degradation to guarantee available CRISPR plasmid and GOx release in target cells. These tandem reactions deplete glucose and oxygen, leading to logic-gated-triggered gene editing as well as synergistic gene/H2O2-mediated/starvation therapy. Overall, this approach highlights the biocomputing-based CRISPR delivery and underscores the great potential of precise cancer therapy.

HIV-1 Subtype Diversity and Factors Affecting Drug Resistance among Patients with Virologic Failure in Antiretroviral Therapy in Hainan Province, China, 2014-2020 / 生物医学与环境科学（英文）

OBJECTIVE@#This study aimed to determine the HIV-1 subtype distribution and HIV drug resistance (HIVDR) in patients with ART failure from 2014 to 2020 in Hainan, China.@*METHODS@#A 7-year cross-sectional study was conducted among HIV/AIDS patients with ART failure in Hainan. We used online subtyping tools and the maximum likelihood phylogenetic tree to confirm the HIV subtypes with pol sequences. Drug resistance mutations (DRMs) were analyzed using the Stanford University HIV Drug Resistance Database.@*RESULTS@#A total of 307 HIV-infected patients with ART failure were included, and 241 available pol sequences were obtained. Among 241 patients, CRF01_AE accounted for 68.88%, followed by CRF07_BC (17.00%) and eight other subtypes (14.12%). The overall prevalence of HIVDR was 61.41%, and the HIVDR against non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleotide reverse transcriptase inhibitors (NRTIs), and protease inhibitors (PIs) were 59.75%, 45.64%, and 2.49%, respectively. Unemployed patients, hypoimmunity or opportunistic infections in individuals, and samples from 2017 to 2020 increased the odd ratios of HIVDR. Also, HIVDR was less likely to affect female patients. The common DRMs to NNRTIs were K103N (21.99%) and Y181C (20.33%), and M184V (28.21%) and K65R (19.09%) were the main DRMs against NRTIs.@*CONCLUSION@#The present study highlights the HIV-1 subtype diversity in Hainan and the importance of HIVDR surveillance over a long period.

Glutamine synthetase-negative hepatocellular carcinoma has better prognosis and response to sorafenib treatment after hepatectomy / 中华医学杂志(英文版)

BACKGROUND@#Glutamine synthetase (GS) and arginase 1 (Arg1) are widely used pathological markers that discriminate hepatocellular carcinoma (HCC) from intrahepatic cholangiocarcinoma; however, their clinical significance in HCC remains unclear.@*METHODS@#We retrospectively analyzed 431 HCC patients: 251 received hepatectomy alone, and the other 180 received sorafenib as adjuvant treatment after hepatectomy. Expression of GS and Arg1 in tumor specimens was evaluated using immunostaining. mRNA sequencing and immunostaining to detect progenitor markers (cytokeratin 19 [CK19] and epithelial cell adhesion molecule [EpCAM]) and mutant TP53 were also conducted.@*RESULTS@#Up to 72.4% (312/431) of HCC tumors were GS positive (GS+). Of the patients receiving hepatectomy alone, GS negative (GS-) patients had significantly better overall survival (OS) and recurrence-free survival (RFS) than GS+ patients; negative expression of Arg1, which is exclusively expressed in GS- hepatocytes in the healthy liver, had a negative effect on prognosis. Of the patients with a high risk of recurrence who received additional sorafenib treatment, GS- patients tended to have better RFS than GS+ patients, regardless of the expression status of Arg1. GS+ HCC tumors exhibit many features of the established proliferation molecular stratification subtype, including poor differentiation, high alpha-fetoprotein levels, increased progenitor tumor cells, TP53 mutation, and upregulation of multiple tumor-related signaling pathways.@*CONCLUSIONS@#GS- HCC patients have a better prognosis and are more likely to benefit from sorafenib treatment after hepatectomy. Immunostaining of GS may provide a simple and applicable approach for HCC molecular stratification to predict prognosis and guide targeted therapy.

Analysis of urinary calculi composition in Longnan, Gansu province / 现代泌尿外科杂志

【Objective】 To analyze the composition of urinary calculi in Longnan, Gansu province, and the relationship between the composition and clinical characteristics of patients, so as to provide reference for the prevention and treatment of this disease. 【Methods】 The composition of 500 cases of urinary calculi hospitalized in our department during Apr. 2021 and Feb.2023 were analyzed using the infrared spectrum stone composition analyzer. The clinical characteristics of the patients were evaluated and analyzed. 【Results】 The male-to-female ration of patients was 2.70∶1. Most patients aged 21 to 60 years (437, 87.4%). Most cases were ureteral calculi (72.8%), followed by renal calculi (22.2%), and bladder calculi (5.0%). There were 166 cases of calcium oxalate calculi, 293 cases of calcium oxalate + carbonated apatite calculi, 24 cases of calcium oxalate + carbonated apatite + hydroxyl apatite calculi, 4 cases of calcium oxalate + calcium bicarbonate calculi, 7 cases of urate calculi, 6 cases of carbonated apatite + struvite calculi. Oxalate calculi were the most common in all age groups, and urate calculi were the most common in the 21 to 40 age group. Calcium oxalate calculi were most common in the ureter (127, 76.5%), significantly higher than in other sites (χ2=3.222, P=0.020). Calcium oxalate + calcium hydrogen phosphate calculi was the least common in the bladder, significantly different from the other parts (χ2=2.092, P=0.037). Magnesium ammonium phosphate hexahydrate and/or calcium carbonate or calcium oxalate calculi were the most common in the kidney (50.0%), significantly different from the other parts (χ2=9.448, P=0.007). 【Conclusion】 In Longnan area, the incidence of urinary calculi is significantly higher in male than in female. Ureteral calculi are mainly composed of calcium oxalate + carbonated apatite and calcium oxalate. According to different risk factors, individual prevention programs should be developed.

Comprehensive Study of Microsatellite Instability Testing and Its Comparison With Immunohistochemistry in Gastric Cancers

Purpose@#In this study, polymerase chain reaction (PCR)-based microsatellite instability (MSI) testing was comprehensively analyzed and compared with immunohistochemistry (IHC) for mismatch repair (MMR) protein expression in patients with gastric cancer (GC). @*Materials and Methods@#In 5,676 GC cases, PCR-based MSI testing using five microsatellites (BAT-26, BAT-25, D5S346, D2S123, and D17S250) and IHC for MLH1 were performed. Reevaluation of MSI testing/MLH1 IHC and additional IHC for MSH2, MSH6, and PMS2 were performed in discordant/indeterminate cases. @*Results@#Of the 5,676 cases, microsatellite stable (MSS)/MSI-low and intact MLH1 were observed in 5,082 cases (89.5%), whereas MSI-high (MSI-H) and loss of MLH1 expression were observed in 502 cases (8.8%). We re-evaluated the remaining 92 cases (1.6%) with a discordant/ indeterminate status. Re-evaluation showed 1) 37 concordant cases (0.7%) (18 and 19 cases of MSI-H/MMR-deficient (dMMR) and MSS/MMR-proficient (pMMR), respectively), 2) 6 discordant cases (0.1%) (3 cases each of MSI-H/pMMR and MSS/dMMR), 3) 14 MSI indeterminate cases (0.2%) (1 case of dMMR and 13 cases of pMMR), and 4) 35 IHC indeterminate cases (0.6%) (22 and 13 cases of MSI-H and MSS, respectively). Finally, MSI-H or dMMR was observed in 549 cases (9.7%), of which 47 (0.8%) were additionally confirmed as MSI-H or dMMR by reevaluation. Sensitivity was 99.3% for MSI testing and 95.4% for MMR IHC. @*Conclusions@#Considering the low incidence of MSI-H or dMMR, discordant/indeterminate results were occasionally identified in GCs, in which case complementary testing is required.These findings could help improve the accuracy of MSI/MMR testing in daily practice.

Clinicopathological features of rectal adenocarcinoma with enteroblastic differentiation / 中华病理学杂志

Objective: To investigate the clinicopathological features, immunophenotype, and genetic alterations of rectal adenocarcinoma with enteroblastic differentiation. Methods: Four cases of rectal adenocarcinoma with enteroblastic differentiation were collected at the Affiliated Hospital of Qingdao University, Qingdao, China (three cases) and Yantai Yeda Hospital of Shandong Province, China (one case) from January to December 2022. Their clinical features were summarized. Hematoxylin and eosin stain and immunohistochemical stain were performed, while next-generation sequencing was performed to reveal the genetic alterations of these cases. Results: All four patients were male with a median age of 65.5 years. The clinical manifestations were changes of stool characteristics, bloody stools and weight loss. All cases showed mixed morphology composed of conventional adenocarcinoma and adenocarcinoma with enteroblastic differentiation. Most of the tumors consisted of glands with tubular and cribriform features. In one case, almost all tumor cells were arranged in papillary structures. The tumor cells with enteroblastic differentiation were columnar, with relatively distinct cell boundaries and characteristic abundant clear cytoplasm, forming fetal gut-like glands. Immunohistochemically, the tumor cells were positive for SALL4 (4/4), Glypican-3 (3/4) and AFP (1/4, focally positive), while p53 stain showed mutated type in 2 cases. The next-generation sequencing revealed that 2 cases had TP53 gene mutation and 1 case had KRAS gene mutation. Conclusions: Rectal adenocarcinoma with enteroblastic differentiation is rare. It shows embryonal differentiation in morphology and immunohistochemistry, and should be distinguished from conventional colorectal adenocarcinoma.

Erratum: Author correction to "Coordinated regulation of BACH1 and mitochondrial metabolism through tumor targeted self-assembled nanoparticles for effective triple negative breast cancer combination therapy" Acta Pharmaceutica Sinica B 12 (2022) 3934-3951

[This corrects the article DOI: 10.1016/j.apsb.2022.06.009.].

MANF brakes TLR4 signaling by competitively binding S100A8 with S100A9 to regulate macrophage phenotypes in hepatic fibrosis

The mesencephalic astrocyte-derived neurotrophic factor (MANF) has been recently identified as a neurotrophic factor, but its role in hepatic fibrosis is unknown. Here, we found that MANF was upregulated in the fibrotic liver tissues of the patients with chronic liver diseases and of mice treated with CCl4. MANF deficiency in either hepatocytes or hepatic mono-macrophages, particularly in hepatic mono-macrophages, clearly exacerbated hepatic fibrosis. Myeloid-specific MANF knockout increased the population of hepatic Ly6Chigh macrophages and promoted HSCs activation. Furthermore, MANF-sufficient macrophages (from WT mice) transfusion ameliorated CCl4-induced hepatic fibrosis in myeloid cells-specific MANF knockout (MKO) mice. Mechanistically, MANF interacted with S100A8 to competitively block S100A8/A9 heterodimer formation and inhibited S100A8/A9-mediated TLR4-NF-κB signal activation. Pharmacologically, systemic administration of recombinant human MANF significantly alleviated CCl4-induced hepatic fibrosis in both WT and hepatocytes-specific MANF knockout (HKO) mice. This study reveals a mechanism by which MANF targets S100A8/A9-TLR4 as a "brake" on the upstream of NF-κB pathway, which exerts an impact on macrophage differentiation and shed light on hepatic fibrosis treatment.

Investigation on the current situation of the development of intensive care units in Inner Mongolia Autonomous Region in 2022 / 中华危重病急救医学

OBJECTIVE@#To investigate the development present situation of the department of critical care medicine in Inner Mongolia Autonomous Region (hereinafter referred to as Inner Mongolia), in order to promote the standardized and homogeneous development of critical care medicine in Inner Mongolia, and also provide a reference for discipline construction and resource allocation.@*METHODS@#A survey study was conducted in comprehensive intensive care unit (ICU) of tertiary and secondary hospitals in Inner Mongolia by online questionnaire survey and telephone data verification. The questionnaire was based on the Guidelines for the Construction and Management of Intensive Care Units (Trial) (hereinafter referred to as the Guidelines) issued by the National Health Commission in 2009 and the development trend of the discipline. The questionnaire covered six aspects, including hospital basic information, ICU basic information, personnel allocation, medical quality management, technical skill and equipment configuration. The questionnaire was distributed in September 2022, and it was filled out by the discipline leaders or department heads of each hospital.@*RESULTS@#As of October 24, 2022, a total of 101 questionnaires had been distributed, 85 questionnaires had been recovered, and the questionnaire recovery rate had reached 84.16%, of which 71 valid questionnaires had been collected in a total of 71 comprehensive ICU. (1) There were noticeable regional differences in the distribution of comprehensive ICU in Inner Mongolia, with a relatively weak distribution in the east and west, and the overall distribution was uneven. The development of critical care medicine in Inner Mongolia was still lacking. (2) Basic information of hospitals: the population and economy restricted the development of ICU. The average number of comprehensive ICU beds in the western region was only half of that in the central region (beds: 39.0 vs. 86.0), and the average number of ICU beds in the eastern region was in the middle (83.6 beds), which was relatively uneven. (3) Basic information of ICU: among the 71 comprehensive ICU surveyed, there were 44 tertiary hospitals and 27 secondary hospitals. The ratio of ICU beds to total beds in tertiary hospitals was significantly lower than that in secondary hospitals [(1.59±0.81)% vs. (2.11±1.07)%, P < 0.05], which were significantly lower than the requirements of the Guidelines of 2%-8%. The utilization rate of ICU in tertiary and secondary hospitals [(63.63±22.40)% and (44.65±20.66)%, P < 0.01] were both lower than the bed utilization rate required by the Guidelines (75% should be appropriate). (4) Staffing of ICU: there were 376 doctors and 1 117 nurses in tertiary hospitals, while secondary hospitals had 122 doctors and 331 nurses. There were significant differences in the composition ratio of the titles of doctors, the degree of doctors, and the titles of nurses between tertiary and secondary hospitals (all P < 0.05). Most of the doctors in tertiary hospitals had intermediate titles (attending physicians accounted for 41.49%), while most of the doctors in secondary hospitals had junior titles (resident physicians accounted for 43.44%). The education level of doctors in tertiary hospitals was generally higher than that in secondary hospitals (doctors: 2.13% vs. 0, masters: 37.24% vs. 8.20%). The proportion of nurses in tertiary hospitals was significantly lower than that in secondary hospitals (17.01% vs. 24.47%). The ratio of ICU doctors/ICU beds [(0.64±0.27)%, (0.59±0.34)%] and ICU nurses/ICU beds [(1.76±0.56)%, (1.51±0.48)%] in tertiary and secondary hospitals all failed to meet the requirements above 0.8 : 1 and 3 : 1 of the Guidelines. (5) Medical quality management of ICU: compared with secondary hospitals, the proportion of one-to-one drug-resistant bacteria care in tertiary hospitals (65.91% vs. 40.74%), multimodal analgesia and sedation (90.91% vs. 66.67%), and personal digital assistant (PDA) barcode scanning (43.18% vs. 14.81%) were significantly higher (all P < 0.05). (6) Technical skills of ICU: in terms of technical skills, the proportion of bronchoscopy, blood purification, jejunal nutrition tube placement and bedside ultrasound projects carried out in tertiary hospitals were higher than those in secondary hospitals (84.09% vs. 48.15%, 88.64% vs. 48.15%, 61.36% vs. 55.56%, 88.64% vs. 70.37%, all P < 0.05). Among them, the placement of jejunal nutrition tube, bedside ultrasound and extracorporeal membrane oxygenation were mainly completed independently in tertiary hospitals, while those in secondary hospitals tended to be completed in cooperation. (7) Equipment configuration of ICU: in terms of basic equipment, the ratio of the total number of ventilators/ICU beds in tertiary and secondary hospitals [0.77% (0.53%, 1.07%), 0.88% (0.63%, 1.38%)], and the ratio of injection pump/ICU beds [1.70% (1.00%, 2.56%), 1.25% (0.75%, 1.88%)] didn't meet the requirements of the Guidelines. The equipment ratio was insuffcient, which means that the basic needs of development had not been met yet.@*CONCLUSIONS@#The development of comprehensive ICU in Inner Mongolia has tended to mature, but there is still a certain gap in the development scale, personnel ratio and instruments and equipment compared with the Guidelines. Moreover, the comprehensive ICU appears the characteristics of relatively weak eastern and western regions, and the overall distribution is uneven. Therefore, it is necessary to increase efforts to invest in the construction of the department of critical care medicine.

Baveno-VII criteria to predict decompensation and initiate non-selective beta-blocker in compensated advanced chronic liver disease patients

Background/Aims@#The utility of Baveno-VII criteria of clinically significant portal hypertension (CSPH) to predict decompensation in compensated advanced chronic liver disease (cACLD) patient needs validation. We aim to validate the performance of CSPH criteria to predict the risk of decompensation in an international real-world cohort of cACLD patients. @*Methods@#cACLD patients were stratified into three categories (CSPH excluded, grey zone, and CSPH). The risks of decompensation across different CSPH categories were estimated using competing risk regression for clustered data, with death and hepatocellular carcinoma as competing events. The performance of “treating definite CSPH” strategy to prevent decompensation using non-selective beta-blocker (NSBB) was compared against other strategies in decision curve analysis. @*Results@#One thousand one hundred fifty-nine cACLD patients (36.8% had CSPH) were included; 7.2% experienced decompensation over a median follow-up of 40 months. Non-invasive assessment of CSPH predicts a 5-fold higher risk of liver decompensation in cACLD patients (subdistribution hazard ratio, 5.5; 95% confidence interval, 4.0–7.4). “Probable CSPH” is suboptimal to predict decompensation risk in cACLD patients. CSPH exclusion criteria reliably exclude cACLD patients at risk of decompensation, regardless of etiology. Among the grey zone, the decompensation risk was negligible among viral-related cACLD, but was substantially higher among the non-viral cACLD group. Decision curve analysis showed that “treating definite CSPH” strategy is superior to “treating all varices” or “treating probable CSPH” strategy to prevent decompensation using NSBB. @*Conclusions@#Non-invasive assessment of CSPH may stratify decompensation risk and the need for NSBB in cACLD patients.

Effect of Anmeidan on Serum Levels of BDNF， GFAP， and Irisin in Patients with Chronic Insomnia / 中国实验方剂学杂志

ObjectiveTo explore the effect of Anmeidan on the sleep quality and serum levels of brain-derived neurotrophic factor （BDNF）， glial fibrillary acidic protein （GFAP）， and irisin in the patients with chronic insomnia. MethodA multicenter， randomized， double-blind， placebo-controlled clinical study was carried out， including 480 patients with chronic insomnia （deficiency syndrome） in Wuhan （Hubei）， Guangzhou （Guangdong）， and Lanzhou （Gansu）. They were randomized into an observation group and a control group at a ratio of 1∶1. The observation group was orally administered with Anmeidan granules at a dose of 11 g， 3 times per day， and the control group with Anmeidan simulant at a dose of 11 g， 3 times per day， Both groups of patients received sleep education after enrollment. After 4 weeks of medication， the Athens insomnia scale （AIS） scores， Spiegel scale scores， and serum levels of BDNF， GFAP， and irisin were compared between the two groups as well as between before and after treatment. ResultA total of 480 adult patients with chronic insomnia were enrolled in this study， with 64 patients falled off. Finally， the 415 patients were included in the analysis， including 213 patients in the observation group and 202 patients in the control group. There was no difference in age or sex between the two groups of patients. Compared with before treatment， the treatment in both groups decreased the AIS and Spiegel scores （P<0.01）. After treatment， the observation group had lower AIS and Spiegel scores than the control group （P<0.01）. The treatment in the observation group slightly lowered the level of BDNF， elevated the level of irisin （P<0.05）， and lowered the level of GFAP （P<0.05） in the serum. After treatment， the observation group showed higher level of irisin （P<0.05） and lower levels of BDNF and GFAP in the serum than the control group. ConclusionAnmeidan may improve the sleep quality of patients with chronic insomnia by elevating the irisin level and lowering the GFAP level in the serum.

Comparison of digital PCR platforms using the molecular marker

Assays of clinical diagnosis and species identification using molecular markers are performed according to a quantitative method in consideration of sensitivity, cost, speed, convenience, and specificity. However, typical polymerase chain reaction (PCR) assay is difficult to quantify and have various limitations. In addition, to perform quantitative analysis with the quantitative real-time PCR (qRT-PCR) equipment, a standard curve or normalization using reference genes is essential. Within the last a decade, previous studies have reported that the digital PCR (dPCR) assay, a third-generation PCR, can be applied in various fields by overcoming the shortcomings of typical PCR and qRT-PCR assays. We selected Stilla Naica System (Stilla Technologies), Droplet Digital PCR Technology (Bio-Rad), and Lab on an Array Digital Real-Time PCR analyzer system (OPTOLANE) for comparative analysis among the various droplet digital PCR platforms currently in use commercially. Our previous study discovered a molecular marker that can distinguish Hanwoo species (Korean native cattle) using Hanwoo-specific genomic structural variation. Here, we report the pros and cons of the operation of each dPCR platform from various perspectives using this species identification marker. In conclusion, we hope that this study will help researchers to select suitable dPCR platforms according to their purpose and resources.

Research progress on cold ischemia injury of steatotic donor livers / 器官移植

Liver transplantation is a vital treatment for end-stage liver disease. However, the shortage of donor livers has limited the development of liver transplantation. How to expand the source of donor livers has become a challenge in the academic community. In recent years, the proportion of donors with non-alcoholic fatty liver disease (NAFLD) has been increased. Rational use of steatotic donor livers is a feasible approach to expand the donor pool. Cold ischemia injury during donor liver preservation before liver transplantation increases the risk of postoperative organ dysfunction. Therefore, it is of significance to unravel the mechanism and intervention measures of cold ischemia injury of steatotic donor livers. Cold ischemia injury of steatotic donor livers is characterized as the damage of mitochondria, lysosomes and endoplasmic reticulum at the organelle level, and up-regulated expression of adenosine monphosphate activated protein kinase (AMPK), aldehyde dehydrogenase 2 (ALDH2) and heme oxygenase (HO)-1 at the protein level. In this article, the research progresses on cold ischemia injury of steatotic donor livers and relevant intervention measures were reviewed.

Visual perception and its related factors of distance for Paralympic athletes with physical disabilities / 中国康复理论与实践

ObjectiveTo investigate the impact of posture and sports experience on distance perception in Paralympic athletes with lower limbs disabilities. MethodsFrom May to August, 2019, athletes were selected from the wheelchair racing team (n = 19) and the wheelchair fencing team (n = 16) in Shanghai, China. The athletes were tested the relative distance perception and absolute distance perception using the successive equal-appearing distance and blind walking tasks. ResultsThe interaction effects between sport and posture (F = 4.118, P < 0.05), sports events and distance judgment (F = 8.913, P < 0.01), and posture and distance judgment (F = 11.894, P < 0.01) were significant; while the main effects of sport (F = 7.467, P < 0.01) and posture (F = 11.918, P < 0.01) were significant; the relative distance judgment accuracy was better in the athletes of wheelchair fencing than in those of wheelchair racing, and in standing posture than those in sitting posture. ConclusionThe relative distance judgment accuracy is better for the Paralympic athletes standing and playing wheelchair fencers. There was no significant difference in the accuracy of absolute distance judgment between the different postures and the different sports.

Honokiol alleviated neurodegeneration by reducing oxidative stress and improving mitochondrial function in mutant SOD1 cellular and mouse models of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting both upper and lower motor neurons (MNs) with large unmet medical needs. Multiple pathological mechanisms are considered to contribute to the progression of ALS, including neuronal oxidative stress and mitochondrial dysfunction. Honokiol (HNK) has been reported to exert therapeutic effects in several neurologic disease models including ischemia stroke, Alzheimer's disease and Parkinson's disease. Here we found that honokiol also exhibited protective effects in ALS disease models both in vitro and in vivo. Honokiol improved the viability of NSC-34 motor neuron-like cells that expressed the mutant G93A SOD1 proteins (SOD1-G93A cells for short). Mechanistical studies revealed that honokiol alleviated cellular oxidative stress by enhancing glutathione (GSH) synthesis and activating the nuclear factor erythroid 2-related factor 2 (NRF2)-antioxidant response element (ARE) pathway. Also, honokiol improved both mitochondrial function and morphology via fine-tuning mitochondrial dynamics in SOD1-G93A cells. Importantly, honokiol extended the lifespan of the SOD1-G93A transgenic mice and improved the motor function. The improvement of antioxidant capacity and mitochondrial function was further confirmed in the spinal cord and gastrocnemius muscle in mice. Overall, honokiol showed promising preclinical potential as a multiple target drug for ALS treatment.

PRMT6 promotes tumorigenicity and cisplatin response of lung cancer through triggering 6PGD/ENO1 mediated cell metabolism

Metabolic reprogramming is a hallmark of cancer, including lung cancer. However, the exact underlying mechanism and therapeutic potential are largely unknown. Here we report that protein arginine methyltransferase 6 (PRMT6) is highly expressed in lung cancer and is required for cell metabolism, tumorigenicity, and cisplatin response of lung cancer. PRMT6 regulated the oxidative pentose phosphate pathway (PPP) flux and glycolysis pathway in human lung cancer by increasing the activity of 6-phospho-gluconate dehydrogenase (6PGD) and α-enolase (ENO1). Furthermore, PRMT6 methylated R324 of 6PGD to enhancing its activity; while methylation at R9 and R372 of ENO1 promotes formation of active ENO1 dimers and 2-phosphoglycerate (2-PG) binding to ENO1, respectively. Lastly, targeting PRMT6 blocked the oxidative PPP flux, glycolysis pathway, and tumor growth, as well as enhanced the anti-tumor effects of cisplatin in lung cancer. Together, this study demonstrates that PRMT6 acts as a post-translational modification (PTM) regulator of glucose metabolism, which leads to the pathogenesis of lung cancer. It was proven that the PRMT6-6PGD/ENO1 regulatory axis is an important determinant of carcinogenesis and may become a promising cancer therapeutic strategy.

Steroids and dihydroisocoumarin glycosides from Xylaria sp. by the one strain many compounds strategy and their bioactivities / 中国天然药物

The fungus Xylaria sp. KYJ-15 was isolated from Illigera celebica. Based on the one strain many compounds (OSMAC) strategy, the strain was fermented on potato and rice solid media, respectively. As a result, two novel steroids, xylarsteroids A (1) and B (2), which are the first examples of C28-steroid with an unusual β- and γ-lactone ring, respectively, along with two new dihydroisocoumarin glycosides, xylarglycosides A (3) and B (4), were identified. Their structures were elucidated by spectroscopic methods, X-ray diffraction and electronic circular dichroism (ECD) experiments. All isolated compounds were evaluated for cytotoxicity, DPPH radical scavenging activity, acetylcholinesterase inhibitory and antimicrobial effect. Compound 1 exhibited potent AChE inhibitory activity with an IC50 value of 2.61 ± 0.05 μmol·L-1. The β-lactone ring unit of 1 is critical for its AChE inhibitory activity. The finding was further confirmed through exploring the interaction of 1 with AChE by molecular docking. In addition, both compounds 1 and 2 exhibited obvious antibacterial activity against Bacillus subtilis with a minimum inhibitory concentration (MIC) of 2 μg·mL-1. Compounds 3 and 4 exhibited antibacterial activities against Staphylococcus aureus with MICs of 4 and 2 μg·mL-1, respectively, which also exhibited DPPH radical scavenging activity comparable to the positive control with IC50 values of 9.2 ± 0.03 and 13.3 ± 0.01 μmol·L-1, respectively.

MAGED4B Promotes Glioma Progression via Inactivation of the TNF-α-induced Apoptotic Pathway by Down-regulating TRIM27 Expression / 神经科学通报·英文版

MAGED4B belongs to the melanoma-associated antigen family; originally found in melanoma, it is expressed in various types of cancer, and is especially enriched in glioblastoma. However, the functional role and molecular mechanisms of MAGED4B in glioma are still unclear. In this study, we found that the MAGED4B level was higher in glioma tissue than that in non-cancer tissue, and the level was positively correlated with glioma grade, tumor diameter, Ki-67 level, and patient age. The patients with higher levels had a worse prognosis than those with lower MAGED4B levels. In glioma cells, MAGED4B overexpression promoted proliferation, invasion, and migration, as well as decreasing apoptosis and the chemosensitivity to cisplatin and temozolomide. On the contrary, MAGED4B knockdown in glioma cells inhibited proliferation, invasion, and migration, as well as increasing apoptosis and the chemosensitivity to cisplatin and temozolomide. MAGED4B knockdown also inhibited the growth of gliomas implanted into the rat brain. The interaction between MAGED4B and tripartite motif-containing 27 (TRIM27) in glioma cells was detected by co-immunoprecipitation assay, which showed that MAGED4B was co-localized with TRIM27. In addition, MAGED4B overexpression down-regulated the TRIM27 protein level, and this was blocked by carbobenzoxyl-L-leucyl-L-leucyl-L-leucine (MG132), an inhibitor of the proteasome. On the contrary, MAGED4B knockdown up-regulated the TRIM27 level. Furthermore, MAGED4B overexpression increased TRIM27 ubiquitination in the presence of MG132. Accordingly, MAGED4B down-regulated the protein levels of genes downstream of ubiquitin-specific protease 7 (USP7) involved in the tumor necrosis factor-alpha (TNF-α)-induced apoptotic pathway. These findings indicate that MAGED4B promotes glioma growth via a TRIM27/USP7/receptor-interacting serine/threonine-protein kinase 1 (RIP1)-dependent TNF-α-induced apoptotic pathway, which suggests that MAGED4B is a potential target for glioma diagnosis and treatment.