Role of cell adhesion signal molecules in hepatocellular carcinoma cell apoptosis

AIM： Cell adhesion molecules and their signal molecules play a very important role in carcinogenesis. The aim of this study is to elucidate the role of these molecules and the signal molecules of integrins and E-cadherins, such as （focal adhesion kinase） FAK, （integrin linked kinase） ILK, and β-catenin in hepatocellular carcinoma cell apoptosis. METHODS： We first synthesized the small molecular compound, S-（1,2-dichlorovinyl）-L-cysteine （DCVC）, and identified it, by element analysis and ^1H NMR. To establish the apoptosis model of the SMMC-7721 hepatocellular carcinoma cell, we treated cells with DCVC in EBSS for different concentrations or for various length times in the presence of 20 μmol/L N,N-cliphenyl-p-phenylenediamine, which blocks necrotic cell death and identified this model by flow cytometry and DNA ladder. Then we studied the changes of FAK, ILK, β-catenin, and PKB in this apoptotic model by Western blot. RESULTS： We found that the loss or decrease of cell adhesion signal molecules is an important reason in apoptosis of SMMC-7721 hepatocellular carcinoma cell and the apoptosis of SMMC-7721 cell was preceded by the loss or decrease of FAK, ILK, PKB, and β-catenin or the damage of cell-matrix and cell-cell adhesion. CONCLUSION： Our results suggested that the decrease of adhesion signal molecules, FAK, ILK, PKB, and β-catenin, could induce hepatocellular carcinoma cell apoptosis.

Carbon Monoxide Modulates Auxin Transport and Nitric Oxide Signaling in Plants under Iron Deficiency Stress

Carbon monoxide(CO)and nitric oxide(NO)are signal molecules that enhance plant adaptation to environmental stimuli.Auxin is an essential phytohormone for plant growth and development.CO and NO play crucial roles in modulating the plant’s response to iron deficiency.Iron deficiency leads to an increase in the activity of heme oxygenase(HO)and the subsequent generation of CO.Additionally,it alters the polar subcellular distribution of Pin-Formed 1(PIN1)proteins,resulting in enhanced auxin transport.This alteration,in turn,leads to an increase in NO accumulation.Furthermore,iron deficiency enhances the activity of ferric chelate reductase(FCR),as well as the expression of the Fer-like iron deficiency-induced transcription factor 1(FIT)and the ferric reduction oxidase 2(FRO2)genes in plant roots.Overexpression of the long hypocotyl 1(HY1)gene,which encodes heme oxygenase,or the CO donor treatment resulted in enhanced basipetal auxin transport,higher FCR activity,and the expression of FIT and FRO2 genes under Fe deficiency.Here,a potential mechanism is proposed:CO and NO interact with auxin to address iron deficiency stress.CO alters auxin transport,enhancing its accumulation in roots and up-regulating key iron-related genes like FRO2 and IRT1.Elevated auxin levels affect NO signaling,leading to greater sensitivity in root development.This interplay promotes FCR activity,which is crucial for iron absorption.Together,these molecules enhance iron uptake and root growth,revealing a novel aspect of plant physiology in adapting to environmental stress.

Lactate metabolism in neurodegenerative diseases

Lactate,a byproduct of glycolysis,was thought to be a metabolic waste until the discovery of the Warburg effect.Lactate not only functions as a metabolic substrate to provide energy but can also function as a signaling molecule to modulate cellular functions under pathophysiological conditions.The Astrocyte-Neuron Lactate Shuttle has cla rified that lactate plays a pivotal role in the central nervous system.Moreover,protein lactylation highlights the novel role of lactate in regulating transcription,cellular functions,and disease development.This review summarizes the recent advances in lactate metabolism and its role in neurodegenerative diseases,thus providing optimal pers pectives for future research.

Long chikungunya?An overview to immunopathology of persistent arthralgia

Chikungunya fever(CF)is caused by an arbovirus whose manifestations are extremely diverse,and it has evolved with significant severity in recent years.The clinical signs triggered by the Chikungunya virus are similar to those of other arboviruses.Generally,fever starts abruptly and reaches high levels,followed by severe polyarthralgia and myalgia,as well as an erythematous or petechial maculopapular rash,varying in severity and extent.Around 40%to 60%of affected individuals report persistent arthralgia,which can last from months to years.The symptoms of CF mainly represent the tissue tropism of the virus rather than the immunopathogenesis triggered by the host's immune system.The main mechanisms associated with arthralgia have been linked to an increase in T helper type 17 cells and a consequent increase in receptor activator of nuclear factor kappa-Βligand and bone resorption.This review suggests that persistent arthralgia results from the presence of viral antigens post-infection and the constant activation of signaling lymphocytic activation molecule family member 7 in synovial macrophages,leading to local infiltration of CD4+T cells,which sustains the inflammatory process in the joints through the secretion of pro-inflammatory cytokines.The term"long chikungunya"was used in this review to refer to persistent arthralgia since,due to its manifestation over long periods after the end of the viral infection,this clinical condition seems to be characterized more as a sequel than as a symptom,given that there is no active infection involved.

Local signals in stem cell-based bone marrow regeneration

The cellular basis of bone marrow （BM） tissue development and regeneration is mediated through hematopoietic stem cells （HSCs） and mesenchymal stem cells （MSCs）. Local interplays between hematopoietic cells and BM stromal cells （BMSCs） determine the reconstitution of hematopoiesis after myelosuppression. Here we review the BM local signals in control of BM regeneration after insults. Hematopoietic growth factors （HGFs） and cytokines produced by BMSCs are primary factors in regulation ofBM hematopoiesis. Morphogens which are critical to early embryo development in multiple species have been added to the family of HSCs regulators, including families of Wnt proteins, Notch ligands, BMPs, and Hedgehogs. Global gene expression analysis of HSCs and BMSCs has begun to reveal signature groups of genes for both cell types. More importantly, analysis of global gene expression coupled with biochemical and biological studies of local signals during BM regeneration have strongly suggested that HGFs and cytokines may not be the primary local regulators for BM recovery, rather chemokines （SDF- 1, FGF-4） and angiogenic growth factors （VEGF-A, Ang- 1） play instructive roles in BM reconstitution after myelosuppression. A new direction of management of BM toxicity is emerging from the identification of BM regenerative regulators.

Signal molecule-mediated hepatic cell communication during liver regeneration

Liver regeneration is a complex and well-orchestrated process,during which hepatic cells are activated to produce large signal molecules in response to liver injury or mass reduction.These signal molecules,in turn,set up the connections and cross-talk among liver cells to promote hepatic recovery.In this review,we endeavor to summarize the network of signal molecules that mediates hepatic cell communication in the regulation of liver regeneration.

Role of PLC-PIP2 and cAMP-PKA Signal Pathways in Radiation-induced Immune-suppressing Effect

Objective The purpose of the present study was to observe the changes in CD4＋CD25＋Nrpl＋Treg cells after irradiation with different doses and explore the possible molecular mechanisms involved. Methods ICR mice and mouse lymphoma cell line （EL-4 cells） was used. The expressions of CD4, CD25, Nrpl, calcineurin and PKC-α were detected by flow cytometry. The expressions of TGF-131, IL-10, PKA and cAMP were estimated with ELISA. Results At 12 h after irradiation, the expression of Nrpl increased significantly in 4.0 Gy group, compared with sham-irradiation group （P〈0.05） in the spleen and thymus, respectively, when ICR mice received whole-body irradiation （WBI）. Meanwhile the synthesis of Interleukin 10 （IL-20） and transforming growth factor-β1 （TGF-β1） increased significantly after high dose irradiation （HDR） （〉 or = 1.0 Gy）. In addition, the expression of cAMP and PKA protein increased, while PKC-α, calcineurin decreased at 12h in thymus cells after 4.0 Gy X-irradiation. While TGF-β1 was clearly inhibited when the PLC-PIP2 signal pathway was stimulated or the cAMP-PKA signal pathway was blocked after 4.0 Gy X-irradiation, this did not limit the up-regulation of CD4＋CD25＋Nrpl＋Treg cells after ionizing radiation. Conclusion These results indicated that HDR might induce CD4＋CD25＋Nrpl＋Treg cells production and stimulate TGF-β1 secretion by regulating signal molecules in mice.

Seed Priming and Foliar Supplementation withβ-aminobutyric Acid Alleviates Drought Stress through Mitigation of Oxidative Stress and Enhancement of Antioxidant Defense in Linseed(Linum usitatissimum L.)

Drought is one of the critical limitations to agricultural soils and crop plants.Scarcity of water is increasing due to climate change that lead to increasing threats to global food security.Therefore,ecofriendly and cost effective strategies are highly desirable for mitigating drought stress along with sustainable and smart agricultural production.The aim of the study was to mitigate DS using seed priming and exogenous supplementation ofβ-aminobutyric acid(BABA)in linseed(Linum usitatissimum L.).Different doses(0,50,100 and 150μM)of BABA were used for seed priming agent and foliar spraying under three soil moisture levels viz.,25%(SM25),45%(SM45)and 65%(SM65).The response variables of both experiments included different agro-botanical traits and oxidative stress indicators such as melondialdehyde content,free proline accumulation,and antioxidant defense in plants.The linseed plants showed water stress at SM25 that reduced plant height,number of branches per plant,time taken to flower initiation and heading,and root and shoot dry weights.Additionally,the number of capsules and seeds per capsule showed a significant decline at SM25,which led to a drastic reduction in 100-seed weight yield in linseed plants in both experiments.However,seed priming and foliar supplementation with of BABA(50–100μM)significantly improved these morpho-agronomical attributes in linseed plants under DS.The results revealed that the BABA was fully active in linseed plants at SM25.Interestingly,the combination of SM25 with BABA significantly improved the antioxidant enzymes superoxide dismutase(SOD),catalase(CAT),ascorbate peroxidase(APX),and peroxidase(POD)activity,which significantly enhanced DS tolerance in linseed plants.These findings might be useful to oil seed breeders and farmers linseed for breeding program in linseed plants as well as sustainable agricultural production of oil seed crop plants.

TIR enzymatic functions:signaling molecules and receptor mechanisms

The evolutionarily conserved Toll/Interleukin-1 Receptor(TIR)domains across kingdoms of prokaryotes,plants,and animals play critical roles in innate immunity.Recent studies have revealed the enzymatic functions of TIRs,the structural bases of TIRs as holoenzymes,and the identity of TIR-generated small signaling molecules and their receptors,which significantly advanced our understanding on TIR-mediated immune signaling pathways.We reviewed the most up-to-date findings in TIR enzymatic functions from the perspectives of signaling molecules and receptor mechanisms.

Effects of C_6-HSL on Potato Growth and Capacity against Soft Rot Disease

[Objective]The aim of this study was to investigate whether communication signal C6-HSL among individual bacteria can influence plant growth and disease resistance ability. [Method]With potato virus-free plantlets as the test materials and C6-HSL as the inducer,the potato＇s growth and the ability of resistance against Erwinia carotovora subp carotovora were tested after being treated by C6-HSL with different concentrations. The effects of C6-HSL on plant landmark defense enzyme activities and H2O2 content in potato leaves were measured especially. [Result]C6-HSL with different concentrations could obviously inhibit the growth rate of root and the number of roots,but had no effect on plant height,number of nodes and leaf size. POD or SOD activity and H2O2 content in plant landmark defense enzymes significantly increased after induction of C6-HSL,but PAL and PPO activity had no obvious change. In the resistant test,potato plants induced by C6-HSL could inhibit the infection of Erwinia carotovora subp carotovora effectively,and its incidence was significantly lower than the control group. [Conclusion]Bacteria AHL can be possibly used as a new kind of plant disease-resistant activator.

Encouraging specific biomarkers-based therapeutic strategies for hepatocellular carcinoma

The prevention,early discovery and effective treatment of patients with hepatocellular carcinoma(HCC)remain a global medical challenge.At present,HCC is still mainly treated by surgery,supplemented by vascular embolization,radio frequency,radiotherapy,chemotherapy and biotherapy.The application of multikinase inhibitor sorafenib,chimeric antigen receptor T cells,or PD-1/PD-L1 inhibitors can prolong the median survival of HCC patients.However,the treatment efficacy is still unsatisfactory due to HCC metastasis and postoperative recurrence.During the process of hepatocyte malignant transformation,HCC tissues can express and secrete many types of specific biomarkers,or oncogenic antigen molecules into blood,for example,alpha-fetoprotein,glypican-3,Wnt3a(one of the key signaling molecules in the Wnt/β-catenin pathway),insulin-like growth factor(IGF)-II or IGF-I receptor,vascular endothelial growth factor,secretory clusterin and so on.In addition,combining immunotherapy with noncoding RNAs might improve anti-cancer efficacy.These biomarkers not only contribute to HCC diagnosis or prognosis,but may also become molecular targets for HCC therapy under developing or clinical trials.This article reviews the progress in emerging biomarkers in basic research or clinical trials for HCC immunotherapy.

Effects of abiotic stress and hormones on the expressions of five13-CmLOXs and enzyme activity in oriental melon(Cucumis melo var.makuwa Makino)

Lipoxygenases（LOXs） are a group of non-heme,iron-containing enzymes and extensively involved in plant growth and development,ripening and senescence,stress responses,biosynthesis of regulatory molecules and defense reaction.In our previous study,18 LOXs in melon genome were screened and identified,and five 13-LOX genes（CmLOX08,CmLOX10,CmLOX12,CmLOX13 and CmLOX18） were predicted to locate in chloroplast.Phylogenetic analysis result showed that the five genes have high homology with jasmonic acid（JA） biosynthesis-related LOXs from other plants.In addition,promoter analysis revealed that motifs of the five genes participate in gene expression regulated by hormones and stresses.Therefore,we analyzed the expressions of the five genes and LOX activity in leaves of four-leaf stage seedlings of oriental melon cultivar Yumeiren under abiotic stress：wounding,cold,high temperature and hydrogen peroxide（H_2O_2）,and signal molecule treatments：methyl jasmonate（MeJA）,abscisic acid（ABA） and salicylic acid（SA）.Real time qPCR revealed that wounding and H_2O_2 induced the expressions of all the five genes.Only CmLOX08 was induced by cold while only CmLOX13 was suppressed by high temperature.ABA induced the expressions of CmLOXIO and CmLOX12 while inhibited CmLOX13 and CmLOX18.MeJA increased the 3 genes expressions except CmLOX08 and CmLOX13,whereas SA decreased the effect,apart from CmLOX12.All the abiotic stresses and signal molecules treatments increased the LOX activity in leaves of oriental melon.In summary,the results suggest that the five genes have diverse functions in abiotic stress and hormone responses,and might participate in defense response.The data generated in this study will be helpful in subcellular localization and transgenic experiment to understand their precise roles in plant defense response.

Msx homeobox gene family and craniofacial development

Vertebrate Msx genes are unlinked,homeobox-containing genes that bear homology to the Drosophila muscle segment homeobox gene.These genes are expressed at multiple sites of tissue-tissue interactions during vertebrate embryonic development.Inductive interactions mediated by the Msx genes are essential for normal craniofacial,limb and ectodermal organ morphogenesis,and are also essential to survival in mice,as manifested by the phenotypic abnormalities shown in knockout mice and in humans.This review summarizes studies on the expression,regulation,and functional analysis of Msx genes that bear relevance to craniofacial development in humans and mice.

Roles of dietary supplementation with arginine or N-carbamylglutamate in modulating the inflammation, antioxidant property, and m RNA expression of antioxidant-relative signaling molecules in the spleen of rats under oxidative stress

This study evaluated the effects of arginine(Arg) or N-carbamylglutamate(NCG) on inflammation, antioxidant property, and antioxidant-related gene expression in rat spleen under oxidative stress. A total of 52 rats were randomly distributed into 4 treatment groups with 13 replicates per group. Rats were fed a basal diet(BD) or BD supplemented with Arg or NCG for 30 days. On day 28, half of the BD-fed rats were intraperitoneally injected with sterile saline(control group), and the other half with 12 mg/kg body weight of diquat(DT; DT group). The other 2 diet groups were intraperitoneally injected with 12 mg/kg body weight of DT with either Arg(1%)(DT t Arg) or NCG(0.1%)(DT t NCG). Rat spleen samples were collected for analysis at 48 h after DT injection. Results showed that DT damaged the antioxidant defense in rats compared with the control group(P < 0.05). Compared with the DT group, the DT t Arg and DT t NCG groups manifested improved anti-hydroxyl radical, catalase, and total superoxide dismutase(T-SOD) activities, increased glutathione content(P < 0.05), and decreased malondialdehyde content(P < 0.05).Moreover, compared with the DT group, the DT t Arg and DT t NCG groups enhanced mRNA expression of superoxide dismutase(SOD), glutathione peroxidase 1(GPx1), glutathione reductase(GR), nuclear factor erythroid 2-related factor 2(Nrf2), Kelch-like ECH-associated protein 1(Keap-1), and mammalian target of rapamycin(m TOR)(P < 0.05). Both NCG and Arg significantly increased anti-inflammatory cytokine mRNA level but suppressed the pro-inflammatory cytokine mRNA expression under oxidative stress(P < 0.05). In summary, NCG and Arg effectively alleviated oxidative stress, improved the antioxidant capacity and regulated the antioxidant-related signaling molecular expression in rat spleen. N-carbamylglutamate and Arg reduced the inflammation in the spleen by mediating the gene expression of anti-inflammatory and pro-inflammatory cytokines and transforming growth factor-β(TGF-β).

Insights into constructing a stable and efficient microbial consortium

Microbial consortia are ubiquitous in nature,in which multiple microbial species cooperate to complete some important tasks such as lignocellulose degradation.Because of the advantages such as reduced metabolic burden and robustness to environment disturbances,developing a microbial consortium is a promising approach for valuable product synthesis,lignocellulose utilization,human health care,bioremediation and sustainable energy,etc.Despite the benefits,however,most artificial microbial consortia confront the problems of instability and low efficiency due to growth competition and metabolite incompatibility.To overcome these challenges,multiple strategies to design efficient synthetic microbial consortia have been reported.In this review,the interactions that determine the stability and performance of microbial consortia were described.Progress of artificial microbial consortia research was summarized,and the key strategies i.e.,spatial or temporal segregation,separated utilization of nutrients,nutrient cross-feeding and division of labor,that will be of great importance for achieving a stable and efficient microbial consortium were highlighted.Two novel advanced tools,signaling molecule systems and computational models,were also introduced and discussed.We believed that combining the universal cell–cell signaling molecule systems with computational models will be promising for synthetic microbial consortia construction in the future.

Emerging role of cystic fibrosis transmembrane conductance regulator- an epithelial chloride channel in gastrointestinal cancers

Cystic fibrosis transmembrane conductance regulator(CFTR), a glycoprotein with 1480 amino acids, has been well established as a chloride channel mainly expressed in the epithelial cells of various tissues and organs such as lungs, sweat glands, gastrointestinal system, and reproductive organs. Although defective CFTR leads to cystic fibrosis, a common genetic disorder in the Caucasian population, there is accumulating evidence that suggests a novel role of CFTR in various cancers, especially in gastroenterological cancers, such as pancreatic cancer and colon cancer. In this review, we summarize the emerging findings that link CFTR with various cancers, with focus on the association between CFTR defects and gastrointestinal cancers as well as the underlying mechanisms. Further study of CFTR in cancer biology may help pave a new way for the diagnosis and treatment of gastrointestinal cancers.

Recent advances in nano-enabled agriculture for improving plant performance

Nano-enabled agriculture is an emerging hot topic.To facilitate the development of nano-enabled agriculture,reviews addressing or discussing the applications,knowledge gap,future research needs,and possible new research field of plant nanobiotechnology in agricultural production are encouraged.Here we review the following topics in plant nanobiotechnology for agriculture:1)improving stress tolerance,2)stress sensing and early detection,3)targeted delivery and controlled release of agrochemicals,4)transgenic events in non-model crop species,and 5)seed nanopriming.We discuss the knowledge gaps in these topics.Besides the use of nanomaterials for harvesting more electrons to improve photosynthetic performance,they could be used to convert n IR and UV to visible light to expand the light spectrum for photosynthesis.We discuss this approach to maintaining plant photosynthesis under light-insufficient conditions.Our aim in this review is to aid researchers to learn quickly how to use plant nanobiotechnology for improving agricultural production.

Quantitative Structure-property Relationship Studies on Amino Acid Conjugates of Jasmonic Acid as Defense Signaling Molecules

Jasmonates and related compounds, including amino acid conjugates of jasmonic acid, have regulatory functions in the signaling pathway for plant developmental processes and responses to the complex equilibrium of biotic and abiotic stress. But the molecular details of the signaling mechanism are still poorly understood. Statistically significant quantitative structure-property relationship models （r^2 〉 0.990） constructed by genetic function approximation and molecular field analysis were generated for the purpose of deriving structural requirements for lipophilicity of amino acid conjugates of jasmonic acid. The best models derived in the present study provide some valuable academic information in terms of the 2/3D-descriptors influencing the lipophilicity, which may contribute to further understanding the mechanism of exogenous application ofjasmonates in their signaling pathway and designing novel analogs of jasmonic acid as ecological pesticides.

Interplay between hydrogen sulfide and other signaling molecules in the regulation of guard cell signaling and abiotic/biotic stress response

Stomatal aperture controls the balance between transpirational water loss and photosynthetic carbon dioxide(CO2)uptake.Stomata are surrounded by pairs of guard cells that sense and transduce environmental or stress signals to induce diverse endogenous responses for adaptation to environmental changes.In a recent decade,hydrogen sulfide(H2S)has been recognized as a signaling molecule that regulates stomatal movement.In this review,we summarize recent progress in research on the regulatory role of H2S in stomatal movement,including the dynamic regulation of phytohormones,ion homeostasis,and cell structural components.We focus especially on the cross talk among H2S,nitric oxide(NO),and hydrogen peroxide(H2O2)in guard cells,as well as on H2S-mediated post-translational protein modification(cysteine thiol persulfidation).Finally,we summarize the mechanisms by which H2S interacts with other signaling molecules in plants under abiotic or biotic stress.Based on evidence and clues from existing research,we propose some issues that need to be addressed in the future.

Quantitative modeling of bacterial quorum sensing dynamics in time and space

Quorum sensing (QS) refers to the cell communication through signaling molecules that regulate many important biological functions of bacteria by monitoring their population density. Although a wide spectrum of studies on the QS system mechanisms have been carried out in experiments, mathematical modeling to explore the QS system has become a powerful approach as well. In this paper, we review the research progress of network modeling in bacterial QS to capture the system's underlying mechanisms. There are four types of QS system models for bacteria: the Gram-negative QS system model, the Gram-positive QS system model, the model for both Gram-negative and Gram-positive QS system, and the synthetic QS system model. These QS system models are mostly described by the ordinary differential equations (ODE) or partial differential equations (PDE) to study the changes of signaling molecule dynamics in time and space and the cell population density variations. Besides the deterministic simulations, the stochastic modeling approaches have also been introduced to discuss the noise effects on kinetics in QS systems. Taken together, these current modeling efforts advance our understanding of the QS system by providing systematic and quantitative dynamics description, which can hardly be obtained in experiments.