The Role and Mechanism of Unfolded Protein Response Pathway in Tumor Drug Resistance

In the process of tumor proliferation and metastasis,tumor cells encounter hypoxia,low glucose,acidosis,and other stressful environments.These conditions prompt tumor cells to generate endoplasmic reticulum stress(ERS).As a signal mechanism that mitigates ERS in eukaryotic cells,the unfolded protein response(UPR)pathway can activate cells and tissues,regulating pathological activities in various cells,and maintaining ER homeostasis.It forms the most crucial adaptive and defensive mechanism for cells.However,under the continuous influence of chemotherapy drugs,the quantity of unfolded proteins and erroneous proteins produced by tumor cells significantly increases,surpassing the normal regulatory range of UPR.Consequently,ERS fails to function properly,fostering tumor cell proliferation and the development of drug resistance.This review delves into the study of three UPR pathways(PERK,IRE1,and ATF6),elucidating the mechanisms of drug resistance and research progress in the signal transduction pathway of UPR related to cancers.It provides a profound understanding of the role and relationship between UPR and anti-tumor drugs,offering a new direction for effective clinical treatment.

The Role of Endoplasmic Reticulum Stress Sensor Protein CREB3L2 in the Development of Tissues and Tumors

The endoplasmic reticulum plays an extremely important role in the process of cellular protein secretion.The cyclic AMP-responsive element-binding protein 3(CREB3)transcription factor family is closely associated with the secretion and transport of proteins within the endoplasmic reticulum.As a member of the CREB3 transcription factor family,cyclic AMP-responsive element-binding protein 3-like protein 2(CREB3L2)stands out as a non-classical sensor within the endoplasmic reticulum.CREB3L2 can detect and regulate endoplasmic reticulum pressure,exert control over the processes of protein transport and secretion,participate in the development of tumor cells,and is also closely linked to the development of certain human tissues and organs.This article aims to review the role of CREB3L2 in tissue development and disease,shedding light on the related mechanisms of CREB3L2 in cancer development.The goal is to provide insights and directions for further analysis of CREB3L2.

Responses of nutrient biogeochemistry and nitrogen cycle to seasonal upwelling in coastal waters of the eastern Hainan Island

The coastal upwelling has profound influence on the surrounding ecosystem by supplying the nutrient-replete water to the euphotic zone.Nutrient biogeochemistry was investigated in coastal waters of the eastern Hainan Island in summer 2015 and autumn 2016.From perspectives of nutrient dynamics and physical transport,the nutrient fluxes entered the upper 50 m water depth(between the mixed layer and the euphotic zone)arisen from the upwelling were estimated to be 2.5-5.4 mmol/(m^(2)·d),0.15-0.28 mmol/(m^(2)·d),and 2.2-7.2 mmol/(m^(2)·d)for dissolved inorganic nitrogen(DIN),phosphate(DIP),and dissolved silicate(DSi),respectively,which were around 6-to 12-fold those in the background area.The upwelled nutrients supported an additional plankton growth of(14.70±8.95)mg/m^(2)for chlorophyll a(Chl a).The distributions of nitrateδ^(15)N andδ^(18)O above the 300 m water depth(top of the North Pacific Intermediate Water)were different among the upwelling area,background area in summer,and the stations in autumn,and the difference of environmental and biogeochemical conditions between seasons should be the reason.The higher DIN/DIP concentration ratio,nitrate concentration anomaly,and lower nitrate isotope anomaly(Δ(15,18))in the upper ocean in summer than in autumn indicated the stronger nitrogen fixation and atmospheric deposition,and the following fixed nitrogen regeneration in summer.The higher values of Chl a and nitrateδ^(15)N andδ^(18)O within the euphotic zone in autumn than the background area in summer suggested the stronger nitrate assimilation in autumn.The differences in relatively strength of the assimilation,nitrogen fixation and atmospheric deposition,and the following remineralization and nitrification between the two seasons made the higherδ^(18)O:δ^(15)N and larger difference of enzymatic isotope fractionation factors^(15)εand^(18)εfor nitrate assimilation in summer than in autumn above the North Pacific Tropical Water.

Association of four GSTs gene polymorphisms with Parkinson disease: A meta-analysis

Parkinson disease (PD) is a neurological disorder with huge destruction to human body, which affects approximately 2% of the population aged 65 years or older. As antioxidants in the stress defence systems, glutathione S-transferases (GSTs) are dimeric cytosolic enzymes with an important role in the pathogenesis of PD. The aim of this study was to evaluate the association between the polymorphisms of GST genes and PD. Meta-analyses were conducted from 17 studies (38 stages) among 3419 cases and 5686 controls between four polymorphisms (GSTT1 deletion polymorphism;GSTM1 deletion polymorphism;GSTP1-104: rs1695;GSTP1-114: rs1799811) and PD. There is no significant association between the four GST gene variants and PD. A further subgroup study by ethnicity observed a risky role of GSTM1 deletion polymorphism with PD in Europeans (p = 0.013, OR = 1.126, 95% CI = 1.025-1.236), and a protective role of GSTM1 deletion polymorphism with PD in Latin Americans (p = 0.032, OR = 0.750, 95% CI = 0.577-0.975). Our meta-analysis suggested that GSTM1 deletion polymorphism increased the risk of PD in Europeans, but reduced the risk of PD in Latin Americans. Future large-scale studies might be needed to confirm the ethnic difference of GSTM1 deletion polymorphism, and to check whether there was significant association of PD for other GST genetic polymorphisms.

A comprehensive meta-analysis of the association between three <i>IL</i>1B polymorphisms and rheumatoid arthritis

Rheumatoid arthritis (RA) is an immune-mediated chronic inflammatory disease that causes huge destruction to human body. IL1B encodes key mediator IL-1β protein, which plays an important role in the pathogenesis of inflammatory syndromes. The aim of this study was to evaluate the association between IL1B polymorphisms and RA. A meta-analysis was performed on the association between three IL1B polymorphisms (IL1B-31: rs1143627;IL1B-511: rs16944;IL1B + 3954: rs1143634) and RA. A trend of significant association was observed between IL1B + 3954 and RA (p = 0.06, odd ratio (OR) = 1.19, 95% confidential interval (CI) = 1.00-1.42). A significant association was found in Europeans under the dominant model between IL1B-511T and RA (p = 0.03, OR = 0.89, 95% CI = 0.81-0.99). Our meta-analysis indicated that IL1B ? 511-T played a protective role against RA in Europeans, and that IL1B + 3954-T had the potential to increase the risk of RA. Future large-scale studies should be considered to confirm the association between IL1B polymorphisms and RA.

Meta-analyses of nine polymorphisms of six genes with the risk of schizophrenia

The aim of this study was to determine whether 9 genetic polymorphisms confered susceptibility to schizophrenia (SCZ). The authors conducted meta-analyses on associations between SCZ and 9 variants of 6 genes including PIK3C3 (432C > T), ABCB1 (C3435T and G2677T), CTLA4 (+49A/G), OLIG2 (rs762178), GAD1 (rs1978340, rs3749034 and rs769395), and GRIN1 (G1001C). A total of 34 case-control studies were involved in our meta-analyses. Our results showed no significant association between all the loci and SCZ. This meta-analysis confirmed a lack of association of SCZ for 9 genetic polymorphisms including GRIN1 G1001C, ABCB1 C3435T and G2677T, CTLA4 + 49A/G, OLIG2 rs762178, GAD1 gene rs1978340, rs3749034 and rs769395, and PIK3C3 432C > T.

The Expression and Clinical Significance of Sema4A in Triple Negative Breast Cancer

Objective:To explore the expression and clinical significance of Sema4A in triple-negative breast cancer.Metlods:Eighty patients with invasive ductal carcinoma of the breast and 40 normal tissues adjacent to cancer were selected.Immumohistochemical methods were used to detect the expression of Sema4A in breast cancer and normal tissues adjacent to cancer,and its relationship with breast cancer clinicopathological features and prognosis.Results:The expression of Sema4a in the serum of BCA patients was significantly higher than that of healthy controls.In addition,the expression of sema4a in BCA cells and in the cell supernatants was also up-regulated under hypoxia.Conclusion:Exogenous Sema4A can protect BCA cells from hypoxia-induced cytotoxicity,inhibit cell apoptosis and promote cell proliferation.

Gibberellin promotes cambium reestablishment during secondary vascular tissue regeneration after girdling in an auxin-dependent manner in Populus

Secondary vascular tissue(SVT)development and regeneration are regulated by phytohormones.In this study,we used an in vitro SVT regeneration system to demonstrate that gibberellin(GA)treatment significantly promotes auxin-induced cambium reestablishment.Altering GA content by overexpressing or knocking down ent-kaurene synthase(KS)affected secondary growth and SVT regeneration in poplar.The poplar DELLA gene GIBBERELLIC ACID INSENSITIVE(PtoGAI)is expressed in a specific pattern during secondary growth and cambium regeneration after girdling.Overexpression of PtoGAI disrupted poplar growth and inhibited cambium regeneration,and the inhibition of cambium regeneration could be partially restored by GA application.Further analysis of the PtaDR5:GUS transgenic plants,the localization of PIN-FORMED 1(PIN1)and the expression of auxin-related genes found that an additional GA treatment could enhance the auxin response as well as the expression of PIN1,which mediates auxin transport during SVT regeneration.Taken together,these findings suggest that GA promotes cambium regeneration by stimulating auxin signal transduction.

The traditional Chinese medicines treat chronic heart failure and their main bioactive constituents and mechanisms

Chronic heart failure(CHF)is a severe public health problem with increasing morbidity and mortality,any treatment targeting a single session is insufficient to tackle this.CHF is characterized by reduced cardiac output resulting from neurohumoral dysregulation and cardiac remodeling,which might be related to oxidative stress,inflammation,endoplasmic reticulum stress,apoptosis,autophagy,mitochondrial function,and angiogenesis.These molecular mechanisms interact with each other through crosstalk.Historically,Chinese medicinal herbs have been widely applied in the treatment of CHF,and therapeutic effects of Chinese medicinal herbs and their ingredients have been scientifically confirmed over the past decades.Traditional Chinese medicine(TCM)with multiple components can confront the different pathogenesis of CHF through multiple targets.This review analyzes commonly used TCM patent drugs and TCM decoctions that are applicable to different stages of CHF based on clinical trials.Diverse bioactive ingredients in Chinese medicinal herbs have been found to treat CHF via multiple molecular mechanisms.This review comprehensively covers the key works on the effects and underlying mechanisms of TCM,herbal ingredients and synergistic effects of constituent compatibility in treating CHF,providing additional ideas to address this threat.

Brassinosteroid signaling and molecular crosstalk with nutrients in plants

As sessile organisms,plants have evolved sophisticated mechanisms to optimize their growth and development in response to fluctuating nutrient levels.Brassinosteroids(BRs)are a group of plant steroid hormones that play critical roles in plant growth and developmental processes as well as plant responses to environmental stimuli.Recently,multiple molecular mechanisms have been proposed to explain the integration of BRs with different nutrient signaling processes to coordinate gene expression,metabolism,growth,and survival.Here,we review recent advances in understanding the molecular regulatory mechanisms of the BR signaling pathway and the multifaceted roles of BR in the intertwined sensing,signaling,and metabolic processes of sugar,nitrogen,phosphorus,and iron.Further understanding and exploring these BR-related processes and mechanisms will facilitate advances in crop breeding for higher resource efficiency.

The PtoTCP20-miR396d-PtoGRF15 module regulates secondary vascular development in Populus

Secondary vascular development is a key biological characteristic of woody plants and the basis of wood formation.Our understanding of gene expression regulation and dynamic changes in microRNAs(miRNAs)during secondary vascular development is still limited.Here we present an integrated analysis of the miRNA and mRNA transcriptome of six phase-specific tissues-the shoot apex,procambium,primary vascular tissue,cambium,secondary phloem,and secondary xylem-in Populus tomentosa.Several novel regulatory modules,including the PtoTCP20-miR396d-PtoGRF15 module,were identified during secondary vascular development in Populus.A series of biochemical and molecular experiments confirmed that PtoTCP20 activated transcription of the miR396d precursor gene and that miR396d targeted PtoGRF15 to downregulate its expression.Plants overexpressing miR396d(35S:miR396d)showed enhanced secondary growth and increased xylem production.Conversely,during the transition from primary to secondary vascular development,plants with downregulated PtoTCP20expression(PtoTCP20-SRDX),downregulated miR396 expression(35S:STTM396),and PtoGRF15 overexpression(35S:PtoGRF15)showed delayed secondary growth.Novel regulatory modules were identified by integrated analysis of the miRNA and mRNA transcriptome,and the regulatory role of the PtoTCP20-miR396d-PtoGRF15 signaling cascade in secondary vascular development was validated in Populus,providing information to support improvements in forest cultivation and wood properties.

(+)/(-)-Yanhusuosines A and B, two dimeric benzylisoquinoline-protoberberine alkaloid atropo-enantiomers featuring polycyclic skeletons from Corydalis yanhusuo

(+)/(-)-Yanhusuosines A(1) and B(2), two pairs of trace benzylisoquinoline-protoberberine atropoenantiomeric homodimers featuring an unprecedented 6/7/6/6/6/6 hexacyclic skeleton, were isolated from the tubers of Corydalis yanhusuo. The structures of(+)/(-)-1 and(+)/(-)-2 were elucidated using spectroscopic and quantum-chemical calculation approaches.(+)/(-)-Yanhusuosines A(1) and B(2)represent a new class of alkaloid dimers biogenetically constructed by a molecule of benzylisoquinoline with a unit of protoberberine via an intermolecular [4 + 3] cycloaddition. Their plausible biosynthetic pathways are discussed, and compound 2 exerted moderate inhibitory activity of NO formation in LPS induced RAW264.7 macrophages.

Optimizing strain response in lead-free(Bi_(0.5)Na_(0.5))TiO_(3)-BaTiO_(3)-NaNbO_(3)solid solutions via ferroelectric/(non-)ergodic relaxor phase boundary engineering

Lead-free bismuth sodium titanate(Bi_(0.5)Na_(0.5))TiO_(3)(BNT)and related solid solutions are potential piezoelectric materials for such applications as actuators and transducers if their excellent strain responses and piezoelectric properties can be optimized.In this work,a large strain response of 0.61%is achieved in lead-free(0.94-x%)(Bi_(0.5)Na_(0.5))TiO_(3)-0.06BaTiO_(3)-x%NaNbO_(3)(x=0 e6,BNT-6BT-xNN)ceramics with the composition of x=3.5 in a pseudo-cubic structure.Coexistence of ferroelectric(FE)and relaxor(RE)domain structures is observed in all the unpoled ceramics and the enhanced strain response is believed to be related to the evolution of the ergodic relaxor(ER)and non-ergodic(NR)states thanks to the substitution of antiferroelectric NN.BNT-6BT-3.5NN is a critical composition near the FE/NR/ER phase boundary close to room temperature(RT)and its high strain response arises from a synergistic combination of a reversible electric-field-induced phase transition and an active domain switching in the mixed NR/ER state.This work provides new insights into the dynamic interplay between mesoscopic domains and macroscopic electrical properties in the BNT-based piezoceramics.

Orientation dependence on piezoresponse of lead-free piezoelectric sodium bismuth titanate epitaxial thin films

Lead-free piezoelectric sodium bismuth titanate((Bi0.5Na0.5)TiO3,BNT)thin films were epitaxially grown onto(001)-,(110)-,and(111)-oriented Nb:SrTiO3(STO)single crystal substrates prepared by sol-gel processing.Highly oriented growth in(001),(110),and(111)BNT thin films was obtained in this work benefiting from the lattice match between the BNT film and the STO substrate.The different growth models in thin films with various orientations result in various surface morphologies dependent on the film orientation.The piezoresponse of the BNT thin films was represented exhibiting a strong orientation dependence that(110)>(001)>(111).This is contributed by the various domain switching contribution related to the crystal symmetry and polarization distribution in the three oriented thin films.

(+)/(-)-Yanhusamides A-C,three pairs of unprecedented benzylisoquinoline-pyrrole hetero-dimeric alkaloid enantiomers from Corydalis yanhusuo

A chemical investigation on the aqueous extract of Corydalis yanhusuo tubers led to the isolation and structural elucidation of three pairs of trace enantiomeric hetero-dimeric alkaloids,(+)/(-)-yanhusamides A-C(1-3),featuring an unprecedented 3,8-diazatricylco[5.2.2.0^(2,6)]undecane-8,10-diene bridged system.Their structures were exhaustively characterized by X-ray diffraction,comprehensive spectroscopic data analysis,and computational methods.Guided by the hypothetical biosynthetic pathway for 1-3,a gram-scale biomimetic synthesis of(±)-1 was achieved in 3 steps using photoenolization/Diels-Alder(PEDA)[4+2]cycloaddition.Compounds 1-3 exhibited potent inhibition of NO production induced by LPS in RAW264.7 macrophages.The in vivo assay showed that oral administration of 30 mg/kg of(±)-1 attenuated the severity of rat adjuvant-induced arthritis(AIA).Additionally,(±)-1 induced a dose-dependent antinociceptive effect in the acetic acid-induced mice writhing assay.

基于超高效液相色谱-质谱技术对野蚕茧和家蚕茧化学成分进行比较

鉴定并比较野蚕茧与家蚕茧的化学成分对于理解家蚕的驯化具有重要的意义。利用高温高压结合甲醇-水提取的方法获得蚕茧中的化学成分,利用UHPLC-MS技术对野蚕、家蚕大造品种和皓月品种3种蚕茧丝中的小分子成分进行鉴定和比较分析。通过阳离子模式和阴离子模式的UHPLC-MS获得了野蚕、大造和皓月蚕茧丝的代谢指纹图谱,对鉴定到的高丰度化合物进行注释,发现其中包括了氨基酸、黄酮、生物碱、萜类、有机酸和木脂素等成分。PLS-DA的得分图表明,野蚕、家蚕大造品种和皓月品种的3种蚕茧的代谢组存在显著差异。发现脯氨酸、亮氨酸/异亮氨酸和苯丙氨酸在大造茧中的含量显著高于在野蚕和皓月茧中的含量,黄酮类植物次生代谢物在大造茧中的含量显著提高,包括槲皮素、异槲皮素、槲皮素-3-O-槐糖苷、槲皮素-3-O-L-鼠李糖苷、槲皮素-3-O-芸香糖苷和山奈酚;而神经碱、白桥楼碱、毛果芸香次碱、美洲豚草内酯、线叶泽兰素和中缅木莲素等生物碱、萜类和木脂素类的植物次生代谢物在野蚕茧中的含量显著高于在家蚕茧中的含量。在紫外光的激发下观察黄酮的绿色荧光发现家蚕大造茧中的黄酮含量最高,家蚕皓月茧中的黄酮含量最低,而野蚕茧中的黄酮含量居中。生物碱和有机酸是良好的抗虫抗菌剂,它们在野蚕茧中的含量较高,能够提高野蚕茧的防护能力。黄酮类物质在家蚕大造茧中的含量较高,是导致家蚕大造茧呈黄绿色的主要原因。

浅裂剪秋萝和丝瓣剪秋萝传粉特性的初步研究

为了探究浅裂剪秋萝(Lychnis cognata)和丝瓣剪秋萝(L.wilfordii)的传粉生物学特征,从花部特征、花粉呈现规律及传粉者访花行为等方面对其开展研究。结果表明,2种剪秋萝的花期持续时间相近,但浅裂剪秋萝始花日期较早;二者花部特征虽有显著差异,但主要传粉者均为碧翠凤蝶(Papilio bianor)。在开花过程中,2种剪秋萝的雄蕊均分2批呈现花粉,第1批雄蕊的花粉生活力在开花后第1天达到最大值,而第2批雄蕊在第2天达到最大值。浅裂剪秋萝的柱头可授性在开花后第5天最强,而丝瓣剪秋萝在开花后第4天最强,花粉生活力和柱头活性的时间差异表明两物种均为雌雄异熟。两物种共同的传粉者碧翠凤蝶对浅裂剪秋萝的访花高峰出现在上午8:00–11:00,而对丝瓣剪秋萝的访花高峰出现在上午11:00–12:00,导致访花高峰出现差异的主要影响因素可能是生境和花药开裂时间。

Non-proteolytic ubiquitination of OTULIN regulates NF-κB signaling pathway

NF-κB signaling regulates diverse processes such as cell death,inflammation,immunity,and cancer.The activity of NF-κB is controlled by methionine 1-linked linear polyubiquitin,which is assembled by the linear ubiquitin chain assembly complex(LUBAC)and the ubiquitin-conjugating enzyme UBE2L3.Recent studies found that the deubiquitinase OTULIN breaks the linear ubiquitin chain,thus inhibiting NF-κB signaling.Despite the essential role of OTULIN in NF-κB signaling has been established,the regulatory mechanism for OTULIN is not well elucidated.To discover the potential regulators of OTULIN,we analyzed the OTULIN protein complex by proteomics and revealed several OTULIN-binding proteins,including LUBAC and tripartite motif-containing protein 32(TRIM32).TRIM32 is known to activate NF-κB signaling,but the mechanism is not dear.Genetic complement experiments found that TRIM32 is upstream of OTULIN and TRIM32-mediated NF-κB activation is dependent on OTULIN.Mutagenesis of the E3 ligase domain showed that the E3 ligase activity is essential for TRIM32-mediated NF-κB activation.Further experiments found that TRIM32 conjugates polyubiquitin onto OTULIN and the polyubiquitin blocks the interaction between HOIP and OTULIN,thereby activating NF-κB signaling.Taken together,we report a novel regulatory mechanism by which TRIM32-mediated non-proteolytic ubiquitination of OTULIN impedes the access of OTULIN to the LUBAC and promotes NF-κB activation.

Locomotor activity and anxiety status, but not spatial working memory,are affected in mice after brief exposure to cuprizone

Chronic long-term exposure to cuprizone causes severe brain demyelination in mice,which leads to changes in locomotion,working memory and anxiety.These findings suggest the importance of intact myelin for these behaviors.This study aimed to investigate the possible behavioral changes in mice with mild oligodendrocyte/myelin damage that parallels the white matter changes seen in the brains of patients with psychiatric disporders.We used the cuprizonetreated mouse model to test both tissue changes and behavioral functions（locomotor activity,anxiety status,and spatial working memory）.The results showed that mice given cuprizone in their diet for 7 days had no significant myelin breakdown as evaluated by immunohistochemical staining for myelin basic protein,while the number of mature oligodendrocytes was reduced.The number and length of Caspr protein clusters,a structural marker of the node of Ranvier,did not change.The locomotor activity of the cuprizonetreated mice increased whereas their anxiety levels were lower than in normal controls;spatial working memory,however,did not change.These results,for the first time,link emotion-related behavior with mild white matter damage in cuprizone-treated mice.

Circularly polarized luminescence of talarolactones(+)/(-)-A and(+)/(-)-C:The application of CPL-calculation in stereochemical assignment

Two pairs of fluorescent natural products,talarolactones(+)/(−)-A and(+)/(−)-C[(+)/(−)-1 and(+)/(−)-2],were discovered and characterized as a new family of circularly polarized luminescence-active small organic molecules(CPL-SOMs)with high fluorescence efficiency and fascinating CPL properties.The CPL(|glum|)levels of enantiomerically pure(+)/(−)-1 and(+)/(−)-2 in solution falls into the usual range(10−5−10−3)considering their pure organic nature,but the sign of CPL were found to be closely related to the absolute configuration of C-8.The high agreement of the measured CPL spectra of(+)/(−)-1 and(+)/(−)-2 with the time-dependent density functional theory(TDDFT)calculated ones demonstrated the usefulness of CPL-calculation as a unique method for stereochemical assignment.This study may open up a new perspective for the stereochemical studies and the future development of CPL materials.