eIF3a is a N ⁶-methyladenosine (m⁶A) reader that regulates mRNA translation by recognizing m⁶A modifications of these mRNAs. It has been suggested that eIF3a may play an important role in regulating translation initiation via m⁶A during infection when canonical cap-dependent initiation is inhibited. However, the death of animal model studies impedes our understanding of the functional significance of eIF3a in immunity and regulation in vivo. In this study, we investigated the in vivo function of eIF3a using eIF3a knockout and knockdown mouse models and found that eIF3a deficiency resulted in splenic tissue structural disruption and multi-organ damage, which contributed to severe sepsis induced by Lipopolysaccharide (LPS). Ectopic eIF3a overexpression in the eIF3a knockdown mice rescued mice from LPS-induced severe sepsis. We further showed that eIF3a maintains a functional and healthy immune system by regulating B cell function and quantity through m⁶A modification of mRNAs. These findings unveil a novel mechanism underlying sepsis, implicating the pivotal role of B cells in this complex disease process regulated by eIF3a. Furthermore, eIF3a may be used to develop a potential strategy for treating sepsis.

Objective: To examine the prevalence and factors influencing the inconsistency for knowledge and behavior in condom use among college students, so as to provide suggestions for AIDS prevention and education in universities. Methods: From October to December 2019, a multistage cluster sampling method was employed to collect data relating to inconsistency for knowledge and behavior in condom use and other related factors among 1 303 students from six colleges in Zhuhai, China. Chi square test and Logistic regression were performed to analyze the influencing factors and moderating effect. Results: The reporting rate of in consistency of knowledge and behavior in condom use among college students was 41.1%. Multivariate Logistic regression analysis showed that seeking sexual partners offline was negatively correlated with inconsistency for knowledge and behavior in condom use ( OR=0.70, 95%CI =0.51-0.95). However, condom nonuse during the first sexual experience (OR=7.11, 95%CI=5.23-9.67), smoking before sex ( OR=1.47, 95%CI =1.07-2.02), drinking before sex ( OR=1.44, 95%CI =1.09-1.91), history of intimate partner violence ( OR=1.53, 95%CI =1.13-2.07), and having multiple sexual partners ( OR=1.69, 95%CI =1.25-2.29) were positively correlated with inconsistency for knowledge and behavior in condom use ( P <0.05). The moderating effect analysis showed that condom use during the first sexual experience had a moderating effect on smoking before sex and inconsistency for knowledge and behavior in condom use ( β=0.92, P <0.05). Among students who did not use condoms during the first sexual experience, a positive correlation was observed between smoking before sex and inconsistency for knowledge and behavior in condom use ( OR= 2.76 , 95%CI=1.09-6.99, P <0.05). However, no correlation was found between smoking before sex and inconsistency for knowledge and behavior in condom use ( OR=1.32, 95%CI=0.92-1.88, P >0.05) among students who used condoms during the first sexual experience. Conclusion High levels of inconsistency for knowledge and behavior in condom use are found among college students in Zhuhai City. Colleges should carry out sex education activities as soon as possible, and explore new health education models to promote the transformation of their knowledge into behavior.

To explore the pharmacogenomic markers that affect the platinum-based chemotherapy response in non-small-cell lung carcinoma (NSCLC), we performed a two-cohort of genome-wide association studies (GWAS), including 34 for WES-based and 433 for microarray-based analyses, as well as two independent validation cohorts. After integrating the results of two studies, the genetic variations related to the platinum-based chemotherapy response were further determined by fine-mapping in 838 samples, and their potential functional impact were investigated by eQTL analysis and in vitro cell experiments. We found that a total of 68 variations were significant at P < 1 × 10^-3 in cohort 1 discovery stage, of which 3 SNPs were verified in 262 independent samples. A total of 541 SNPs were significant at P < 1 × 10^-4 in cohort 2 discovery stage, of which 8 SNPs were verified in 347 independent samples. Comparing the validated SNPs in two GWAS, ADCY1 gene was verified in both independent studies. The results of fine-mapping showed that the G allele carriers of ADCY1 rs2280496 and C allele carriers of rs189178649 were more likely to be resistant to platinum-based chemotherapy. In conclusion, our study found that rs2280496 and rs189178649 in ADCY1 gene were associated the sensitivity of platinum-based chemotherapy in NSCLC patients.

Recent insights collectively suggest the important roles of lysyl oxidase (LysOX) in the pathological processes of several acute and chronic neurological diseases, but the molecular regulatory mechanisms remain elusive. Herein, we explore the regulatory role of LysOX in the seizure-induced ferroptotic cell death of neurons. Mechanistically, LysOX promotes ferroptosis-associated lipid peroxidation in neurons via activating extracellular regulated protein kinase (ERK)-dependent 5-lipoxygenase (Alox5) signaling. In addition, overexpression of LysOX via adeno-associated viral vector (AAV)-based gene transfer enhances ferroptosis sensitivity and aggravates seizure-induced hippocampal damage. Our studies show that pharmacological inhibition of LysOX with β-aminopropionitrile (BAPN) significantly blocks seizure-induced ferroptosis and thereby alleviates neuronal damage, while the BAPN-associated cardiotoxicity and neurotoxicity could further be reduced through encapsulation with bioresponsive amorphous calcium carbonate-based nanocarriers. These findings unveil a previously unrecognized LysOX-ERK-Alox5 pathway for ferroptosis regulation during seizure-induced neuronal damage. Suppressing this pathway may yield therapeutic implications for restoring seizure-induced neuronal injury.

Antipsychotic-induced weight gain (AIWG) is a common adverse effect of this treatment, particularly with second-generation antipsychotics, and it is a major health problem around the world. We aimed to review the progress of pharmacogenetic studies on AIWG in the Chinese population to compare the results for Chinese with other ethnic populations, identify the limitations and problems of current studies, and provide future research directions in China. Both English and Chinese electronic databases were searched to identify eligible studies. We determined that > 25 single-nucleotide polymorphisms in 19 genes have been investigated in association with AIWG in Chinese patients over the past few decades. HTR2C rs3813929 is the most frequently studied single-nucleotide polymorphism, and it seems to be the most strongly associated with AIWG in the Chinese population. However, many genes that have been reported to be associated with AIWG in other ethnic populations have not been included in Chinese studies. To explain the pharmacogenetic reasons for AIWG in the Chinese population, genome-wide association studies and multiple-center, standard, unified, and large samples are needed.
Antipsychotic Agents ; adverse effects ; Asian Continental Ancestry Group ; genetics ; China ; Genome-Wide Association Study ; Genotype ; Humans ; Lipid Metabolism ; genetics ; Neurosecretory Systems ; drug effects ; Pharmacogenomic Testing ; Polymorphism, Single Nucleotide ; Receptors, Adrenergic ; genetics ; Receptors, Dopamine ; genetics ; Receptors, Histamine ; genetics ; Receptors, Serotonin ; genetics ; Weight Gain ; drug effects ; genetics

Translation control in eukaryotes contributes significantly to gene expression regulation during cellular processes,which enables rapid changes of specific proteins to maintain cellular homeostasis.Eukaryotic translation is a multiple-step process that comprised of four phases:initiation,elongation,termination and ribosome recycling.The initiation phase is rate-limiting and orchestrated by a set of eukaryotic translation initiation factors (eIFs).Defects in translation initiation can result in a series of diseases.Among all eIFs,eIF3 is the largest and less-known initiation factor due to its intrinsic complexity.Aberration in eIF3A,the largest subunit of eIF3,is known to contribute to carcinogenesis and protection against evolution into higher-grade malignancy,and the altered expression or mutation of eIF3A affects the responses of cancer patients to platinum-based chemotherapy.Besides its role in cancinogenesis,eIF3A is also implicated in fibrosis,and the agents inhibiting eIF3A delay the progression of this disorder.The dual roles of eIF3A in tumorigenesis are probably due to the regulation of translation of different mRNAs at different stages of tumor progression by eIF3A.In tum the encoded products serve as pro-tumor or anti-tumor proteins at different stages.

Background:Platinum?based chemotherapy is the ifrst?line treatment of non?small cell lung cancer (NSCLC); it is therefore important to discover biomarkers that can be used to predict the effcacy and toxicity of this treatment. Four important transporter genes are expressed in the kidney, including organic cation transporter 2 (OCT2), multidrug and toxin extrusion 1 (MATE1), ATP?binding cassette subfamily B member 1 (ABCB1), and ATP?binding cassette subfamily C member 2 (ABCC2), and genetic polymorphisms in these genes may alter the effcacy and adverse effects of platinum drugs. This study aimed to evaluate the association of genetic polymorphisms of these transporters with platinum?based chemotherapy response and toxicity in NSCLC patients. Methods:A total of 403 Chinese NSCLC patients were recruited for this study. All patients were newly diagnosed with NSCLC and received at least two cycles of platinum?based chemotherapy. The tumor response and toxicity were evaluated after two cycles of treatment, and the patients’ genomic DNA was extracted. Seven single?nucleotide polymorphisms in four transporter genes were selected to investigate their associations with platinum?based chemo?therapy toxicity and response. Results:OCT2 rs316019 was associated with hepatotoxicity (P=0.026) and hematological toxicity (P=0.039), and MATE1 rs2289669 was associated with hematological toxicity induced by platinum (P=0.016). In addition,ABCC2 rs717620 was signiifcantly associated with the platinum?based chemotherapy response (P=0.031).ABCB1 polymor?phisms were associated with neither response nor toxicity. Conclusion:OCT2 rs316019,MATE1 rs2289669, andABCC2 rs717620 might be potential clinical markers for predicting chemotherapy toxicity and response induced by platinum?based treatment in NSCLC patients. Trial registration Chinese Clinical Trial Registry ChiCTR?RNC?12002892

Aim To assess the protective role of chry-sophanol in rats with diabetes-associated cognitive de-cline (DACD) and explore the potential molecular mechanisms.Methods The learning and memory performance was assessed by Morris water maze test;the activities of AChE,ChAT,iNOS and oxidative stress markers including CAT,SOD and GSH-PX in the hippocampus were detected using respective com-mercial kits.The level of BDNF was also measured with commercial ELISA kit.Results Chrysophanol significantly improved learning and memory functions in the diabetic groups.Additionally,the activities of AChE,BDNF also found to be evidently increased, while decreased activities of ChAT,iNOS,CAT,SOD and GSH-PX were observed in the hippocampus of dia-betic rats.Conclusions Collectively,chrysophanol has a protective role against DACD and this neuropro-tection is associated with increasing BDNF level.Chry-sophanol can also suppress the activities of iNOS, CAT,SOD and GSH-PX in diabetic rats.It is likely to be a novel therapeutic drug for the treatment of diabetic patients with cognitive deficits in clinical practice.

OBJECTIVE: To investigate the neuroprotective effects of osthole (OST) on glutamate-induced toxicity in hippocampal HT22 cells and to explore the correlation between the protection and phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) signaling pathway.
 METHODS: The cell injury model of HT22 was induced by glutamate and the cell viability was detected by MTS assay. The lactate dehydrogenase (LDH) release and the caspase-3 activity were determined by commercial kits. Western blot analysis was utilized to detect the protein levels of PI3K, Akt, p-PI3K and p-Akt. 
 RESULTS: OST markedly improved the cell survival and decreased the LDH release in glutamate-treated HT22 cells in a dose-dependent manner. Furthermore, the levels of p-PI3K and p-Akt proteins were significantly increased in glutamate and OST-co-treated HT22 cells. The effect of OST on p-Akt phosphorylation in HT22 cells was attenuated in the presence of PI3K specific inhibitor (LY294002).
 CONCLUSION OST protects HT22 cells from glutamate excitotoxicity through a mechanism involving the activation of PI3K/Akt signaling pathway.
Animals ; Caspase 3 ; metabolism ; Cell Line ; Cell Survival ; Chromones ; pharmacology ; Coumarins ; pharmacology ; Glutamic Acid ; adverse effects ; Hippocampus ; cytology ; Mice ; Morpholines ; pharmacology ; Neuroprotective Agents ; pharmacology ; Phosphatidylinositol 3-Kinases ; metabolism ; Phosphorylation ; Proto-Oncogene Proteins c-akt ; metabolism ; Signal Transduction

Translation is a fundamental step in regulation of gene expression and abnormalities in this process may lead to cancer. In eukaryotic cells, translation of mRNA is mainly regulated by many eukaryotic initiation factors ( eIFs) . EIF3 plays an impor-tant role in translational regulation, cell growth and oncogenesis. The largest subunit of eIF3, eIF3a may play a role as a regulator of mRNAs. The relationship between eIF3a and oncogenesis has been found. Moreover, the eIF3a mRNA is ubiquitously ex-pressed in different cancer cells and can modulate the cell cycle. However, some studies indicate that eIF3a could provide protec-tion against evolution into higher malignancy and reduce the re-sistance to chemotherapy . The patients of high eIF3a expression could get a better prognosis . In fact, the role of eIF3a is still un-clear in cancer cells. EIF3a may be involved in the process of tumor pathophysiology, but its regulatory role is undulatory.