HPV-associated cervicovaginal microbiome and host metabolome characteristics.

BACKGROUND: Cervicovaginal microbiome plays an important role in the persistence of HPV infection and subsequent disease development. However, cervicovaginal microbiota varied cross populations with different habits and regions. Identification of population-specific biomarkers from cervicovaginal microbiota and host metabolome axis may support early detection or surveillance of HPV-induced cervical disease at all sites. Therefore, in the present study, to identify HPV-specific biomarkers, cervicovaginal secretion and serum samples from HPV-infected patients (HPV group, n = 25) and normal controls (normal group, n = 17) in Xichang, China were collected for microbiome (16S rRNA gene sequencing) and metabolome (UHPLC-MS/MS) analysis, respectively. RESULTS: The results showed that key altered metabolites of 9,10-DiHOME, α-linolenic acid, ethylparaben, glycocholic acid, pipecolic acid, and 9,12,13-trihydroxy-10(E),15(Z)-octadecadienoic acid, correlating with Sneathia (Sneathia_amnii), Lactobacillus (Lactobacillus_iners), Atopobium, Mycoplasma, and Gardnerella, may be potential biomarkers of HPV infection. CONCLUSION: The results of current study would help to reveal the association of changes in cervicovaginal microbiota and serum metabolome with HPV infections.

Role of miRNAs in macrophage-mediated kidney injury.

Macrophages, crucial components of the human immune system, can be polarized into M1/M2 phenotypes, each with distinct functions and roles. Macrophage polarization has been reported to be significantly involved in the inflammation and fibrosis observed in kidney injury. MicroRNA (miRNA), a type of short RNA lacking protein-coding function, can inhibit specific mRNA by partially binding to its target mRNA. The intricate association between miRNAs and macrophages has been attracting increasing interest in recent years. This review discusses the role of miRNAs in regulating macrophage-mediated kidney injury. It shows how miRNAs can influence macrophage polarization, thereby altering the biological function of macrophages in the kidney. Furthermore, this review highlights the significance of miRNAs derived from exosomes and extracellular vesicles as a crucial mediator in the crosstalk between macrophages and kidney cells. The potential of miRNAs as treatment applications and biomarkers for macrophage-mediated kidney injury is also discussed.

Chemical profiling and quality evaluation of Liuweizhiji Gegen-Sangshen oral liquid by UPLC-Q-TOF-MS and HPLC-diode array detector fingerprinting.

INTRODUCTION: Liuweizhiji Gegen-Sangshen (LGS) oral liquid is a Chinese patent medicine that is widely used for the prevention and treatment of alcoholic liver disease in clinical practice. However, the chemical complexity of LGS has not yet been investigated. OBJECTIVE: The aim of this study was to rapidly identify chemical constituents of LGS and establish a quality control method based on fingerprint and quantitative analysis. METHODOLOGY: A comprehensive strategy was used by combining qualitative analysis by ultra-performance liquid chromatography tandem quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) and fingerprint analysis by high-performance liquid chromatography with diode array detection (HPLC-DAD). RESULTS: A total of 162 chemical components in LGS, including 91 flavonoids, 31 organic acids, and 20 phenolic compounds, were identified or preliminarily characterized in both positive and negative ion modes based on the UPLC-Q-TOF-MS results. Of these, 37 were confirmed with the reference standards. In fingerprint analysis, 23 peaks were chosen as common peaks and used to evaluate the similarity of different batches of LGS. Subsequently, a rapid quantification method was optimized and validated for the simultaneous determination of multiple chemical markers in LGS. The validated quantitative method was successfully used to analyze different batches of LGS samples. CONCLUSION: The proposed comprehensive strategy combining HPLC-DAD fingerprinting and multi-component quantification demonstrated satisfactory results with high efficiency, accuracy, and reliability. This can be used as a reference for the overall quality consistency evaluation of Chinese patent medicines.

Synthesis of Oleanolic Acid-Dithiocarbamate Conjugates and Evaluation of Their Broad-Spectrum Antitumor Activities.

Efficient and mild synthetic routes for bioactive natural product derivatives are of current interest for drug discovery. Herein, on the basis of the pharmacophore hybrid strategy, we report a two-step protocol to obtain a series of structurally novel oleanolic acid (OA)-dithiocarbamate conjugates in mild conditions with high yields. Moreover, biological evaluations indicated that representative compound 3e exhibited the most potent and broad-spectrum antiproliferative effects against Panc1, A549, Hep3B, Huh-7, HT-29, and Hela cells with low cytotoxicity on normal cells. In terms of the IC50 values, these OA-dithiocarbamate conjugates were up to 30-fold more potent than the natural product OA. These compounds may be promising hit compounds for the development of novel anti-cancer drugs.

Dopamine receptor D1 signaling stimulates lipolysis and browning of white adipocytes.

Adipocytes express several kinds of catecholamine receptors, including adrenergic receptors, and dopamine receptors. Signaling pathways mediated by catecholamine receptors, such as ß3-adrenergic receptor pathway, can induce body energy expenditure via activating thermogenesis of adipose tissue. However, the roles of adipose dopamine receptors on adipocytes are still unclear. Here, we investigate the role of dopamine receptor D1 (DRD1) on adipocytes. To this end, we use DRD1 agonist Fenoldopam and antagonist SCH23390 to stimulate and inhibit DRD1 signaling, respectively. We found that, compared with control group mice, Fenoldopam-treated and SCH23390-treated high-fat-diet (HFD)-fed mice showed smaller and bigger white adipose tissue/adipocyte sizes, respectively. Meanwhile, activating of DRD1 signaling enhanced intracellular levels of cAMP, phosphorylation levels of protein kinase A substrates, and hormone-sensitive lipase, a key enzyme for lipolysis in mature 3T3-L1 adipocytes and white adipose tissue of HFD-fed mice. As a result, the levels of free fatty acid or glycerol were increased, indicating stimulation of lipolysis by DRD1 activation. Moreover, activating DRD1 can induce the browning of adipocytes, as indicated by enhanced phosphorylation of P38 MAP kinase, increased expression of beige cell markers (PGC-1α, UCP-1, and CD81), mitochondrion content, and expression of ß-oxidation related genes. All of these effects were reduced after treating with SCH23390 both in vitro and in HFD-fed mice. Collectively, our study indicated that DRD1 signaling stimulates lipolysis and browning of white adipocytes in vitro and in vivo. Understanding the functions of DRD1 on human adipocytes and adipose tissues will help us to design novel strategies to treat obesity.

The distinct roles of exosomes in tumor-stroma crosstalk within gastric tumor microenvironment.

Gastric cancer (GC) development is a complex process displaying polytropic cell and molecular landscape within gastric tumor microenvironment (TME). Stromal cells in TME, including fibroblasts, endothelial cells, mesenchymal stem cells, and various immune cells, support tumor growth, metastasis, and recurrence, functioning as the soil for gastric tumorigenesis. Importantly, exosomes secreted by either stromal cells or tumor cells during tumor-stroma crosstalk perform as crucial transporter of agents including RNAs and proteins for cell-cell communication in GC pathogenesis. Therefore, given the distinct roles of exosomes secreted by various cell types in GC TME, increasing evidence has indicated that exosomes present as new biomarkers for GC diagnosis and prognosis and shed light on novel approaches for GC treatment.

Molecular insights into the sex-differential regulation of signal transduction in the cerebral ganglion and metabolism in the hepatopancreas of Eriocheir sinensis during reproduction.

The Chinese mitten crab (Eriocheir sinensis), an economically valuable crustacean that is popular for its flavor, exhibits catadromous spawning migration. Overfishing and environmental pollution have inflicted serious damage on wild E. sinensis populations, and the Chinese government has banned the commercial fishing of this species in the Yangtze River. Studies have examined the sexual dimorphism in the body size and morphology of crabs, but there are few reports on the molecular regulatory mechanisms that occur during the reproduction of E. sinensis. In this study, we performed the first comparative transcriptome analyses of the cerebral ganglion and hepatopancreas of E. sinensis during reproduction. The results indicate that E. sinensis has significant sexual dimorphism in signal transduction, metabolism, substance transportation, and cellular protection. This study aims to provide information that can be used as a basis for further research on the molecular mechanisms that underlie sexual dimorphism in E. sinensis during reproduction. Furthermore, the results can be used to support the development of the E. sinensis breeding industry and the restoration of wild E. sinensis.

Akt-targeted therapy as a promising strategy to overcome drug resistance in breast cancer - A comprehensive review from chemotherapy to immunotherapy.

Breast cancer is the most frequently occurring cancer in women. Chemotherapy in combination with immunotherapy has been used to treat breast cancer. Atezolizumab targeting the protein programmed cell death-ligand (PD-L1) in combination with paclitaxel was recently approved by the Food and Drug Administration (FDA) for Triple-Negative Breast Cancer (TNBC), the most incurable type of breast cancer. However, the use of such drugs is restricted by genotype and is effective only for those TNBC patients expressing PD-L1. In addition, resistance to chemotherapy with drugs such as lapatinib, geftinib, and tamoxifen can develop. In this review, we address chemoresistance in breast cancer and discuss Akt as the master regulator of drug resistance and several oncogenic mechanisms in breast cancer. Akt not only directly interacts with the mitogen-activated protein (MAP) kinase signaling pathway to affect PD-L1 expression, but also has crosstalk with Notch and Wnt/ß-catenin signaling pathways involved in cell migration and breast cancer stem cell integrity. In this review, we discuss the effects of tyrosine kinase inhibitors on Akt activation as well as the mechanism of Akt signaling in drug resistance. Akt also has a crucial role in mitochondrial metabolism and migrates into mitochondria to remodel breast cancer cell metabolism while also functioning in responses to hypoxic conditions. The Akt inhibitors ipatasertib, capivasertib, uprosertib, and MK-2206 not only suppress cancer cell proliferation and metastasis, but may also inhibit cytokine regulation and PD-L1 expression. Ipatasertib and uprosertib are undergoing clinical investigation to treat TNBC. Inhibition of Akt and its regulators can be used to control breast cancer progression and also immunosuppression, while discovery of additional compounds that target Akt and its modulators could provide solutions to resistance to chemotherapy and immunotherapy.

Natural killer cells as a double-edged sword in cancer immunotherapy: A comprehensive review from cytokine therapy to adoptive cell immunotherapy.

Natural killer (NK) cells are immune cells which are able to kill tumor and virus-infected cells and play an important role in both innate immunity and acquired immunity. Tumor immunotherapy is an emerging model of tumor treatment in the clinic. It is a re-emerging type of anticancer immunotherapy with the purpose of killing tumor cells by modulating the body's immune function and enhancing the antitumor immunity in tumor microenvironment. At present, many immune cells including lymphokine-activated killer cells, NK cells, cytokine-induced killer cells, and dendritic cells are involved in tumor immunotherapy studies. NK cells, which lyse tumor cells without prior stimulation, has become a research hotspot in cancer immunotherapy for clinical application. In this article, we discussed the surface receptors of NK cells and the anticancer function of NK cells. We also reviewed the biological characteristics and the current research status of NK cells, their clinical application in cancer immunotherapy and its future perspectives.

Glyoxalase 1 gene improves the antistress capacity and reduces the immune inflammatory response.

BACKGROUND: Fish immunity is not only affected by the innate immune pathways but is also triggered by stress. Transport and loading stress can induce oxidative stress and further activate the immune inflammatory response, which cause tissue damage and sudden death. Multiple genes take part in this process and some of these genes play a vital role in regulation of the immune inflammatory response and sudden death. Currently, the key genes regulating the immune inflammatory response and the sudden death caused by stress in Coilia nasus are unknown. RESULTS: In this study, we studied the effects of the Glo1 gene on stress, antioxidant expression, and immune-mediated apoptosis in C. nasus. The full-length gene is 4356 bp, containing six exons and five introns. Southern blotting indicated that Glo1 is a single-copy gene in the C. nasus genome. We found two single-nucleotide polymorphisms (SNPs) in the Glo1 coding region, which affect the three-dimensional structure of Glo1 protein. An association analysis results revealed that the two SNPs are associated with stress tolerance. Moreover, Glo1 mRNA and protein expression of the heterozygous genotype was significantly higher than that of the homozygous genotype. Na+ and sorbitol also significantly enhanced Glo1 mRNA and protein expression, improved the fish's antioxidant capacity, and reduced the immune inflammatory response, thus sharply reducing the mortality caused by stress. CONCLUSIONS: Glo1 plays a potential role in the stress response, antioxidant capacity, and immune-mediated apoptosis in C. nasus.

Transcriptome analysis gene expression in the liver of Coilia nasus during the stress response.

BACKGROUND: The estuarine tapertail anchovy (Coilia nasus) is widely distributed in the Yangtze River, the coastal waters of China, Korea, and the Ariake Sound of Japan. It is a commercially important species owing to its nutritional value and delicate flavor. However, Coilia nasus is strongly responsive to stress, this often results in death, which causes huge losses. In this study, we used next-generation sequencing technologies to study changes in gene expression in response to loading stress and the mechanism of death caused by loading stress in Coilia nasus. RESULTS: Using next-generation RNA-seq technologies on an Illumina HiSeq 2000 platform, we assembled a de novo transcriptome and tested for differential expression in response to stress. A total of 65,129 unigenes were generated, the mean unigene size and N50 were 607 bp and 813 bp, respectively. Of the assembled unigenes, we identified 2,990 genes that were significantly up-regulated, while 3,416 genes were significantly down-regulated in response to loading stress. Pathway enrichment analysis based on loading stress-responsive unigenes identified significantly stress related pathways. "Metabolism" and "immunity" were the two most frequently represented categories. In the "metabolism" category, "glucose metabolism" and "lipid metabolism" were major subclasses. The transcriptional expression of rate-limiting enzymes in "glucose metabolism" and "lipid metabolism" was detected by RT-qPCR, all were significantly increased after stress. Apoptosis associated proteins tumor necrosis factor alpha (TNF-α), caspase 9, cytochrome c and caspase 3 in the stress group were significantly elevated, moreover, liver injury indicators (Alanine aminotransferase, ALT, and aspartate transaminase, AST) were also significantly elevated, which indicates that loading stress induced liver injury. CONCLUSION: This study provided abundant unigenes that could contribute greatly to the discovery of novel genes in fish. The alterations in predicted gene expression patterns reflected possible responses to stress. Loading stress may induce liver injury through the mitochondrial apoptosis pathway, which was activated by TNF-α. Taken together, our data not only provide information that will aid the identification of novel genes from fish, but also shed new light on the understanding of mechanisms by which physical stressors cause death in fish.

Potential applications of dual haptoglobin expression in the reclassification and treatment of hepatocellular carcinoma.

HCC is a malignancy characterized by high incidence and mortality rates. Traditional classifications of HCC primarily rely on tumor morphology, phenotype, and multicellular molecular levels, which may not accurately capture the cellular heterogeneity within the tumor. This study integrates scRNA-seq and bulk RNA-seq to spotlight HP as a critical gene within a subgroup of HCC malignant cells. HP is highly expressed in HCC malignant cells and lowly expressed in T cells. Within malignant cells, elevated HP expression interacts with C3, promoting Th1-type responses via the C3/C3AR1 axis. In T cells, down-regulating HP expression favors the expression of Th1 cell-associated marker genes, potentially enhancing Th1-type responses. Consequently, we developed a "HP-promoted Th1 response reclassification" gene set, correlating higher activity scores with improved survival rates in HCC patients. Additionally, four predictive models for neoadjuvant treatment based on HP and C3 expression were established: 1) Low HP and C3 expression with high Th2 cell infiltration; 2) High HP and low C3 expression with high Th2 cell infiltration; 3) High HP and C3 expression with high Th1 cell infiltration; 4) Low HP and high C3 expression with high Th1 cell infiltration. In conclusion, the HP gene selected from the HCC malignant cell subgroup (Malignant_Sub 6) might serve as a potential ally against the tumor by promoting Th1-type immune responses. The establishment of the "HP-promoted Th1 response reclassification" gene set offers predictive insights for HCC patient survival prognosis and neoadjuvant treatment efficacy, providing directions for clinical treatments.

Emerging role of RNA modification and long noncoding RNA interaction in cancer.

RNA modification, especially N6-methyladenosine, 5-methylcytosine, and N7-methylguanosine methylation, participates in the occurrence and progression of cancer through multiple pathways. The function and expression of these epigenetic regulators have gradually become a hot topic in cancer research. Mutation and regulation of noncoding RNA, especially lncRNA, play a major role in cancer. Generally, lncRNAs exert tumor-suppressive or oncogenic functions and its dysregulation can promote tumor occurrence and metastasis. In this review, we summarize N6-methyladenosine, 5-methylcytosine, and N7-methylguanosine modifications in lncRNAs. Furthermore, we discuss the relationship between epigenetic RNA modification and lncRNA interaction and cancer progression in various cancers. Therefore, this review gives a comprehensive understanding of the mechanisms by which RNA modification affects the progression of various cancers by regulating lncRNAs, which may shed new light on cancer research and provide new insights into cancer therapy.

Identification of tumor stemness and immunity related prognostic factors and sensitive drugs in head and neck squamous cell carcinoma.

The presence of cancer stem cells (CSCs) contributes significantly to treatment resistance in various cancers, including head and neck squamous cell carcinoma (HNSCC). Despite this, the relationship between cancer stemness and immunity remains poorly understood. In this study, we aimed to identify potential immunotherapeutic targets and sensitive drugs for CSCs in HNSCC. Using data from public databases, we analyzed expression patterns and prognostic values in HNSCC. The stemness index was calculated using the single-sample gene set enrichment analysis (ssgsea) algorithm, and weighted gene co-expression network analysis (WGCNA) was employed to screen for key stemness-related modules. Consensus clustering was then used to group samples for further analysis, and prognosis-related key genes were identified through regression analysis. Our results showed that tumor samples from HNSCC exhibited higher stemness indices compared to normal samples. WGCNA identified a module highly correlated with stemness, comprising 187 genes, which were significantly enriched in protein digestion and absorption pathways. Furthermore, we identified sensitive drugs targeting prognostic genes associated with tumor stemness. Notably, two genes, HLF and CCL11, were found to be highly associated with both stemness and immunity. In conclusion, our study identifies a stemness-related gene signature and promising drug candidates for CSCs of HNSCC. Additionally, HLF and CCL11, which are associated with both stemness and immunity, represent potential targets for immunotherapy in HNSCC.

The investigation of oncolytic viruses in the field of cancer therapy.

Oncolytic viruses (OVs) have emerged as a potential strategy for tumor treatment due to their ability to selectively replicate in tumor cells, induce apoptosis, and stimulate immune responses. However, the therapeutic efficacy of single OVs is limited by the complexity and immunosuppressive nature of the tumor microenvironment (TME). To overcome these challenges, engineering OVs has become an important research direction. This review focuses on engineering methods and multi-modal combination therapies for OVs aimed at addressing delivery barriers, viral phagocytosis, and antiviral immunity in tumor therapy. The engineering approaches discussed include enhancing in vivo immune response, improving replication efficiency within the tumor cells, enhancing safety profiles, and improving targeting capabilities. In addition, this review describes the potential mechanisms of OVs combined with radiotherapy, chemotherapy, cell therapy and immune checkpoint inhibitors (ICIs), and summarizes the data of ongoing clinical trials. By continuously optimizing engineering strategies and combination therapy programs, we can achieve improved treatment outcomes and quality of life for cancer patients.

Fingerprint profiling for quality evaluation and the related biological activity analysis of polysaccharides from Liuweizhiji Gegen-Sangshen beverage.

Introduction: Liuweizhiji Gegen-Sangshen beverage (LGS) is popular in China, which has been used for alleviating alcohol-mediated discomfort and preventing alcoholic liver disease (ALD). This beverage is consisted of six herbal components that are known as functional foods and fruits. LGS is rich in polysaccharides, however, the activity and quality evaluation of LGS-derived polysaccharides remain unexplored. The purpose of this study is thus to establish a comprehensive quality control methodology for the assessment of LGS polysaccharides (LGSP) and to further explore the anti-oxidant, anti-inflammatory as well as prebiotic effect of LGSP. Methods: LGSP was extracted, followed by analysis of molecular weight distribution, monosaccharide content and structural characterization via integrating the application of high-performance size exclusion chromatography (HPSEC), 1-phenyl-3-methyl-5-pyrazolone-HPLC (PMP-HPLC), fourier transform infrared spectroscopy (FT-IR) as well as nuclear magnetic resonance spectroscopy (NMR) techniques. The anti-oxidation activity of LGSP was determined by DPPH, ABTS, hydroxyl radical scavenging capacity and total antioxidant capacity. The anti-inflammation of LGSP were assessed on the RAW 264.7 cells. The effect of LGSP on growth of Lactobacillus, Bifidobacterium bifidum and Bifidobacterium adolescentis was evaluated. Results: The results demonstrated that LGSP had two molecular weight distribution peaks, with the average molecular weights of (6.569 ± 0.12) × 104 Da and (4.641 ± 0.30) × 104 Da. LGSP was composed of 8 monosaccharides, with galacturonic acid, glucose rhamnose and galactose representing the highest molar ratios. Homogalacturonic acid (HG) type and rhamnosegalacturonic acid glycans I (RG-I) type and α-1,4-glucan were present in LGSP. LGSP concentration in LGS was 17.94 ± 0.28 mg/mL. Furthermore, fingerprint analysis combined with composition quantification of 10 batches of LGSP demonstrated that there was a high similarity among batches. Notably, LGSP exhibited anti-oxidant effect and inhibited expressions of pro-inflammatory factors (TNF-α and IL-6) in LPS-stimulated RAW 264.7 cells. In addition, LGSP remarkably promoted the proliferation of probiotics Lactobacillus, Bifidobacterium bifidum and Bifidobacterium adolescentis, showing good prebiotic activity. Discussion: The results of present study would be of help to gain the understanding of structure-activity relationship of LGSP, provide a reference for quality evaluation of bioactive LGSP, and facilitate development of unique health and functional products in the future.

Key oncogenic signaling pathways affecting tumor-infiltrating lymphocytes infiltration in hepatocellular carcinoma: basic principles and recent advances.

The incidence of hepatocellular carcinoma (HCC) ranks first among primary liver cancers, and its mortality rate exhibits a consistent annual increase. The treatment of HCC has witnessed a significant surge in recent years, with the emergence of targeted immune therapy as an adjunct to early surgical resection. Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) has shown promising results in other types of solid tumors. This article aims to provide a comprehensive overview of the intricate interactions between different types of TILs and their impact on HCC, elucidate strategies for targeting neoantigens through TILs, and address the challenges encountered in TIL therapies along with potential solutions. Furthermore, this article specifically examines the impact of oncogenic signaling pathways activation within the HCC tumor microenvironment on the infiltration dynamics of TILs. Additionally, a concise overview is provided regarding TIL preparation techniques and an update on clinical trials investigating TIL-based immunotherapy in solid tumors.

Downregulation of PDIA3 inhibits gastric cancer cell growth through cell cycle regulation.

OBJECTIVE: Protein disulfide isomerase A3 (PDIA3) promotes the correct folding of newly synthesized glycoproteins in the endoplasmic reticulum. PDIA3 is overexpressed in most tumors, and it may become a biomarker of cancer prognosis and immunotherapy. Our study aims to detect the expression level of PDIA3 in gastric cancer (GC) and its association with GC development as wells as the underlying mechanisms. METHODS: GC cell lines with PDIA3 knockdown by siRNA, CRISPR-cas9 sgRNAs or a pharmacological inhibitor of LOC14 were prepared and used. PDIA3 knockout GC cells were established by CRISPR-cas9-PDIA3 system. The proliferation, migration, invasion and cell cycle of GC cells were analyzed by cell counting kit-8 assay, wound healing assay, transwell assay and flow cytometry, respectively. Immunodeficient nude mice was used to evaluate the role of PDIA3 in tumor formation. Quantitative PCR and western blot were used for examining gene and protein expressions. RNA sequencing was performed to see the altered gene expression. RESULTS: The expressions of PDIA3 in GC tissues and cells were increased significantly, and its expression was negatively correlated with the three-year survival rate of GC patients. Down-regulation of PDIA3 by siRNA, LOC14 or CRISPR-cas9 significantly inhibited proliferation, invasion and migration of GC cells TMK1 and AGS, with cell cycle arrested at G2/M phase. Meanwhile, decreased PDIA3 significantly inhibited growth of tumor xenograft in vivo. It was found that cyclin G1 (encoded by CCNG1 gene) expression was decreased by downregulation of PDIA3 in GC cells both in vitro and in vivo. In addition, protein levels of other cell cycle related factors including cyclin D1, CDK2, and CDK6 were also significantly decreased. Further study showed that STAT3 was associated with PDIA3-mediated cyclin G1 regulation. CONCLUSION: PDIA3 plays an oncogenic role in GC. Our findings unfolded the functional role of PDIA3 in GC development and highlighted a novel target for cancer therapeutic strategy.

Mesenchymal Stromal Cells: New Generation Treatment of Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract, which has a high recurrence rate and is incurable due to a lack of effective treatment. Mesenchymal stromal cells (MSCs) are a class of pluripotent stem cells that have recently received a lot of attention due to their strong self-renewal ability and immunomodulatory effects, and a large number of experimental and clinical models have confirmed the positive therapeutic effect of MSCs on IBD. In preclinical studies, MSC treatment for IBD relies on MSCs paracrine effects, cell-to-cell contact, and its mediated mitochondrial transfer for immune regulation. It also plays a therapeutic role in restoring the intestinal mucosal barrier through the homing effect, regulation of the intestinal microbiome, and repair of intestinal epithelial cells. In the latest clinical trials, the safety and efficacy of MSCs in the treatment of IBD have been confirmed by transfusion of autologous or allogeneic bone marrow, umbilical cord, and adipose MSCs, as well as their derived extracellular vesicles. However, regarding the stable and effective clinical use of MSCs, several concerns emerge, including the cell sources, clinical management (dose, route and frequency of administration, and pretreatment of MSCs) and adverse reactions. This article comprehensively summarizes the effects and mechanisms of MSCs in the treatment of IBD and its advantages over conventional drugs, as well as the latest clinical trial progress of MSCs in the treatment of IBD. The current challenges and future directions are also discussed. This review would add knowledge into the understanding of IBD treatment by applying MSCs.

Cloning and preliminary functional studies of the JAM-A gene in grass carp (Ctenopharyngodon idellus).

Grass carp (Ctenopharyngodon idellus) is a very important aquaculture species in China and other South-East Asian countries; however, disease outbreaks in this species are frequent, resulting in huge economic losses. Grass carp hemorrhage caused by grass carp reovirus (GCRV) is one of the most serious diseases. Junction adhesion molecule A (JAM-A) is the mammalian receptor for reovirus, and has been well studied. However, the JAM-A gene in grass carp has not been studied so far. In this study, we cloned and elucidated the structure of the JAM-A gene in grass carp (GcJAM-A) and then studied its functions during grass carp hemorrhage. GcJAM-A is composed of 10 exons and 9 introns, and its full-length cDNA is 1833 bp long, with an 888 bp open reading frame (ORF) that encodes a 295 amino acid protein. The GcJAM-A protein is predicted to contain a typical transmembrane domain. Maternal expression pattern of GcJAM-A is observed during early embryogenesis, while zygote expression occurs at 8 h after hatching. GcJAM-A is expressed strongly in the gill, liver, intestine and kidney, while it is expressed poorly in the blood, brain, spleen and head kidney. Moreover, lower expression is observed in the gill, liver, intestine, brain, spleen and kidney of 30-month-old individuals, compared with 6-month-old. In a GcJAM-A-knockdown cell line (CIK) infected with GCRV, the expression of genes involved in the interferon and apoptosis pathways was significantly inhibited. These results suggest that GcJAM-A could be a receptor for GCRV. We have therefore managed to characterize the GcJAM-A gene and provide evidence for its role as a receptor for GCRV.