Versatile Polymerization-Induced Emission Polymers from Barbier Polymerization of Cinnamic Esters with Tunable Emission.

Cinnamic ester is a common and abundant chemical substance, which can be extracted from natural plants. Compared with traditional esters, cinnamic ester contains α,ß-unsaturated carbonyl structure with multiple reactive sites, resulting in more abundant reactivities and chemical structures. Here, a versatile polymerization-induced emission (PIE) is successfully demonstrated through Barbier polymerization of cinnamic ester. Attributed to its abundant reactivities of α,ß-unsaturated carbonyl structure, Barbier polymerization of cinnamic esters with different organodihalides gives polyalcohol and polyketone via 1,2-addition and 1,4-addition, respectively, which is also confirmed by small molecular model reactions. Meanwhile, these organodihalides dependant polyalcohol and polyketone exhibit different non-traditional intrinsic luminescence (NTIL) from aggregation-induced emission (AIE) type to aggregation-caused quenching (ACQ) type, where novel PIE luminogens (PIEgens) are revealed. Further potential applications in explosive detection are carried out, where it achieves TNT detection sensitivity at ppm level in solution and ng level on the test paper. This work therefore expands the structure and functionality libraries of monomer, polymer and NTIL, which might cause inspirations to different fields including polymer chemistry, NTIL, AIE and PIE.

The m6A reader IGF2BP1 attenuates the stability of RPL36 and cell proliferation to mediate benzene hematotoxicity by recognizing m6A modification.

Benzene exposure leads to hematotoxicity, and epigenetic modification is considered to be a potential mechanism of benzene pathogenesis. As a newly discovered post-transcriptional modification, the roles of N6-methyladenosine (m6A) in benzene hematotoxicity are still unclear. m6A can only exert its gene regulatory function after being recognized by m6A reading proteins. In this study, we found that the expression of m6A reader IGF2BP1 decreased in benzene poisoning workers and in 20 µM benzene metabolite 1,4-BQ-treated AHH-1 cells. Further overexpression of IGF2BP1 in mice alleviated 50 ppm benzene-induced hematopoietic damage, suggesting that IGF2BP1 plays a critical role in benzene hematotoxicity. Next, we examined transcriptome-wide m6A methylation in vitro to search for target genes of IGF2BP1. We found that benzene metabolite 1,4-BQ treatment altered the m6A methylation levels of various genes. The comprehensive analysis of mRNA expression and m6A methylation uncovered that the hypomethylated Ribosomal Protein L36 (RPL36) and its consequent reduced expression impaired cell proliferation. Mechanically, m6A modification reduced RNA stability to down-regulate RPL36 expression. Moreover, overexpression of IGF2BP1 relieved RPL36 reduction and cell proliferation inhibition caused by benzene in vitro and in vivo by directly binding with RPL36 mRNA. In conclusion, the m6A reader IGF2BP1 attenuates the stability of RPL36 and cell proliferation to mediate benzene hematotoxicity by recognizing m6A modification. IGF2BP1 and RPL36 may be key molecules and potential therapeutic targets for benzene hematotoxicity.

Integrative pharmacology reveals the mechanisms of Erzhi pills, A traditional Chinese formulation, stimulating melanogenesis.

ETHNOPHARMACOLOGICAL RELEVANCE: Erzhi pills (EZP), a traditional Chinese medicine formula prescribed for the treatment of vitiligo, has shown promising efficacy. However, the oral bioactive components and mechanisms underlying the promotion of melanogenesis by EZP remain unclear. AIM OF THE STUDY: This study aimed to investigate the pharmacological basis and mechanism of EZP in promoting melanogenesis. MATERIALS AND METHODS: UHPLC-TOF-MS analysis was used to identify absorbed phytochemicals in serum after oral administration of EZP. Network pharmacology methods were used to predict potential targets and pathways involved in the melanogenic activity of EZP, resulting in the construction of a "compound-target-pathway" network. Zebrafish and B16F10 cells were used to evaluate the effects of EZP on tyrosinase activity and melanin content. Western blot and ELISA analyses were used to validate the effects of EZP on melanogenesis-related proteins, including MITF, TYR, CREB, p-CREB, and cAMP. RESULTS: UHPLC-TOF-MS analysis identified 36 compounds derived from EZP in serum samples. Network pharmacology predictions revealed 89 target proteins associated with the identified compounds and closely related to vitiligo. GO and KEGG analyses indicated the involvement of the cAMP/PKA signaling pathway in the promotion of melanogenesis by EZP. Experimental results showed that EZP increased tyrosinase activity and melanin content in zebrafish and B16F10 cells without inducing toxicity. Western blot and ELISA results suggested that the melanogenic effect of EZP may be related to the activation of the cAMP/PKA signaling pathway. These results confirm the feasibility of combining serum pharmacological and network pharmacological approaches. CONCLUSIONS: EZP have the potential to increase tyrosinase activity and melanin content in zebrafish and cells possibly through activation of the cAMP/PKA pathway.

Case report: Identification of a novel triplication of alpha-globin gene by the third-generation sequencing: pedigree analysis and genetic diagnosis.

BACKGROUND: Thalassemia, a common autosomal hereditary blood disorder worldwide, mainly contains α- and ß-thalassemia. The α-globin gene triplicates allele is harmless for carriers, but aggravates the phenotype of ß-thalassemia. Therefore, it is particularly crucial to accurately detect the structural variants of α-globin gene clusters. CASE REPORT: We reported a 28-year-old man, the proband, with microcytic hypochromic anemia. From pedigree analysis, his mother and sister had hypochromic microcytosis, and his father was normal. Genetic testing of thalassemia identified a novel α-globin gene triplicate named αααanti4.2del726bp (NC_000016.10:g.170769_174300dupinsAAAAAA) by third-generation sequencing (TGS) in the proband and his father, which was further validated by multiplex ligation-dependent probe amplification (MLPA) and Sanger sequencing. The genotypes of the proband's mother and sister were both -α3.7/αα compounded with heterozygous HBB:c.126_129delCTTT. They were categorized as silent α-thalassemia with co-inheritance of ß-thalassemia trait. The proband's genotype additionally had the α-globin gene triplicates compared with his mother and sister, which increased the imbalance between α/ß-globin, so the proband had more severe hematological parameters. The proband's wife was diagnosed as HBA2:c.427T > C heterozygosis, and his daughter had the novel α-globin gene triplicates compounded with HBA2:c.427T > C, therefore the girl might be asymptomatic. CONCLUSION: The identification of the novel α-globin gene triplicates provides more insight for the research of thalassemia variants and indicates that TGS has significant advantages on genetic testing of thalassemia for the reliability, accuracy and comprehensiveness.

Sec1 regulates intestinal mucosal immunity in a mouse model of inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a common immune-mediated condition with its molecular pathogenesis remaining to be fully elucidated. This study aimed to deepen our understanding of the role of FUT2 in human IBD, by studying a new surrogate gene Sec1, a neighboring gene of Fut2 and Fut1 that co-encodes the α 1,2 fucosyltransferase in mice. CRISPR/Cas9 was used to prepare Sec1 knockout (Sec1-/-) mice. IBD was induced in mice using 3% w/v dextran sulphate sodium. Small interfering RNA (siRNA) was employed to silence Sec1 in murine colon cancer cell lines CT26.WT and CMT93. IBD-related symptoms, colonic immune responses, proliferation and apoptosis of colon epithelial cells were assessed respectively to determine the role of Sec1 in mouse IBD. Impact of Sec1 on the expression of death receptor 5 (DR5) and other apoptosis-associated proteins were determined. Sec1 knockout was found to be associated with deterioration of IBD in mice and elevated immune responses in the colonic mucosa. Silencing Sec1 in CT26.WT and CMT93 cells led to greater secretion of inflammatory cytokines IL-1ß, IL-6 and TNF-α. Cell counting kit 8 (CCK8) assay, flow cytometry and TUNEL detection suggested that Sec1 expression promoted the proliferation of colon epithelial cells, inhibited cell apoptosis, reduced cell arrest in G0/G1 phase and facilitated repair of inflammatory injury. Over-expression of DR5 and several apoptosis-related effector proteins was noticed in Sec1-/- mice and Sec1-silenced CT26.WT and CMT93 cells, supporting a suppressive role of Sec1 in cell apoptosis. Our results depicted important regulatory roles of Sec1 in mouse IBD, further reflecting the importance of FUT2 in the pathogenesis of human IBD.

Dexmedetomidine Preconditioning Attenuates Myocardial Ischemia/Reperfusion Injury in Rats by Suppressing Mitophagy Via Activating Α2-Adrenergic Receptor. / O Pré-Condicionamento com Dexmedetomidina Atenua a Lesão de Isquemia/Reperfusão Miocárdica em Ratos, Suprimindo a Mitofagia Via Ativação do Receptor Α2-Adrenérgico.

BACKGROUND: Dexmedetomidine (DEX), a specific α2-adrenergic receptor agonist, is protective against myocardial ischemia/reperfusion injury (MIRI). However, the association between DEX preconditioning-induced cardioprotection and mitophagy suppression remains unclear. OBJECTIVE: Hence, we aimed to investigate whether DEX preconditioning alleviates MIRI by suppressing mitophagy via α2-adrenergic receptor activation. METHOD: Sixty isolated rat hearts were treated with or without DEX before inducing ischemia and reperfusion; an α2-adrenergic receptor antagonist, yohimbine (YOH), was also administered before ischemia, alone or with DEX. The heart rate (HR), left ventricular diastolic pressure (LVDP), left ventricular end-diastolic pressure (LVEDP), maximal and minimal rate of left ventricular pressure development (±dp/dtmax), and myocardial infarction size were measured. The mitochondrial ultrastructure and autophagosomes were assessed using transmission electron microscopy. Mitochondrial membrane potential and reactive oxygen species (ROS) levels were measured using JC-1 and dichloride hydrofluorescein diacetate assays, respectively. The expression levels of the mitophagy-associated proteins Beclin1, LC3II/I ratio, p62, PINK1, and Parkin were detected by western blotting. RESULTS: Compared with the control group, in the ischemia/reperfusion group, the HR, LVDP, and ±dp/dtmax were remarkably decreased (p< 0.05), whereas LVEDP and infarct sizes were significantly increased (p< 0.05). DEX preconditioning significantly improved cardiac dysfunction reduced myocardial infarction size, maintained mitochondrial structural integrity, increased mitochondrial membrane potential, inhibited autophagosomes formation, and decreased ROS production and Beclin1, LC3II/I ratio, PINK1, Parkin, and p62 expression(p< 0.05). When DEX and YOH were combined, YOH canceled the effect of DEX, whereas the use of YOH alone had no effect. CONCLUSION: Therefore, DEX preconditioning was cardioprotective against MIRI in rats by suppressing mitophagy via α2-adrenergic receptor activation.

FUNDAMENTO: A dexmedetomidina (DEX), um agonista específico do receptor α2-adrenérgico, é protetora contra lesão de isquemia/reperfusão miocárdica (I/R). No entanto, a associação entre a cardioproteção induzida pelo pré-condicionamento DEX e a supressão da mitofagia permanece pouco clara. OBJETIVO: Portanto, nosso objetivo foi investigar se o pré-condicionamento com DEX alivia a I/R, suprimindo a mitofagia via ativação do receptor α2-adrenérgico. MÉTODO: Sessenta corações de ratos isolados foram tratados com ou sem DEX antes de induzir isquemia e reperfusão; um antagonista do receptor α2-adrenérgico, a ioimbina (YOH), também foi administrado antes da isquemia, isoladamente ou com DEX. A frequência cardíaca (FC), pressão diastólica do ventrículo esquerdo (PDVE), pressão diastólica final do ventrículo esquerdo (PDFVE), taxa máxima e mínima de desenvolvimento da pressão ventricular esquerda (±dp/dtmax) e tamanho do infarto do miocárdio foram medidos. A ultraestrutura mitocondrial e as autofagossomas foram avaliadas por microscopia eletrônica de transmissão. O potencial de membrana mitocondrial e os níveis de espécies reativas de oxigênio (ROS) foram medidos usando os ensaios JC-1 e diacetato de diclorodi hidrofluoresceína, respectivamente. Os níveis de expressão das proteínas associadas à mitofagia Beclin1, relação LC3II/I, p62, PINK1 e Parkin foram detectados por western blotting. RESULTADOS: Em comparação com o grupo controle, no grupo isquemia/reperfusão, a FC, PDVE e ±dp/dtmax foram notavelmente diminuídas (p<0,05), enquanto os tamanhos da PDFVE e do infarto aumentaram significativamente (p<0,05). O pré-condicionamento com DEX melhorou significativamente a disfunção cardíaca, reduziu o tamanho do infarto do miocárdio, manteve a integridade estrutural mitocondrial, aumentou o potencial de membrana mitocondrial, inibiu a formação de autofagossomas e diminuiu a produção de ROS e a relação Beclin1, relação LC3II/I, expressão PINK1, Parkin e p62(p<0,05). Quando DEX e YOH foram combinados, o YOH cancelou o efeito da DEX, enquanto o uso de YOH sozinha não teve efeito. CONCLUSÃO: Portanto, o pré-condicionamento DEX foi cardioprotetor contra I/R em ratos, suprimindo a mitofagia por meio da ativação do receptor α2-adrenérgico.

Cryo-EM structures of human GPR34 enable the identification of selective antagonists.

GPR34 is a functional G-protein-coupled receptor of Lysophosphatidylserine (LysoPS), and has pathogenic roles in numerous diseases, yet remains poorly targeted. We herein report a cryo-electron microscopy (cryo-EM) structure of GPR34 bound with LysoPS (18:1) and Gi protein, revealing a unique ligand recognition mode with the negatively charged head group of LysoPS occupying a polar cavity formed by TM3, 6 and 7, and the hydrophobic tail of LysoPS residing in a lateral open hydrophobic groove formed by TM3-5. Virtual screening and subsequent structural optimization led to the identification of a highly potent and selective antagonist (YL-365). Design of fusion proteins allowed successful determination of the challenging cryo-EM structure of the inactive GPR34 complexed with YL-365, which revealed the competitive binding of YL-365 in a portion of the orthosteric binding pocket of GPR34 and the antagonist-binding-induced allostery in the receptor, implicating the inhibition mechanism of YL-365. Moreover, YL-365 displayed excellent activity in a neuropathic pain model without obvious toxicity. Collectively, this study offers mechanistic insights into the endogenous agonist recognition and antagonist inhibition of GPR34, and provides proof of concept that targeting GPR34 represents a promising strategy for disease treatment.

Mitochondrial dynamics-related genes DRP1 and OPA1 contributes to early diagnosis of cognitive impairment in diabetes.

BACKGROUND AND AIM: DRP1 and OPA1 play important roles in mitochondrial fusion and fission. However, the role of DRP1 and OPA1 amplification in mitochondrial cognitive impairment has not been reported. This study aimed to investigate the relationship between DRP1 and OPA1 and the risk of cognitive impairment. METHODS: In this study, 45 elderly patients with diabetes admitted to the Lianyungang Second People's Hospital from September 2020 to January 2021 were included. The patients were divided into normal group, mild cognitive impairment group and dementia group by using MMSE score, and the clinical characteristics of the three groups were compared. The amplification multiples of the two genes' DNA were calculated by ΔΔCT and defined as 2- K. Spearman rank correlation was used to analyze the correlation between the DNA amplification multiples of patients' DRP1 and OPA1 and AD8 and MoCA scores. The sensitivity and specificity of DNA amplification multiples of DRP1 and OPA1 to predict clinical outcomes of diabetic cognitive impairment were evaluated using Receiver operator characteristic (ROC) curves. Multiple logistic regression was used to evaluate the relationship between DNA amplification factor of DRP1 and OPA1 and cognitive function. RESULTS: DRP1(2- K) and OPA1(2- K) significantly increased and decreased in dementia and MCI groups compared with the normal group (P ≤ 0.001). The DNA amplification factor of DRP1 was positively correlated with AD8 score and negatively correlated with MoCA score (P < 0.001). The DNA amplification factor of OPA1 was positively correlated with the MoCA score (P = 0.0002). Analysis of ROCs showed that the DNA amplification factor of OPA1 had a higher predictive value for dementia (P < 0.0001), and that it had a higher predictive value when used in combination with DRP1. Multiple logistic regression results showed that increased DNA amplification in DRP1 was associated with increased risk of dementia (OR 1.149;95%CI,1.035-1.275), and increased DNA amplification in OPA1 was associated with decreased risk of MCI (OR 0.004;95%CI,0.000-0.251) and dementia (OR 0.000;95%CI,0.000-0.134). CONCLUSION: DNA amplification multiples of DRP1 and OPA1 are associated with the risk of dementia in elderly patients and may serve as potential biomarkers.

Ketyl Radical Anion Mediated Radical Polymerization and Anionic Ring-Opening Polymerization to Give Polymers with Low Molecular Weight Distribution.

The development of novel polymerization capable of yielding polymers with low molecular weight distribution (D) is essential and significant in polymer chemistry, where monofunctional initiator contains only one initiation site in these polymerizations generally. Here, ketyl radical anion species is introduced to develop a novel Ketyl Mediated Polymerization (KMP), which enables radical polymerization at carbon radical site and anionic ring-opening polymerization at oxygen anion site, respectively. Meanwhile, polymerization and corresponding organic synthesis generally couldn't be performed simultaneously in one pot. Through KMP, organic synthesis and polymerization are achieved in one pot, where small molecules (cyclopentane derivates) and polymers with low D are successfully prepared under mild condition simultaneously. At the initiation step, both organic synthesis and polymerization are initiated by single electron transfer reaction with ketyl radical anion formation. Cyclopentane derivates are synthesized through 3-3 coupling reaction and cyclization. Polystyrene and polycaprolactone with low D and a full monomer conversion are prepared by KMP via radical polymerization and anionic ring-opening polymerization, respectively. This work therefore enables both organic synthesis and two different polymerizations from same initiation system, which saves time, labour, resource and energy and expands the reaction mode and method libraries of organic chemistry and polymer chemistry.

LncRNA OBFC2A modulated benzene metabolites-induced autophagy and apoptosis by interacting with LAMP2.

Exposure to benzene results in peripheral blood cell reduction, aplastic anemia, and leukemia. We previously observed that the lncRNA OBFC2A was upregulated significantly in benzene-exposed workers and correlated with reduced blood cell counts. However, the role of lncRNA OBFC2A in benzene hematotoxicity remains unclear. In this study, we discovered that lncRNA OBFC2A was regulated by oxidative stress and played roles in cell autophagy and apoptosis caused by the benzene metabolite 1,4-Benzoquinone (1,4-BQ) in vitro. Mechanistically, protein chip, RNA pull-down, and FISH colocalization uncovered that lncRNA OBFC2A directly bound to LAMP2, a regulator of chaperone-mediated autophagy (CMA), and upregulated its expression in 1,4-BQ-treated cells. LncRNA OBFC2A knockdown alleviated LAMP2 overexpression caused by 1,4-BQ, which confirmed their regulatory relationship. In conclusion, we demonstrate that lncRNA OBFC2A mediates 1,4-BQ-induced apoptosis and autophagy by interacting with LAMP2. LncRNA OBFC2A could serve as a biomarker for hematotoxicity caused by benzene.

Associations between antipsychotics and the risk of incident cardiovascular diseases in individuals with schizophrenia: a nested case-control study.

BACKGROUND: The association between antipsychotics and cardiovascular diseases (CVDs) remains significant yet unestablished, especially in Chinese populations. OBJECTIVE: To investigate the risk of CVDs associated with antipsychotics among Chinese individuals with schizophrenia. METHODS: We conducted a nested case-control study on individuals diagnosed with schizophrenia in Shandong, China. The case group included individuals diagnosed with incident CVDs between 2012 and 2020. Each case was randomly matched with up to three controls. We used weighted logistic regression models to assess the risk of CVDs associated with antipsychotics and restricted cubic spline analysis to explore the dose-response relationship. FINDINGS: In total, 2493 cases and 7478 matched controls were included in the analysis. Compared with non-users, any antipsychotics use was associated with higher risk of any CVDs (weighted OR=1.54, 95% CI 1.32 to 1.79), with the risk mainly driven by ischaemic heart diseases (weighted OR=2.26, 95% CI 1.71 to 2.99). Treatments with haloperidol, aripiprazole, quetiapine, olanzapine, risperidone, sulpiride and chlorpromazine were associated with increased risk of CVDs. A non-linear dose-response relationship between dosage of antipsychotics and risk of CVDs was observed, with a sharp increase in risk in the beginning and then flattening out with higher doses. CONCLUSIONS: Use of antipsychotics was associated with increased risk of incident CVDs among individuals with schizophrenia, and the risk varied substantially among different antipsychotics and specific CVDs. CLINICAL IMPLICATIONS: Clinicians should consider the cardiovascular risk of antipsychotics and choose the appropriate type and dose of drugs in the treatment of schizophrenia.

Association between anxiety and metabolic syndrome: An updated systematic review and meta-analysis.

Objective: Previous studies have demonstrated an association between anxiety and metabolic syndrome (MetS). However, the association is still controversial. This updated meta-analysis aimed to reanalyze the association between anxiety and MetS. Methods: We comprehensively searched PubMed, Embase and Web of Science for all related studies published before January 23, 2023. Observational studies that informed effect size with 95% confidence interval (CI) for the association between anxiety and MetS were included. According to heterogeneity between studies, fixed or random effects models were applied to calculate the pooled effect size. Publication bias was examined by funnel plots. Results: The research included 24 cross-sectional studies: 20 studies used MetS as the dependent variable with a pooled OR of 1.07 (95% CI: 1.01-1.13) and four studies used anxiety as the dependent variable with a pooled OR of 1.14 (95% CI: 1.07-1.23). Three cohort studies were found: two studies detected the association of baseline anxiety with the risk of MetS, one of the studies demonstrated a significant association, but a similar result was not found in another study; one study showed no significant association between baseline MetS and the risk of anxiety. Conclusion: Cross-sectional studies indicated an association between anxiety and MetS. The results from cohort studies are still inconsistent and limited. More large-scale prospective studies are needed to further reveal the causal relationship of anxiety with MetS.

Full-Length Transcriptome Analysis of the Ichthyotoxic Harmful Alga Heterosigma akashiwo (Raphidophyceae) Using Single-Molecule Real-Time Sequencing.

The raphidophyte Heterosigma akashiwo is a harmful algal species. The bloom of this organism has been associated with the massive mortality of fish in many coastal waters. To investigate the molecular mechanism of H. akashiwo blooms, having a reliable reference transcriptome of this species is essential. Therefore, in this study, a full-length transcriptome of H. akashiwo was obtained by single-molecule real-time sequencing. In total, 45.44 Gb subread bases were generated, and 16,668 unigenes were obtained after the sequencing data processing. A total of 8666 (52.00%) unigenes were successfully annotated using seven public databases. Among them, mostly phosphorus and nitrogen metabolism genes were detected. Moreover, there were 300 putative transcription factors, 4392 putative long non-coding RNAs, and 7851 simple sequence repeats predicted. This study provides a valuable reference transcriptome for understanding how H. akashiwo blooms at a molecular level.

Association between autoimmune diseases of the nervous system and schizophrenia: A systematic review and meta-analysis of cohort studies.

INTRODUCTION: Numerous studies have found an association between autoimmune diseases of the nervous system (ADNS) and schizophrenia (SCZ), but the findings remain controversial. We conducted the first meta-analysis to summarize the current evidence from cohort studies that evaluated the association between ADNS and SCZ. METHODS: PubMed, Web of Science, and Embase were comprehensively searched until May 30, 2022 for articles on the association between ADNS and SCZ. Every included study was reported effect size with 95% CIs for the association between ADNS and SCZ. Meta-regression and subgroup analysis were used to assess the heterogeneity. RESULTS: A total of 8 cohort studies with 12 cohorts were included in the meta-analysis. We observed a significant association between ADNS and SCZ (RR = 1.42; 95%CI, 1.18-1.72). Subgroup analysis showed that the risk of SCZ was significantly increased when ADNS were used as exposure factors (RR = 1.48; 95%CI, 1.15-1.89), whereas with SCZ did not observe an increased risk of subsequent ADNS (RR = 1.33; 95%CI, 0.92-1.92); multiple sclerosis (MS) was positively associated with SCZ (RR = 1.36; 95%CI, 1.12-1.66), but no significant association was found between Guillain-Barre syndrome (GBS) and SCZ (RR = 1.90; 95%CI, 0.87-4.17). Meanwhile, we found location was the source of heterogeneity. LIMITATIONS: High heterogeneity was observed (I2 = 92.0%), and only English literature was included in the meta-analysis. CONCLUSIONS: We found a positive association between ADNS and SCZ, and the association was different across the different types of ADNS. The results of the study are helpful for clinicians to carry out targeted preventive measures for ADNS and SCZ.

Recent Advances and Challenges in Barbier Polymerization.

The Barbier reaction, a classical name reaction for carbon-carbon bond formation, has played important roles in organic chemistry for over 120 years. The introduction of the Barbier reaction into polymer chemistry for the development of a novel Barbier polymerization, expands the methodology, monomer, chemical structure and property libraries of polymerization, aggregation-induced emission (AIE) and non-traditional intrinsic luminescence (NTIL). This mini review focuses on Barbier polymerization, including the brief introduction of the history and importance of polymerization methods design and the achievements of Barbier polymerization from molecular design strategies, functionalities and properties. An outlook of Barbier polymerization is also proposed. This mini review on Barbier polymerization therefore may cause inspirations to scientists in different fields.

Imbalance in ALR ubiquitination accelerates the progression of nonalcoholic steatohepatitis to hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer. Accumulating evidence indicates that non-alcoholic steatohepatitis (NASH) is a key predisposing factor for HCC occurrence. However, the precise mechanisms driving NASH transition to HCC remain largely obscure. Augmenter of liver regeneration (ALR) is a sulfhydryl oxidase and cytochrome c reductase that functions as an important regulator of mitochondrial dynamics. In this study, we focused on ALR ubiquitination-mediated degradation and its potential contribution to NASH-driven HCC progression at the mitochondrial level. Hepatic ALR expression in HCC patients was determined using immunohistochemical analysis. Mice with liver-specific deletion of ALR (ALRCKO) and ALRWT mice were fed a western diet (WD) and high-sugar solution for induction of NASH. HCC in animals was induced via peritoneal administration of CCl4. ALR expression was markedly decreased in liver tissues of patients with NASH and HCC compared with non-NASH and non-tumor tissues. Similarly, in ALRWT mice, the ALR level in tumor tissue was reduced relative to that in para-tumor tissue. In the ALRCKO group, mice fed WD plus CCl4 developed HCC starting at week 12 while ALRWT mice fed WD plus CCl4 developed HCC at week 24. Analysis of protein posttranslational modifications revealed ubiquitylation (Ub) and deubiquitination (DUb) of ALR by murine double minute 2 (MDM2) and ubiquitin-specific protease 36 (USP36), respectively. Imbalance between Ub and DUb of ALR resulted in profound ALR degradation, which appeared to be reversibly associated with Edmondson-Steiner tumor grade. Rescue of ALR levels via gene transfection abolished tumor malignant features to a certain extent in vitro. Notably, ALR deletion substantially enhanced mitochondrial fission by activating Drp1 phosphorylation at Ser616, thus disrupting the balance of mitochondrial dynamics between fission and fusion and severely impairing oxidative phosphorylation (OXPHOS) and ATP synthesis, instead enhancing anaerobic metabolism, which might be attributed to steatotic hepatocyte transition into the malignant HCC phenotype. Hepatic ALR depletion via dysregulation of ubiquitination is a critical aggravator of NASH-HCC progression and represents a promising therapeutic target for related liver diseases.

O Pré-Condicionamento com Dexmedetomidina Atenua a Lesão de Isquemia/Reperfusão Miocárdica em Ratos, Suprimindo a Mitofagia Via Ativação do Receptor Α2-Adrenérgico / Dexmedetomidine Preconditioning Attenuates Myocardial Ischemia/Reperfusion Injury in Rats by Suppressing Mitophagy Via Activating Α2-Adrenergic Receptor

Resumo Fundamento A dexmedetomidina (DEX), um agonista específico do receptor α2-adrenérgico, é protetora contra lesão de isquemia/reperfusão miocárdica (I/R). No entanto, a associação entre a cardioproteção induzida pelo pré-condicionamento DEX e a supressão da mitofagia permanece pouco clara. Objetivo Portanto, nosso objetivo foi investigar se o pré-condicionamento com DEX alivia a I/R, suprimindo a mitofagia via ativação do receptor α2-adrenérgico. Método Sessenta corações de ratos isolados foram tratados com ou sem DEX antes de induzir isquemia e reperfusão; um antagonista do receptor α2-adrenérgico, a ioimbina (YOH), também foi administrado antes da isquemia, isoladamente ou com DEX. A frequência cardíaca (FC), pressão diastólica do ventrículo esquerdo (PDVE), pressão diastólica final do ventrículo esquerdo (PDFVE), taxa máxima e mínima de desenvolvimento da pressão ventricular esquerda (±dp/dtmax) e tamanho do infarto do miocárdio foram medidos. A ultraestrutura mitocondrial e as autofagossomas foram avaliadas por microscopia eletrônica de transmissão. O potencial de membrana mitocondrial e os níveis de espécies reativas de oxigênio (ROS) foram medidos usando os ensaios JC-1 e diacetato de diclorodi hidrofluoresceína, respectivamente. Os níveis de expressão das proteínas associadas à mitofagia Beclin1, relação LC3II/I, p62, PINK1 e Parkin foram detectados por western blotting. Resultados Em comparação com o grupo controle, no grupo isquemia/reperfusão, a FC, PDVE e ±dp/dtmax foram notavelmente diminuídas (p<0,05), enquanto os tamanhos da PDFVE e do infarto aumentaram significativamente (p<0,05). O pré-condicionamento com DEX melhorou significativamente a disfunção cardíaca, reduziu o tamanho do infarto do miocárdio, manteve a integridade estrutural mitocondrial, aumentou o potencial de membrana mitocondrial, inibiu a formação de autofagossomas e diminuiu a produção de ROS e a relação Beclin1, relação LC3II/I, expressão PINK1, Parkin e p62(p<0,05). Quando DEX e YOH foram combinados, o YOH cancelou o efeito da DEX, enquanto o uso de YOH sozinha não teve efeito. Conclusão Portanto, o pré-condicionamento DEX foi cardioprotetor contra I/R em ratos, suprimindo a mitofagia por meio da ativação do receptor α2-adrenérgico.

Abstract Background Dexmedetomidine (DEX), a specific α2-adrenergic receptor agonist, is protective against myocardial ischemia/reperfusion injury (MIRI). However, the association between DEX preconditioning-induced cardioprotection and mitophagy suppression remains unclear. Objective Hence, we aimed to investigate whether DEX preconditioning alleviates MIRI by suppressing mitophagy via α2-adrenergic receptor activation. Method Sixty isolated rat hearts were treated with or without DEX before inducing ischemia and reperfusion; an α2-adrenergic receptor antagonist, yohimbine (YOH), was also administered before ischemia, alone or with DEX. The heart rate (HR), left ventricular diastolic pressure (LVDP), left ventricular end-diastolic pressure (LVEDP), maximal and minimal rate of left ventricular pressure development (±dp/dtmax), and myocardial infarction size were measured. The mitochondrial ultrastructure and autophagosomes were assessed using transmission electron microscopy. Mitochondrial membrane potential and reactive oxygen species (ROS) levels were measured using JC-1 and dichloride hydrofluorescein diacetate assays, respectively. The expression levels of the mitophagy-associated proteins Beclin1, LC3II/I ratio, p62, PINK1, and Parkin were detected by western blotting. Results Compared with the control group, in the ischemia/reperfusion group, the HR, LVDP, and ±dp/dtmax were remarkably decreased (p< 0.05), whereas LVEDP and infarct sizes were significantly increased (p< 0.05). DEX preconditioning significantly improved cardiac dysfunction reduced myocardial infarction size, maintained mitochondrial structural integrity, increased mitochondrial membrane potential, inhibited autophagosomes formation, and decreased ROS production and Beclin1, LC3II/I ratio, PINK1, Parkin, and p62 expression(p< 0.05). When DEX and YOH were combined, YOH canceled the effect of DEX, whereas the use of YOH alone had no effect. Conclusion Therefore, DEX preconditioning was cardioprotective against MIRI in rats by suppressing mitophagy via α2-adrenergic receptor activation.

Identify gestational diabetes mellitus by deep learning model from cell-free DNA at the early gestation stage.

Gestational diabetes mellitus (GDM) is a common complication of pregnancy, which has significant adverse effects on both the mother and fetus. The incidence of GDM is increasing globally, and early diagnosis is critical for timely treatment and reducing the risk of poor pregnancy outcomes. GDM is usually diagnosed and detected after 24 weeks of gestation, while complications due to GDM can occur much earlier. Copy number variations (CNVs) can be a possible biomarker for GDM diagnosis and screening in the early gestation stage. In this study, we proposed a machine-learning method to screen GDM in the early stage of gestation using cell-free DNA (cfDNA) sequencing data from maternal plasma. Five thousand and eighty-five patients from north regions of Mainland China, including 1942 GDM, were recruited. A non-overlapping sliding window method was applied for CNV coverage screening on low-coverage (~0.2×) sequencing data. The CNV coverage was fed to a convolutional neural network with attention architecture for the binary classification. The model achieved a classification accuracy of 88.14%, precision of 84.07%, recall of 93.04%, F1-score of 88.33% and AUC of 96.49%. The model identified 2190 genes associated with GDM, including DEFA1, DEFA3 and DEFB1. The enriched gene ontology (GO) terms and KEGG pathways showed that many identified genes are associated with diabetes-related pathways. Our study demonstrates the feasibility of using cfDNA sequencing data and machine-learning methods for early diagnosis of GDM, which may aid in early intervention and prevention of adverse pregnancy outcomes.