Knockdown of HE4 suppresses tumor growth and invasiveness in lung adenocarcinoma through regulation of EGFR signaling

It has been shown that the high expression of human epididymis protein 4(HE4)in most lung cancers is related to the poor prognosis of patients,but the mechanism of pathological transformation of HE4 in lung cancer is still unclear.The current study is expected to clarify the function and mechanism of HE4 in the occurrence and metastasis of lung adenocarcinoma(LUAD).Immunoblotting evaluated HE4 expression in lung cancer cell lines and biopsies,and through analysis of The Cancer Genome Atlas(TCGA)dataset.Frequent HE4 overexpression was demonstrated in LUAD,but not in lung squamous cell carcinoma(LUSC),indicating that HE4 can serve as a biomarker to distinguish between LUAD and LUSC.HE4 knockdown significantly inhibited cell growth,colony formation,wound healing,and invasion,and blocked the G1-phase of the cell cycle in LUAD cell lines through inactivation of the EGFR signaling downstream including PI3K/AKT/mTOR and RAF/MAPK pathways.The first-line EGFR inhibitor gefitinib and HE4 shRNA had no synergistic inhibitory effect on the growth of lung adenocarcinoma cells,while the third-line EGFR inhibitor osimertinib showed additive anti-proliferative effects.Moreover,we provided evidence that HE4 regulated EGFR expression by transcription regulation and protein interaction in LUAD.Our findings suggest that HE4 positively modulates the EGFR signaling pathway to promote growth and invasiveness in LUAD and highlight that targeting HE4 could be a novel strategy for LUAD treatment.

Clinical value of serum pepsinogen in the diagnosis and treatment of gastric diseases

Pepsinogen,secreted from the gastric mucosa,is the precursor of pepsin.It is categorized as pepsinogen 1 and pepsinogen 2 based on its immunogenicity.The pepsinogen content that can enter the blood circulation through the capillaries of the gastric mucosa is approximately 1%and remains stable all the time.The pepsinogen content in serum will change with the pathological changes of gastric mucosa.Therefore,the level of pepsinogen in serum can play a role in serologic biopsy to reflect the function and morphology of different regions of gastric mucosa and serve as an indicator of gastric disease.This study conducts relevant research on serum pepsinogen 1,pepsinogen 2,and the ratio of pepsinogen 1 to pepsinogen 2,and reviews their important value in clinical diagnosis of Helicobacter pylori infection,gastric ulcer,and even gastric carcinoma,providing ideas for other researchers.

Unveiling the spatial distribution and molecular mechanisms of terpenoid biosynthesis in Salvia miltiorrhiza and S. grandifolia using multi-omicsand DESI-MSI

Salvia miltiorrhiza and S.grandifolia are rich in diterpenoids and have therapeutic effects on cardiovascular diseases.In this study,the spatial distribution of diterpenoids in both species was analyzed by a combination of metabolomics and mass spectrometry imaging techniques.The results indicated that diterpenoids in S.miltiorrhiza were mainly abietane-type norditerpenoid quinones with a furan or dihydrofuran D-ring and were mainly distributed in the periderm of the roots,e.g.cryptotanshinone and tanshinone IIA.The compounds in S.grandifolia were mainly phenolic abietane-type tricyclic diterpenoids with six-or seven-membered C-rings,and were widely distributed in the periderm,phloem,and xylem of the roots,e.g.11-hydroxy-sugiol,11,20-dihydroxy-sugiol,and 11,20-dihydroxy-ferruginol.In addition,the leaves of S.grandifolia were rich in tanshinone biosynthesis precursors,such as 11-hydroxy-sugiol,while those of S.miltiorrhiza were rich in phenolic acids.Genes in the upstream pathway of tanshinone biosynthesis were highly expressed in the root of S.grandifolia,and genes in the downstream pathway were highly expressed in the root of S.miltiorrhiza.Here,we describe the specific tissue distributions and mechanisms of diterpenoids in two Salvia species,which will facilitate further investigations of the biosynthesis of diterpenoids in plant synthetic biology.

Protective efficacy evaluation of immunogenic protein AHA_3793 of Aeromonas hydrophila as vaccine candidate for largemouth bass Micropterus salmoides

Aeromonas hydrophila is a Gram-negative pathogen that can infect various fish,including largemouth bass(Micropterus salmoides),which have caused huge economic losses.In present study,largemouth bass anti-A.hydrophila antibodies were produced,then a highly immunogenic outer membrane proteins,AHA_3793,was identified by combined western blotting and mass spectrometry analysis.Moreover,AHA_3793 was expressed,and its immunogenicity was further verified by western blotting.Subsequently,the protective efficacy of AHA_3793 were evaluated in largemouth bass.The results showed that rAHA_3793 could produce a relative percentage survival(RPS)of 61.76% for largemouth bass against A.hydrophila challenge.ELISA analysis showed the specific serum antibodies of largemouth bass against rAHA_3793 and A.hydrophila in vaccinated group in weeks 4 and 5 after immunization were significantly higher than those in control group,which suggested that rAHA_3793 induced production of specific serum antibodies against rAHA_3793 and A.hydrophila.The qRT-PCR analysis showed that expressions of CD4-2 and MHC Ⅱα were also significantly up-regulated after immunization.These results collectively demonstrated that rAHA_3793 could induce a strong humoral immune response of largemouth bass,and then produce high immune protection ef fects against A.hydrophila infection.

Chemico-biological conversion of carbon dioxide

The unabated carbon dioxide(CO_(2))emission into the atmosphere has exacerbated global climate change,resulting in extreme weather events,biodiversity loss,and an intensified greenhouse effect.To address these challenges and work toward carbon(C)neutrality and reduced CO_(2)emissions,the capture and utilization of CO_(2)have become imperative in both scientific research and industry.One cutting-edge approach to achieving efficient catalytic performance involves integrating green bioconversion and chemical conversion.This innovative strategy offers several advantages,including environmental friendliness,high efficiency,and multi-selectivity.This study provides a comprehensive review of existing technical routes for carbon sequestration(CS)and introduces two novel CS pathways:the electrochemicalbiological hybrid and artificial photosynthesis systems.It also thoroughly examines the synthesis of valuable Cnproducts from the two CS systems employing different catalysts and biocatalysts.As both systems heavily rely on electron transfer,direct and mediated electron transfer has been discussed and summarized in detail.Additionally,this study explores the conditions suitable for different catalysts and assesses the strengths and weaknesses of biocatalysts.We also explored the biocompatibility of the electrode materials and developed novel materials.These materials were specifically engineered to combine with enzymes or microbial cells to solve the biocompatibility problem,while improving the electron transfer efficiency of both.Furthermore,this review summarizes the relevant systems developed in recent years for manufacturing different products,along with their respective production efficiencies,providing a solid database for development in this direction.The novel chemical-biological combination proposed herein holds great promise for the future conversion of CO_(2)into advanced organic compounds.Additionally,it offers exciting prospects for utilizing CO_(2)in synthesizing a wide range of industrial products.Ultimately,the present study provides a unique perspective for achieving the vital goals of“peak shaving”and C-neutrality,contributing significantly to our collective efforts to combat climate change and its associated challenges.

Multifaceted p21 in carcinogenesis,stemness of tumor and tumor therapy

Cancer cells possess metabolic properties that are different from those of benign cells.p21,encoded by CDKN1A gene,also named p21Cip1/WAF1,was first identified as a cyclin-dependent kinase regulator that suppresses cell cycle G1/S phase and retinoblastoma protein phosphorylation.CDKN1A(p21)acts as the downstream target gene of TP53(p53),and its expression is induced by wild-type p53 and it is not associated with mutant p53.p21 has been characterized as a vital regulator that involves multiple cell functions,including G1/S cell cycle progression,cell growth,DNA damage,and cell stemness.In 1994,p21 was found as a tumor suppressor in brain,lung and colon cancer by targeting p53 and was associated with tumorigenesis and metastasis.Notably,p21 plays a significant role in tumor development through p53-dependent and p53-independent pathways.In addition,expression of p21 is closely related to the resting state or terminal differentiation of cells.p21 is also associated with cancer stem cells and acts as a biomarker for such cells.In cancer therapy,given the importance of p21 in regulating the G1/S and G2 check points,it is not surprising that p21 is implicated in response to many cancer treatments and p21 promotes the effect of oncolytic virotherapy.

Roles of lncRNAs in Rice: Advances and Challenges

Long non-coding RNAs(lncRNAs) larger than 200 nucleotides in length are eukaryotic RNAs, and do not encode proteins. lncRNAs are considered to be important regulators in many biological processes in plants. In this review, the latest advances in the roles of lncRNAs in rice were reviewed, and functions of lncRNAs were further summarized and classified. lncRNAs play crucial roles in tolerance to biotic and abiotic stresses such as disease, drought, heat, cold, heavy metal, and starvation of nitrogen and phosphorus in rice. In addition, lncRNAs also regulate various growth and development processes in rice. Finally, the prospect and challenges of rice lncRNA function research in future were proposed. This review will not only help us quickly grasp the frontiers of lncRNAs functional research progresses, but also propose suggestions and ideas for the directions of further lncRNA research in rice.

Antimicrobial peptides: mechanism of action, activity and clinical potential

The management of bacterial infections is becoming a major clinical challenge due to the rapid evolution of antibiotic resistant bacteria.As an excellent candidate to overcome antibiotic resistance,antimicrobial peptides(AMPs)that are produced from the synthetic and natural sources demonstrate a broad-spectrum antimicrobial activity with the high specificity and low toxicity.These peptides possess distinctive structures and functions by employing sophisticated mechanisms of action.This comprehensive review provides a broad overview of AMPs from the origin,structural characteristics,mechanisms of action,biological activities to clinical applications.We finally discuss the strategies to optimize and develop AMP-based treatment as the potential antimicrobial and anticancer therapeutics.

Characterization and comparison of two C-type lectins with novel key motifs from mud crab Scylla paramamosain

As an important pattern recognition receptor(PRR)in the innate immune system,C-type lectin plays an important role in the innate immune process of invertebrates.Two C-type lectins Sp CTL-C and Sp CTL-D were characterized from mud crab(Scylla paramamosain).The predicted Sp CTL-C and Sp CTL-D proteins both contain a single carbohydrate-recognition domain(CRD)with key motif Gln-Pro-Ala(QPA)and Met-Pro-Ala(MPA),respectively.Sp CTL-C and Sp CTL-D transcripts distributed in all examined tissues,and the expression level was the highest in hepatopancreas.As PRR,the purifi ed recombinant proteins r Sp CTL-C and r Sp CTL-D have high affi nity for three kinds of pathogen-associated molecular patterns(PAMPs):β-glucan,lipopolysaccharide,and peptidoglycan.Besides,r Sp CTL-D can bind to all nine microorganisms tested,while r Sp CTL-C can bind to seven microorganisms except for Staphylococcus aureus and Micrococcus luteus.Both r Sp CTL-C and r Sp CTL-D showed agglutination activity towards fungi Pichia pastoris and Saccharomyces cerevisiae.However,r Sp CTL-C and r Sp CTL-D exhibited diff erent antimicrobial activities:r Sp CTL-D has a certain inhibitory eff ect on the growth of Vibrio fl uvialis and M.luteus,while r Sp CTL-C has no obvious inhibitory activity.The results show that r Sp CTL-C and r Sp CTL-D had better phagocytosis-promoting eff ect on M.luteus than the negative control.Meanwhile,both r Sp CTL-C and r Sp CTL-D had certain encapsulation-promoting activity.Collectively,two C-type lectins with novel key motifs make an important impact as PRR in immune response towards pathogens.At the same time,they play diff erent functions in the innate immunity of mud crab S.paramamosain.

Genome-wide identification of WRKY gene family and expression analysis under abiotic stresses in Andrographis paniculata

Andrographis paniculata(A.paniculata)is a Chinese herbal medicine that clears away heat,reduces inflammation,protects the liver,and promotes choleretics.The WRKYs of A.paniculata are still not well characterized,although many WRKYs have been identified in various plant species.In the present study,59 A.paniculata WRKY(ApWRKY)genes were identified and renamed on the basis of their respective chromosome distribution.These ApWRKYs were divided into three groups via phylogenetic analysis according to their WRKY domains and combined with WRKY of Arabidopsis.The 59 identified ApWRKY transcription factors were nonuniformity distributed on 23 chromosomes of A.paniculata.From the structural analysis of the conserved motifs,different ApWRKYs structures showed different biological functions,and the ApWRKY transcription factor had certain species-specificity in the evolutionary process.The expression patterns of the 41 ApWRKYs were examined through quantitative real-time PCR(qRT-PCR)in various tissues and under abiotic stresses(salt).The results showed that most of the ApWRKY had different reactions to salt treatment.In addition,the content of the four main secondary metabolites in A.paniculata leaves was determined under salt stress.The results show that under a low concentration of salt treatment,the synthesis of andrographolide can be improved.

Genome-wide identification of NAC gene family and expression analysis under abiotic stresses in Salvia miltiorrhiza

NAC(NAM,ATAF,CUC)is a class of transcription factors involved in plant growth regulation,abiotic stress responses,morphogenesis and metabolism.Salvia miltiorrhiza is an important Chinese medicinal herb,but the characterization of NAC genes in this species is limited.In this study,based on the Salvia miltiorrhiza genomic databases,82 NAC transcription factors were identified,which were divided into 14 groups.Meanwhile,phylogenetic analysis,gene structure,chromosomal localization and potential role of SmNACs in abiotic stress conditions were also studied.The results revealed that some SmNACs had different structures than others,which advised that these genes may have multiple/distinct functions.Real-time quantitative polymerase chain reaction(RT-qPCR)analysis showed that SmNACs exhibited differential expression patterns under salt and drought stress.The NaCl induced salinity treatments modulated the expression of several SmNAC genes more in roots compared with leaves.Conversely,under drought stress conditions,more genes were upregulated in leaves compared with roots.These results will be useful for the further study involved in the functional characteristics of SmNAC genes,especially in response to salt and drought stresses,thereby may facilitate genetic breeding in Salvia miltiorrhiza.

Multiple roles of mothers against decapentaplegic homolog 4 in tumorigenesis, stem cells, drug resistance, and cancer therapy

The transforming growth factor(TGF)-βsignaling pathway controls many cellular processes,including proliferation,differentiation,and apoptosis.Abnormalities in the TGF-βsignaling pathway and its components are closely related to the occurrence of many human diseases,including cancer.Mothers against decapentaplegic homolog 4(Smad4),also known as deleted in pancreatic cancer locus 4,is a typical tumor suppressor candidate gene locating at q21.1 of human chromosome 18 and the common mediator of the TGF-β/Smad and bone morphogenetic protein/Smad signaling pathways.It is believed that Smad4 inactivation correlates with the development of tumors and stem cell fate decisions.Smad4 also interacts with cytokines,miRNAs,and other signaling pathways,jointly regulating cell behavior.However,the regulatory function of Smad4 in tumorigenesis,stem cells,and drug resistance is currently controversial.In addition,Smad4 represents an attractive therapeutic target for cancer.Elucidating the specific role of Smad4 is important for understanding the mechanism of tumorigenesis and cancer treatment.Here,we review the identification and characterization of Smad4,the canonical TGF-β/Smad pathway,as well as the multiple roles of Smad4 in tumorigenesis,stem cells,and drug resistance.Furthermore,we provide novel insights into the prospects of Smad4-targeted cancer therapy and the challenges that it will face in the future.

Genome-wide identification of U-box gene family and expression analysis under abiotic stresses in Salvia miltiorrhiza

Plant U-box(PUB)E3 ubiquitin ligases play important roles in hormone signaling pathways and in response to different abiotic stresses,but little is known about U-box genes in Danshen(root of Salvia miltiorrhiza Bunge).Here,we identified and characterized 70 SmPUB genes based on its genome sequence.Phylogenetic analysis of U-box genes from S.miltiorrhiza and Arabidopsis suggested that they can be clustered into seven subgroups(I–VII).Typical U-box domains were found in all identified SmPUB genes through the analysis of conserved motifs.Moreover,qRT-PCR was applied to analyze the relative expression levels of U-box genes in S.miltiorrhiza roots and leaves under PEG-induced water deficit and salt stresses.Results revealed that the SmPUB genes exhibited stronger response to drought than to salt stress.To the best of our knowledge,this report is the first to perform genome-wide identification and analysis of the U-box gene family in S.miltiorrhiza,and the results provide valuable information for better understanding of the function of U-box in S.miltiorrhiza.

Does Quality of Care Differ When HIV Patients Are Treated by Non-Specialist and Specialist HIV Healthcare Providers in Developed Countries? A Systematic Narrative Review

Introduction: In developed countries, HIV care is mostly provided by trained specialist healthcare professionals. Due to the increasing demand for HIV care, pressure on healthcare providers to reduce cost and the current global economic constraints, many developed countries are searching for alternative HIV care models. This review aims to consider whether HIV treatment and care can be provided as effectively and safely by doctors and nurses with no HIV-specialist training compared to those with HIV-specialist training. Methods: Three electronic bibliographic databases MEDLINE, EMBASE and the Cochrane Library were searched for studies conducted between January 1996 and March 2015. Manual searches of reference lists of all relevant reports retrieved from the electronic databases were conducted. All comparative studies examining the quality of HIV care provided by different types of healthcare providers in developed countries were included. Results: Nine observational studies involving 27,015 patients were included in the review. Eight studies were conducted in the USA and one study in Switzerland. Healthcare providers with HIV-related expertise and or training and those without HIV-related expertise or training who collaborated with providers with HIV-related expertise and or training outperformed other healthcare providers in many virological, immunological and ART-related outcomes. Conclusion: This review found moderate quality evidence that HIV care can be provided effectively by non-HIV specialists if they have access to HIV specialists or experts for advice and support.

Flavanone and flavonoid hydroxylase genes regulate fiber color formation in naturally colored cotton

Using naturally colored cotton(NCC)can eliminate dyeing,printing and industrial processing,and reduce sewage discharge and energy consumption.Proanthocyanidins(PAs),the primary coloration components in brown fibers,are polyphenols formed by oligomers or polymers of flavan-3-ol units derived from anthocyanidins.Three essential structural genes for flavanone and flavonoid hydroxylation encoding flavanone-3-hydroxylase(F3H),flavonoid 3’-hydroxylase(F3’H)and flavonoid 3’5’-hydroxylase(F3’5’H)are initially committed in the flavonoid biosynthesis pathway to produce common precursors.The three genes were all expressed predominantly in developing fibers of NCCs,and their expression patterns varied temporally and spatially among NCC varieties.In GhF3Hi,GhF3’Hi and GhF3’5’Hi silenced lines of NCC varieties XC20 and ZX1,the expression level of the three genes decreased in developing cotton fiber,negatively correlated with anthocyanidin content and fiber color depth.Fiber color depth and type in RNAi lines changed with endogenous gene silencing efficiency and expression pattern,the three hydroxylase genes functioned in fiber color formation.GhF3H showed functional differentiation among NCC varieties and GhF3’H acted in the accumulation of anthocyanin in fiber.Compared with GhF3’H,GhF3’5’H was expressed more highly in brown fiber with a longer duration of expression and caused lighter color of fibers in GhF3’5’H silenced lines.These three genes regulating fiber color depth and type could be used to improve these traits by genetic manipulation.

Microbiota regulation in constipation and colorectal cancer

The relevance of constipation to the development and progression of colorectal cancer(CRC)is currently a controversial issue.Studies have shown that changes in the composition of the gut microbiota,a condition known as ecological imbalance,are correlated with an increasing number of common human diseases,including CRC and constipation.CRC is the second leading cause of cancerrelated deaths worldwide,and constipation has been receiving widespread attention as a risk factor for CRC.Early colonoscopy screening of constipated patients,with regular follow-ups and timely intervention,can help detect early intestinal lesions and reduce the risks of developing colorectal polyps and CRC.As an important regulator of the intestinal microenvironment,the gut microbiota plays a critical role in the onset and progression of CRC.An increasing amount of evidence supports the thought that gut microbial composition and function are key determinants of CRC development and progression,with alterations inducing changes in the expression of host genes,metabolic regulation,and local and systemic immunological responses.Furthermore,constipation greatly affects the composition of the gut microbiota,which in turn influences the susceptibility to intestinal diseases such as CRC.However,the crosstalk between the gut microbiota,constipation,and CRC is still unclear.

GhSCL4 Acts as a Positive Regulator in Both Transgenic Arabidopsis and Cotton during Salt Stress

GRAS transcription factors play important roles in plant abiotic stress response,but their characteristics and functions in cotton have not been fully investigated.A cotton SCL4/7 subgroup gene in the GRAS family,GhSCL4,was found to be induced by NaCl treatments.Nuclear localization and transactivation activity of GhSCL4 indicate its potential role in transcriptional regulation.Transgenic Arabidopsis thaliana over-expressing GhSCL4 showed enhanced resistance to salt and osmotic stress.What’s more,the transcript levels of salt stress-induced genes(AtNHX1 and AtSOS1)and oxidation-related genes(AtAPX3 and AtCSD2)were more highly induced in the GhSCL4 over-expression lines than in wild type after salt treatment.Furthermore,silencing of GhSCL4 resulted in reduced salt tolerance in cotton caused by reactive oxygen species(ROS)enrichment under salt treatment,and antioxidant enzyme activities were accordingly significantly reduced in GhSLC4-silenced lines.These results indicated that GhSCL4 enhances salt tolerance of cotton by detoxifying ROS.In addition,the transient expression assay confirmed an interactive relationship between GhSCL4 and GhCaM7,which indicated that salt tolerance conferred by GhSCL4 might be associated with salt-induced Ca^(2+)/CaM7-mediated signaling.Taken together,GhSCL4 acts as a positive regulator in cotton during salt stress that is potentially useful for engineering salt-tolerant cotton.

The ERF transcription factor LTF1 activates DIR1 to control stereoselective synthesis of antiviral lignans and stress defense in Isatis indigotica roots

Lignans are a powerful weapon for plants to resist stresses and have diverse bioactive functions to protect human health.Elucidating the mechanisms of stereoselective biosynthesis and response to stresses of lignans is important for the guidance of plant improvement.Here,we identified the complete pathway to stereoselectively synthesize antiviral(-)-lariciresinol glucosides in Isatis indigotica roots,which consists of three-step sequential stereoselective enzymes DIR1/2,PLR,and UGT71B2.DIR1 was further identified as the key gene in respoJanuary 2024nse to stresses and was able to trigger stress defenses by mediating the elevation in lignan content.Mechanistically,the phytohormone-responsive ERF transcription factor LTF1 colocalized with DIR1 in the cell periphery of the vascular regions in mature roots and helped resist biotic and abiotic stresses by directly regulating the expression of DIR1.These systematic results suggest that DIR1 as the first common step of the lignan pathway cooperates with PLR and UGT71B2 to stereoselectively synthesize(-)-lariciresinol derived antiviral lignans in I.indigotica roots and is also a part of the LTF1-mediated regulatory network to resist stresses.In conclusion,the LTF1-DIR1 module is an ideal engineering target to improve plant Defenses while increasing the content of valuable lignans in plants.

Advances in the research and application of neurokinin-1 receptor antagonists

Recently,the substance P(SP)/neurokinin-1 receptor(NK-1R)system has been found to be involved in various human pathophysiological disorders including the symptoms of coronavirus disease 2019(COVID-19).Besides,studies in the oncological field have demonstrated an intricate correlation between the upregulation of NK-1R and the activation of SP/NK-1R system with the progression of multiple carcinoma types and poor clinical prognosis.These findings indicate that the modulation of SP/NK-1R system with NK-1R antagonists can be a potential broad-spectrum antitumor strategy.This review updates the latest potential and applications of NK-1R antagonists in the treatment of human diseases and cancers,as well as the underlying mechanisms.Furthermore,the strategies to improve the bioavailability and efficacy of NK-1R antagonist drugs are summarized,such as solid dispersion systems,nanonization,and nanoencapsulation.As a radiopharmaceutical therapeutic,the NK-1R antagonist aprepitant was originally developed as radioligand receptor to target NK-1R-overexpressing tumors.However,combining NK-1R antagonists with other drugs can produce a synergistic effect,thereby enhancing the therapeutic effect,alleviating the symptoms,and improving patients’quality of life in several diseases and cancers.

Early colorectal cancer screening–no time to lose

In this editorial,we comment on the article entitled“Stage at diagnosis of colorectal cancer through diagnostic route:Who should be screened?”by Agatsuma et al.Colorectal cancer(CRC)is emerging as an important health issue as its incidence continues to rise globally,adversely affecting the quality of life.Although the public has become more aware of CRC prevention,most patients lack screening awareness.Some poor lifestyle practices can lead to CRC and symptoms can appear in the early stages of CRC.However,due to the lack of awareness of the disease,most of the CRC patients are diagnosed already at an advanced stage and have a poor prognosis.