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Vitamin D as a prohormone is converted into the active form in vivo and binds to vitamin D receptors, exercising a wide range of biological functions. Recent studies strongly support that vitamin D supplementation is associated with reduced cancer risk and a good prognosis. Gastrointestinal cancer is the leading cause of cancer-related deaths worldwide. The key role of vitamin D in the development of gastrointestinal cancer has been observed. Moreover, Vitamin D can also affect innate immunity and perform anti-inflammation and anti-infection actions. Given the intimate relationship between cancer and inflammation, we herein summarize epidemiological and preclinical studies of vitamin D and the underlying mechanism of its action in inflammation, gastric and colorectal cancer by our group and other researchers. A beneficial effect of vitamin D in cancer and inflammatory disease has been supported by different studies. More controlled and larger clinical trials are needed before a reliable conclusion and realization of vitamin D supplementation in the adjunct treatment of gastrointestinal inflammation and cancer.

Background The biofilm state of pathogens facilitates antimicrobial resistance which makes difficult-to-treat infections. In this regard, it has been found that the compounds screened from plant extracts represent one category of the most promising antibiofilm agents. However, the antibiofilm activities and the active ingredients of plant extracts remain largely unexplored. In this background, the study is (1) to screen out the plant extracts with antibiofilm ability against Pseudomonas aeruginosa, and (2) to identify the active ingredients in the plant extracts and elucidate the underlying mechanism of the antibiofilm activities. Methods Micro-broth dilution method, in vitro biofilm model, LC–MS/MS analysis and P. aeruginosa-mouse infection model were adopted to assess the antibiofilm activity. GC–MS analysis was performed to detect the active ingredients in plasma. RNA-Seq, GO analysis, KEGG analysis and RT-qPCR were adopted to elucidate the underlying mechanism of antibiofilm activities against P. aeruginosa. Results Lonicerae Japonicae Flos (LJF) among 13 plants could exert significant inhibitory effects on bacterial biofilm formation, mobility and toxin release in vitro, and it could exert antibiofilm effect in vivo too. Moreover, quinic acid, as one metabolite of chlorogenic acid, was found as an active ingredient in LJF against the biofilm of P. aeruginosa. The active ingredient significantly inhibited EPS secretion in biofilm formation and maturity and could achieve synergistic antibiofilm effect with levofloxacin. It reduced the biofilm formation by regulating core targets in quorum sensing system. In GO process, it was found that the core targets were significantly enriched in multiple biological processes involving locomotion, chemotaxis and motility mediated by flagellum/cilium, which was related to KEGG pathways such as bacterial chemotaxis, oxidative phosphorylation, ribosome, biofilm formation, cyanoamino acid metabolism and quorum sensing. Finally, the binding of quinic acid with core targets rhlA, rhlR and rhlB were validated by molecular docking and RT-qPCR. Conclusions In summary, the study verified the in vitro and in vivo antibiofilm effects of LJF against P. aeruginosa and elucidated the active ingredients in LJF and its conceivable pharmacological mechanism, indicating that quinic acid could have the potential of an antibiofilm agent against P. aeruginosa and related infections. Graphic abstract

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. Increasing studies showed that long non-coding RNAs (lncRNAs), a novel class of RNAs that are greater than 200 nucleotides in length but lack the ability to encode proteins, exert crucial roles in the occurrence and progression of HCC. LncRNAs promote the proliferation, migration, invasion, autophagy, and apoptosis of tumor cells by regulating downstream target gene expression and cancer-related signaling pathways. Meanwhile, lncRNA can be used as biomarkers to predict the efficacy of HCC treatment strategies, such as surgery, radiotherapy, chemotherapy, and immunotherapy, and as a potential individualized tool for HCC diagnosis and treatment. In this review, we overview up-to-date findings on lncRNAs as potential biomarkers for HCC surgery, radiotherapy, chemotherapy resistance, target therapy, and immunotherapy, and discuss the potential clinical application of lncRNA as tools for HCC diagnosis and treatment.

Fibrinogen-associated protein (FREP) family is a family of proteins with a fibrin domain at the carboxyl terminus. Recent investigations illustrated that two members of FREP family, fibrinogen-like protein-1 (FGL1) and fibrinogen-like protein-2 (FGL2), play crucial roles in cancer by regulating the proliferation, invasion, and migration of tumor cells, or regulating the functions of immune cells in tumor microenvironment. Meanwhile, they are potential targets for medical intervention of tumor development. In this review, we discussed the structure, and the roles of FGL1 and FGL2 in tumors, especially the roles in regulating immune cell functions.

The next-generation immunotherapy can only be effective if researchers have an in-depth understanding of the function and regulation of Treg cells in antitumor immunity combined with the discovery of new immunity targets. This can enhance clinical efficacy of future and novel therapies and reduces any adverse reactions arising from the latter. This review discusses tumor treatment strategies using regulatory T (Treg) cell therapy in a Tumor Microenvironment (TME). It also discusses factors affecting TME instability as well as relevant treatments to prevent future immune disorders. It is prognosticated that PD-1 inhibitors are risky and their adverse effects should be taken into account when they are administered to treat Acute Myeloid Leukemia (AML), lung adenocarcinoma, and prostate adenocarcinoma. In contrast, Treg molecular markers FoxP3 and CD25 analyzed here have stronger expression in almost all kinds of cancers compared with normal people. However, CD25 inhibitors are more effective compared to FoxP3 inhibitors, especially in combination with TGF-β blockade, in predicting patient survival. According to the data obtained from the Cancer Genome Atlas, we then concentrate on AML immunotherapy and discuss different therapeutic strategies including anti-CD25/IL-2, anti-CTLA-4, anti-IDO, antityrosine kinase receptor, and anti-PI3K therapies and highlight the recent advances and clinical achievements in AML immunotherapy. In order to prognosticate the risk and adverse effects of key target inhibitors (namely against CTLA-4, FoxP3, CD25, and PD-1), we finally analyzed and compared the Cancer Genome Atlas derived from ten common cancers. This review shows that Treg cells are strongly increased in AML and the comparative review of key markers shows that Tregbased immunotherapy is not effective for all kinds of cancer. Therefore, blocking CD25(+)FoxP3(+) Treg cells is suggested in AML more than other kinds of cancer; meanwhile, Treg markers studied in other cancers have also great lessons for AML immunotherapy.

Long-term primary culture of mammalian cells has been always difficult due to unavoidable senescence. Conventional methods for generating immortalized cell lines usually require manipulation of genome which leads to change of important biological and genetic characteristics. Recently, conditional reprogramming (CR) emerges as a novel next generation tool for long-term culture of primary epithelium cells derived from almost all origins without alteration of genetic background of primary cells. CR co-cultures primary cells with inactivated mouse 3T3-J2 fibroblasts in the presence of RHO-related protein kinase (ROCK) inhibitor Y-27632, enabling primary cells to acquire stem-like characteristics while retain their ability to fully differentiate. With only a few years’ development, CR shows broad prospects in applications in varied areas including disease modeling, regenerative medicine, drug evaluation, drug discovery as well as precision medicine. This review is thus to comprehensively summarize and assess current progress in understanding mechanism of CR and its wide applications, highlighting the value of CR in both basic and translational researches and discussing the challenges faced with CR., Graphical abstract Conditional reprogramming is a new tool for next generation primary cell culture, which has broad prospect in applications in both basic science and translational medicine.Image 1

Rationale: Methylation at the N6 position of adenosine (m6A) is the most prevalent RNA modification within protein-coding mRNAs in mammals, and it is a reversible modification with various important biological functions. The formation and function of m6A are regulated by methyltransferases (writers), demethylases (erasers), and special binding proteins (readers) as key factors. However, the underlying modification mechanisms of m6A in gastrointestinal (GI) cancer remain unclear. Here, we performed comprehensive molecular profiling of the nine known m6A writer, eraser, and reader proteins in GI cancer. Methods: Data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were used. Gene alteration and pathway analysis were done in cBioportal. The protein network of m6A regulators and its related pathway members was analyzed in STRING online platform. Phylogenetic tree was constructed in MEGA7. m6A modification sites were predicted by SRAMP. m6A related SNPs were analyzed by m6ASNP. The modulation of m6A on its related pathway members was validated by m6A-seq, real-time PCR and phosphor-MAPK array. Results: We found that m6A regulators were mostly upregulated in GI cancer and their differential expression significantly influenced the overall survival of patients with GI cancer. The phosphatidylinositol-3-kinase (PI3K)/Akt and mammalian target of rapamycin (mTOR) signaling pathways were found to be potentially affected by m6A modification in most human cancers, including GI cancer, which was further verified by m6A-Seq and phospho-MAPK array. Conclusions: Our findings suggest that m6A RNA modification has a fundamental role in the regulation of PI3K/Akt and mTOR signaling pathway function in cancer.

Over-expression of calpains in tumor tissues can be associated with cancer progression. Thus, inhibition of calpain activity using specific inhibitors has become a novel approach to control tumor growth. In this study, the anticancer potential of cryptotanshinone in combination with calpain inhibitor had been investigated in colon cancer cells and tumor xenograft. Cryptotanshinone elicited an initial endoplasmic reticular (ER) stress response, whereas prolonged stress would result in the promotion of apoptosis. It was then discovered that cryptotanshinone could cause rapid and sustained increase in cytosolic calcium in colon cancer cells accompanied by early GRP78 overexpression, which could be attenuated by pre-treatment of the calcium chelator BAPTA-AM. Cryptotanshinone also facilitated an early increase in calpain activity, which could be blocked by BAPTA-AM or the calpain inhibitor PD150606. A dynamic interaction between GRP78 and calpain during the action of cryptotanshinone was unveiled. This together with the altered NF-[Formula: see text]B signaling could be abolished by calpain inhibitor. GRP78 knockdown increased the sensitivity of cancer cells to cryptotanshinone-evoked apoptosis and reduction of cancer cell colony formation. Such sensitization of drug action had been confirmed to be p53-dependent by using p53-mutated (HT-29) and p53-deficient (HCT116 p53−∕−) cells. The synergistic antitumor effect of cryptotanshinone and calpain inhibitor was further exhibited in vivo. Taken together, findings in this study exemplify a new chemotherapeutic regimen comprising cryptotanshinone and calpain inhibitor by regulation of calpain and calcium homeostasis. This has provided us with new insights in the search of a potential target-specific neoadjuvant therapy against colon cancer.

Background: Controversy exists as towards the association of excessive fruits intake and certain disease risks. Longan is an edible fruit rich in high levels of fructose, glucose and sucrose. The aim of this study was to provide direct evidence on the effect of the sugar rich longan fruit on the development of non-alcoholic fatty liver disease (NAFLD). Chemical profiling of longan fruit was conducted using LC-HRMS and HPLC-ELSD.Results: Longan extracts at the doses of 4.0 g/kg, 8.0 and 16.0 g/kg were orally administered for 4 weeks to healthy C57BL/6J mice or to C57BL/6J mice fed with a HFD diet. Fecal microbiome was analyzed by 16S rRNA sequencing. The amounts of short chain fatty acids (SCFAs) in colonic contents were determined by GC-MS. Colon and liver tissues were used for histopathological examination after H&E, Masson’s trichrome, and Oil-red O staining. ELISA method was used for biochemical analysis in serum. In mice fed a normal diet, repeated longan intake for 4 weeks at excess doses (8 or 16 g/kg), but not the normal dose (4 g/kg), promoted inflammation and gut dysbiosis-like status and reduced short-chain fatty acids (SCFAs) production. In high-fat diet (HFD)-fed mice, longan intake at 4 g/kg hardly influenced the NAFLD development. In contrast, excess longan intake (8 or 16 g/kg) promoted NAFLD pathogenesis, including increased abnormality in hepatic indices, elevated inflammation, and gut permeability associated with more severe liver steatosis and fibrosis. Moreover, the exacerbated pathogenic markers were positively correlated with increased blood sugar, aggravated HFD-associated microbial dysbiosis. Conclusions: Effects mediated by excess longan intake resembled that of equivalent free sugars supplementation, suggesting that high level of free sugars in fruits contributed to the promotion of NAFLD development as demonstrated in case of excessive longan intake.

Triple-negative breast cancer (TNBC) is the most incurable type of breast cancer, accounting for 15-20% of breast cancer cases. Lapatinib is a dual tyrosine kinase inhibitor targeting EGFR and Her2, and berberine (BBR) is a plant-based alkaloid suggested to inhibit several cancer signaling pathways. We previously reported that lapatinib activates the Akt oncoprotein in MDA-MB231 TNBC cells. The present study determined the mechanism(s) of Akt activation in response to lapatinib, BBR, and capivasertib (Akt inhibitor) as well as the role of Akt signaling in chemoresistance in TNBC cells. Genetic profiles of 10 TNBC cell lines and patients were analyzed using datasets obtained from Gene Expression Omnibus and The Cancer Genome Atlas Database. Then, the effects of lapatinib, BBR, and capivasertib on treated MDA-MB231 and MCF-7 cell lines were studied using cytotoxicity, immunoblot, and RNA-sequencing analyses. For further confirmation, we also performed real-time PCR for genes associated with PI3K signaling. MDA-MB231 and MCF-7 cell lines were both strongly resistant to capivasertib largely due to significant Akt activation in both breast cancer cell lines, while lapatinib and BBR only enhanced Akt signaling in MDA-MB231 cells. Next-generation sequencing, functional enrichment analysis, and immunoblot revealed downregulation of CDK6 and DNMT1 in response to lapatinib and BBR lead to a decrease in cell proliferation. Expression of placental, fibroblast growth factor, and angiogenic biomarker genes, which are significantly associated with Akt activation and/or dormancy in breast cancer cells, was significantly upregulated in TNBC cells treated with lapatinib and BBR. Lapatinib and BBR activate Akt through upregulation of alternative signaling, which lead to chemoresistance in TNBC cell. In addition, lapatinib overexpresses genes related to PI3K signaling in resistant TNBC cell model.

Gastric cancer (GC) is one of the major public health concerns. Long non-coding RNAs (lncRNAs) have been increasingly demonstrated to possess a strong correlation with GC and play a critical role in GC occurrence, progression, metastasis and drug resistance. Many studies have shed light on the understanding of the underlying mechanisms of lncRNAs in GC. In this review, we summarized the updated research about lncRNAs in GC, focusing on their roles in Helicobacter pylori infection, GC metastasis, tumor microenvironment regulation, drug resistance and associated signaling pathways. LncRNAs may serve as novel biomarkers for diagnosis and prognosis of GC and potential therapeutic targets. The research gaps and future directions were also discussed.

Background: Cluster of differentiation molecules are markers of immune cells that have been identified as a potential immunotherapeutic target for cancer treatment. MicroRNAs are small non-coding RNAs that act as tumor suppressors or oncogenes whose importance in diagnosis, prognosis, and treatment of gastric and colorectal cancers has been widely reported. However, their association with cluster of differentiation molecules in gastrointestinal cancers has not been well studied. Therefore, our study aimed to analyze the relationship between microRNAs and cluster of differentiation molecules in gastrointestinal cancers, and to identify cluster of differentiation molecule-associated microRNAs as prognostic biomarkers for gastrointestinal cancer patients. Methods: Targetscan, Starbase, DIANA microT, and miRDB were used to investigate microRNA profiles that might be correlated with cluster of differentiation molecules in gastrointestinal cancers. Moreover, The Cancer Genome Atlas data analysis was used to investigate the association between cluster of differentiation molecules and microRNA expression in patients with gastric, colon, rectal, pancreatic, and esophageal cancers. The Kaplan–Meier plotter was used to identify the association between overall survival and cluster of differentiation molecule-associated microRNA expression in gastrointestinal cancer patients. Results: miR-200a, miR-559, and miR-1236 were negatively associated with CD86, CD81, and CD160, respectively, in almost all types of gastrointestinal cancers, which were further verified in the in vitro studies by transfecting microRNA mimics in gastric cancer, colon cancer, pancreatic, and esophageal cell lines. Conclusion: Our study showed that miR-200a, miR-1236, and miR-559 are identified as cluster of differentiation-associated microRNAs in gastrointestinal cancers, providing a novel perspective to identify new therapeutic targets for cancer immunotherapy in gastrointestinal cancer patients.

Rhodiola species are edible medicinal plants, which have been traditionally used in both Asia and Europe as an adaptogen, a tonic, an anti-depressant and anti-inflammatory supplement. However, whether it presents a therapeutic effect on colitis or not remains unknown. The aim of this study is to investigate the protective effect of a Rhodiola crenulata extract (RCE) on mice with DSS-induced colitis. RCE significantly alleviated the pathological abnormalities in colitic mice, including the correspondingly increased colon length, ameliorated colonic injury and reduced pro-inflammatory factors. The protective effect was similar to that of the positive control, 5-aminosalicylic acid. The DSS-induced epithelial apoptosis and maintained intestinal barrier function were attenuated by RCE through the upregulation of the level of tight junction proteins such as ZO-1 and occludin. Notably, RCE prevented gut dysbiosis in colitic mice by restoring the microbial richness and diversity, and decreasing the abundance of Proteobacteria phylum and opportunistic pathogenic Parasutterella and Staphylococcus, as well as increasing the abundance of beneficial microbes in Lactobacillus and Bifidobacterium, which were closely correlated with its protective effect against colitis. Meanwhile, chemical characterization of RCE was performed by UPLC-HR-MS to explain its material basis. A total of 63 compounds were identified, while the content of two bioactive ingredients (salidroside, 1.81%; rosavin, 0.034%) was determined.

Background: Longan is the fruit of Dimocarpus longan Lour. and the longan arillus has long been used in traditional Chinese medicine possessing various health benefits. However, the excessive intake of longan is found in daily life to cause “shanghuo” syndrome. “Shanghuo” has been linked to increased disease susceptibility. The present study thus aimed to investigate the toxicological outcomes after excessive longan treatment.Methods: Longan extract at a normal dosage of 4 g/kg and two excess dosages of 8 and 16 g/kg was orally administered to normal C57BL/6J mice for two weeks or to C57BL/6J mice with DSS-induced colitis. Mouse gut microbiome were analyzed by 16S rRNA sequencing. Short chain fatty acid (SCFA) contents in colonic contents were measured by GC-MS. Colon tissue was used for histopathological observation after H and E staining, detection of protein expression by western blot, analysis of gene expression by qPCR, and detection of apoptotic cells by TUNEL assay. ELISA was used for biochemical analysis in serum.Results: In normal mice, repeated longan intake at excess doses, but not the normal dose, increased infiltration of inflammatory cells, elevated serum levels of TNF-α and IL-6 and reduced production of SCFAs. In DSS-induced colitic mice, longan intake at 4 g/kg did not promote colitis in mice, while excessive longan (8 or 16 g/kg) aggravated colitis in mice, showing increased inflammation, more serious histological abnormalities, increased gut permeability, and increased epithelia injury when compared to DSS alone. Excessive longan induced a significant reduction of microbial diversity in colitic mice, accompanied with aggravated alterations of DSS-associated bacteria including the increase of Proteobacteria phylum and genera of Bacteroides, Akkermansia, Turicibacter and Escherchia-Shigella, and the decrease of norank_f__Muribaculaceae. The changed microbial compositions were accompanied with decreased SCFAs when longan was supplemented with DSS. The aggravated colon injury by excessive intake of longan in colitic mice was tightly correlated with the altered microbial communities and decreased SCFAs production.Conclusion: Excessive longan intake disturbs gut homeostasis and aggravates colitis via promoting inflammation and altering gut microbe compositions and associated metabolism in mice. Our findings warrant rational longan arillus consumption as a dietary supplement or herbal medicine.

Background: JMJD3 is a jmjd domain containing histone demethylase which can remove methyl groups from lysine 27 of histone 3 (H3K27) to active histone methylated genes. Previous studies have demonstrated that JMJD3 played a crucial role in inflammation. Methods: Our study showed that JMJD3 was significantly down-regulated in pancreatic ductal adenocarcinoma (PDAC) cell lines and tissues. Restored expression of JMJD3 inhibited oncogenic phenotypes of PDAC cells, including cell proliferation, cell migration, and in vivo tumorigenicity, indicating a tumor suppressive role. Gene-expression microarray revealed that Hexokinase domain containing 1 (HKDC1) was one of the JMJD3 downstream targets. Results: The expression of JMJD3 and HKDC1 in PDAC tissues was positively correlated. High H3K27 tri-methylation (H3K27me3) status in HKDC1 gene was attenuated by ectopic expression of JMJD3 in PDAC cells, suggested that JMJD3 regulated HKDC1 expression by histone demethylation activity. The tumor suppressive role of HKDC1 in PDAC was also proved. Moreover, HKDC1 was demonstrated to competitively bind to spectrin beta Ⅱ to induce cytoskeleton disruption, which may contribute to tumor suppression. Conclusion: Taken together, our study indicates that JMJD3 may disrupt spectrin-dependent cytoskeleton via activation of HKDC1 to suppress PDAC.

Cluster of differentiation 44 (CD44) as a transmembrane glycoprotein is found to be expressed in non-small cell lung cancer (NSCLC), is significantly associated with NSLC progression, metastasis and drug resistance. This study aimed to explore whether CD44 inhibition improves the sensitivity of epidermal growth factor receptor (EGFR) wild-type NSCLC cells to cisplatin and how it affects wild-type EGFR in NSCLC cells. Small interfering RNA was used to knockdown CD44 expression in EGFR wild-type NSCLC cell line H460. Results suggested that CD44 downregulation reduced cell growth, promoted G0/G1 cell cycle arrest and induced cell apoptosis in H460 cells and these effects were evidently enhanced when in combination with cisplatin. Deactivation of EGFR signaling pathway including EGFR phosphorylation and its downstream molecules, targets ERK, AKT1 and SRC which were also observed in CD44-silenced H460 cells with or without EGF stimulation. Furthermore, the CD44 expression level was positively correlated with wild-type EGFR level in human lung adenocarcinoma tissues and CD44 inhibition significantly accelerated the degradation of EGFR, indicating that enhanced sensitivity of H460 cells to cisplatin by downregulation of CD44 might be due to EGFR degradation. This study demonstrated that suppression of CD44 deactivated EGFR signals in NSCLC cells with wild-type EGFR, thereby contributing to the inhibition of cell proliferation and the reinforcement of cisplatin sensitivity. It is suggested that downregulation of CD44 could be a novel potential therapeutic strategy for the treatment of EGFR wild-type NSCLC.

Breast cancer is the most common type of cancer among women. Therefore, discovery of new and effective drugs with fewer side effects is necessary to treat it. Sulforaphane (SFN) is an organosulfur compound obtained from cruciferous plants, such as broccoli and mustard, and it has the potential to treat breast cancer. Hence, it is vital to find out how SFN targets certain genes and cellular pathways in treating breast cancer. In this review, molecular targets and cellular pathways of SFN are described. Studies have shown SFN inhibits cell proliferation, causes apoptosis, stops cell cycle and has anti-oxidant activities. Increasing reactive oxygen species (ROS) produces oxidative stress, activates inflammatory transcription factors, and these result in inflammation leading to cancer. Increasing anti-oxidant potential of cells and discovering new targets to reduce ROS creation reduces oxidative stress and it eventually reduces cancer risks. In short, SFN effectively affects histone deacetylases involved in chromatin remodeling, gene expression, and Nrf2 anti-oxidant signaling. This review points to the potential of SFN to treat breast cancer as well as the importance of other new cruciferous compounds, derived from and isolated from mustard, to target Keap1 and Akt, two key regulators of cellular homeostasis.

Over the past few decades, obesity has been recognized as low-grade chronic inflammatory disease and was contributed to systemic metabolic diseases such as type 2 diabetes (T2D). Accumulating evidence indicates that adipose tissue (AT) inflammation is a key event in the pathogenesis of obesity and obesity-associated diseases. While AT-resident immune cells play important roles in maintaining AT homeostasis, obesity changes their numbers and activities, which were accompanied by the activation of inflammatory responses. Recent investigations emphasized the contributions of adaptive immune cells, especially CD4+ T cells, in controlling immune-AT crosstalk in the progression of obesity and obesity-associated disorders. In this review, we focus on the current understandings of the roles of CD4+ T cells in obesity and obesity-associated diseases, and the effects of adipocytes as antigen presenting cells on regulating CD4+ T cell activity.

γδT cells, a subgroup of T cells based on theγδTCR, when compared with conventional T cells (αβT cells), make up a very small proportion of T cells. However, its various subgroups are widely distributed in different parts of the human body and are attractive effectors for infectious disease immunity.γδT cells are activated and expanded by nonpeptidic antigens (P-Ags), major histocompatibility complex (MHC) molecules, and lipids which are associated with different kinds of pathogen infections. Activation and proliferation ofγδT cells play a significant role in diverse infectious diseases induced by viruses, bacteria, and parasites and exert their potential effector function to effectively eliminate infection. It is well known that many types of infectious diseases are detrimental to human life and health and give rise to high incidence of illnesses and death rate all over the world. To date, there is no comprehensive understanding of the correlation betweenγδT cells and infectious diseases. In this review, we will focus on the various subgroups ofγδT cells (mainly Vδ1 T cells and Vδ2 T cells) which can induce multiple immune responses or effective functions to fight against common pathogen infections, such asMycobacterium tuberculosis,Listeria monocytogenes, influenza viruses, HIV, EBV, and HBV. Hopefully, the gamma-delta T cell study will provide a novel effective way to treat infectious diseases.

Minute amounts of tumor vasculature-targeted TNFα was reported to increase endothelial permeability, thereby accelerating drug penetration and increasing the therapeutic index of chemotherapeutic agents. This study aimed at assessing the synergistic anti-cancer effects of three chemotherapeutic drugs and tumor vasculature-targeted TNFα in a murine orthotopic colorectal cancer model. TNFα was firstly coupled with a vascular-homing peptide TCP-1 to form a TNFα derivative (TCP-1/TNFα). After pretreated with 1 ng TCP-1/TNFα, the three chemotherapeutic drugs exerted differential synergistic effects on anti-cancer actions and presented different intratumoral accumulation statuses. To further assess transvascular transport efficiency of these drugs, an in vitro system was carried out to mimic the endothelial cell monolayer. Results showed that 5-fluorouracil which exerted the best anti-cancer action and intratumoral accumulation status with preadministration of 1 ng TCP-1/TNFα had the highest transvascular transportation efficiency. This work would provide important information for designing clinical studies with vasculature-targeted TNFα in combination with chemotherapeutic drugs for optimal synergism.

Objectives: Vitamin D deficiency was found to be associated with increased risk for gastric cancer (GC). We previously found that vitamin D inhibited GC cell growth in vitro. However, the in vivo antitumor effect of vitamin D in GC as well as the underlying mechanisms are not well understood. The aim of this study was to investigate the anticancer effect of vitamin D on GC both in vitro and in vivo. Methods: Human GC cells MKN45, MKN28, and KATO III were used. The expressions of vitamin D receptor (VDR) and CD44 were downregulated by using predesigned siRNA molecules. Cell viability was evaluated by methyl thiazolyl tetrazolium assay. Soft agar assay was used for colony formation of GC cells. Flow cytometry was used to assess CD44-positive cell population. CD44high cancer cells were enriched by using anti–CD44-conjugated magnetic microbeads. Quantitative real-time polymerase chain reaction and Western blot were performed to detect gene and protein expressions, respectively. Clinical samples were collected for evaluation of the correlation of VDR and CD44 expression. Orthotopic tumor-bearing mice were established to evaluate the antitumor effect of vitamin D. Results: The results showed that the active form of vitamin D, 1,25(OH)2D3, had a remarkable inhibitory effect in CD44-expressing human GC MKN45 and KATO III cells, but not in CD44-null MKN28 cells. The gene expressions of CD44 and VDR in GC cell lines and GC patient tissues were positively correlated. Furthermore, 1,25(OH)2D3 suppressed MKN45 and KATO III cell growth through VDR-induced suppression of CD44. Additionally, we demonstrated that 1,25(OH)2D3 inhibited Wnt/β-catenin signaling pathway, which might lead to the downregulation of CD44. In an orthotopic GC nude mice model, both oral intake of vitamin D and intraperitoneal injection with 1,25(OH)2D3 could significantly inhibit orthotopic GC growth and CD44 expression in vivo. Conclusion: To our knowledge, this study provided the first evidence that vitamin D suppressed GC cell growth both in vitro and in vivo through downregulating CD44. The present study sheds light on repurposing vitamin D as a potential therapeutic agent for GC prevention and treatment.

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.

Various vascular-targeted agents fused with tumor necrosis factor α (TNFα) have been shown to improve drug absorption into tumor tissues and enhance tumor vascular function. TCP-1 is a peptide selected through in vivo phage library biopanning against a mouse orthotopic colorectal cancer model and is a promising agent for drug delivery. This study further investigated the targeting ability of TCP-1 phage and peptide to blood vessels in an orthotopic gastric cancer model in mice and assessed the synergistic anti-cancer effect of 5-fluorouracil (5-FU) with subnanogram TNFα targeted delivered by TCP-1 peptide. In vivo phage targeting assay and in vivo colocalization analysis were carried out to test the targeting ability of TCP-1 phage/peptide. A targeted therapy for improvement of the therapeutic efficacy of 5-FU and vascular function was performed through administration of TCP-1/TNFα fusion protein in this model. TCP-1 phage exhibited strong homing ability to the orthotopic gastric cancer after phage injection. Immunohistochemical staining suggested that and TCP-1 phage/TCP-1 peptide could colocalize with tumor vascular endothelial cells. TCP-1/TNFα combined with 5-FU was found to synergistically inhibit tumor growth, induce apoptosis and reduce cell proliferation without evident toxicity. Simultaneously, subnanogram TCP-1/TNFα treatment normalized tumor blood vessels. Targeted delivery of low-dose TNFα by TCP-1 peptide can potentially modulate the vascular function of gastric cancer and increase the drug delivery of chemotherapeutic drugs.

Aims Previous studies have indicated that vitamin D deficiency correlates with cancer risk and vitamin D potentiates antitumor effects in a variety of cancers. The antitumor effect of vitamin D on gastric cancer was rarely studied. We aimed to investigate the antitumor effect of vitamin D on gastric cancer and underlying mechanisms. Main methods We investigated the antitumor activity of the active form of vitamin D, 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) on gastric cancer cells (TMK1) and immortalized normal gastric cells (HFE145) by using MTT, colony formation and Flow cytometry assays. We demonstrated the important role of vitamin D receptor (VDR) and mutant p53 (mutp53) in mediating the antitumor action of 1,25(OH)2D3 by using siRNA, western-blot, immunofluorescent staining and immunoprecipitation assays. Key findings 1,25(OH)2D3 could significantly inhibit proliferation and induce cell cycle arrest in TMK1 but not in HFE145. Furthermore, 1,25(OH)2D3 stimulated p21 expression and suppressed cyclin-dependent kinase 2 (CDK2) expression in TMK1 in a VDR-dependent manner. High levels of VDR in human gastric cancer tissues and cancer cell lines implicated that vitamin D could display more potent pharmacological action against malignant cells. Besides, mutp53 but not wild type p53 was essential for 1,25(OH)2D3-stimulated upregulation of p21 in gastric cancer cells. Indeed, mutp53 could stabilize nuclear VDR level through interaction with VDR. Significance Our results suggest that 1,25(OH)2D3 inhibits gastric cancer cell growth through VDR and mutp53 interaction followed by the modulation of p21/CDK2. We propose that vitamin D might be used for the prophylactic treatment for malignant diseases in the stomach.

Vitamin D has been widely used as a dietary supplement for the prevention and treatment of bone disorders. Epidemiological and preclinical studies demonstrated the anticancer action of vitamin D in a variety of cancers including those in the gastrointestinal (GI) tract. In these studies the inhibitory action of vitamin D on cancer stem cells (CSCs) has been a focus and is also an important subject to revolutionize the therapeutic potential of vitamin D on cancer treatment. Here, we summarize the involvement of CSC markers and factors and also their signaling pathways in the development of cancers in the esophagus, stomach, colon, pancreas and also liver. It is also evidenced that vitamin D could inhibit these markers and factors and their related signaling pathways to suppress tumor progression. All these information could provide new strategies in repurposing vitamin D as therapeutic agent to inhibit cancers in the GI tract.

Ethnopharmacological relevance In China, Penthorum chinense Pursh (P. chinense) has been used for hundreds of years traditionally for alleviating symptoms by excessive intake of alcohol as well as in the treatment of traumatic injury, edema and liver diseases. Recently, P. chinense and its extract have been developed into tea, drinks or medicines for treatment of liver diseases, including hepatic virus infections, alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD) and liver fibrosis. Aim of the study The main purpose of this review is to provide a critical appraisal of the existing knowledge on the phytochemical data, quality control aspect, pharmacological, as well as toxicological and clinical studies performed on P. chinense, including the identification of scientific gaps. Materials and methods A detailed literature search was conducted using various online search engines, such as Pubmed, Scopus, Google Scholar, Mendeley, Web of Science as well as China National Knowledge Infrastructure (CNKI) database. Results In the pharmacological studies, there clearly are links between local/traditional uses and the biomedical investigations. Most pharmacological studies indicated potential liver protective effects in experimental models of chemicals-induced liver injury, acute and chronic alcoholic liver injury, NAFLD, liver fibrosis and viral infection, potentially through antioxidant effects, balancing key liver enzyme levels, inhibition of hepatic virus DNA replication, inhibition of hepatic stellate cells activation and inflammation either in vitro or in vivo. In some models, the effects of P. chinense is comparable with the one of silymarin. Clinical studies have suggested that P. chinense is safe and effective in treating several liver diseases, although most of them are not double-blinded and placebo-controlled studies. Toxicology studies show that P. chinense has no obvious toxicity or side effects in animals or human. Flavonoids, lignans, coumarins, polyphenols and organic acids have been identified. However, only a few studies have investigated the active compounds (mainly flavonoids and lignans) and molecular mechanisms of P. chinense. Conclusion P. chinense seems to be safe and shows relevant liver protecting effects. Therefore, it might be a promising candidate for developing as new hepatoprotective agents. However, a lack of understanding of the active compounds and mechanisms of action needs further attention.

BACKGROUND: Gene expression can be posttranscriptionally regulated by a complex network of proteins. N1-methyladenosine (m1A) is a newly validated RNA modification. However, little is known about both its influence and biogenesis in tumor development. METHODS: This study analyzed TCGA data of patients with five kinds of gastrointestinal (GI) cancers. Using data from cBioPortal, molecular features of the nine known m1A-related enzymes in GI cancers were investigated. Using a variety of bioinformatics approach, the impact of m1A regulators on its downstream signaling pathway was studied. To further confirm this regulation, the effect of m1A writer ALKBH3 knockdown was studied using RNA-seq data from published database. RESULTS: Dysregulation and multiple types of genetic alteration of putative m1A-related enzymes in tumor samples were observed. The ErbB and mTOR pathways with ErbB2, mTOR, and AKT1S1 hub genes were identified as being regulated by m1A-related enzymes. The expression of both ErbB2 and AKT1S1 was decreased after m1A writer ALKBH3 knockdown. Furthermore, Gene Ontology analysis revealed that m1A downstream genes were associated with cell proliferation, and the results showed that m1A genes are reliably linked to mTOR. CONCLUSION: This study demonstrated for the first time the dysregulation of m1A regulators in GI cancer and its signaling pathways and will contribute to the understanding of RNA modification in cancer.

Background Shikonin (SKN), a naphthoquinone compound, is isolated from Chinese herbal medicine Lithospermum root and has been studied as an anticancer drug candidate in human tumor models. This study is designed to investigate whether SKN can sensitize the therapeutic effect of paclitaxel (PTX) in drug-resistant human ovarian carcinoma cells. Methods Human ovarian carcinoma A2780 cell along with the paired PTX-resistant A2780/PTX cells were used. The effects of SKN, PTX or their combination on cell viability were conducted using Sulforhodamine B assay. P-glycoprotein (P-gp) expression was analyzed by flow cytometry after staining with P-gp-FITC anti-body. P-gp activity was determined by a fluorometric MDR assay kit or a rhodamine 123-based efflux assay, respectively. Apoptosis was evaluated by flow cytometry after Annexin V-FITC/PI co-staining. The effect of SKN, PTX or their combination on reactive oxygen species (ROS) generation and expression of pyruvate kinase M2 (PKM2) were investigated using flow cytometry or western blotting, respectively. PKM2 activity was detected by a Pyruvate Kinase Assay Kit. Results SKN/PTX co-treatment led to synergistically enhanced cytotoxicity and apoptosis in PTX-resistant ovarian cancer cells, indicating the circumvention of multidrug resistance (MDR) of PTX by SKN. Further study indicated that the MDR reversal effect of SKN was independent of inhibiting activity of the efflux transporter P-gp. Notably, SKN/PTX significantly increased the generation of intracellular ROS in A2780/PTX cells, and scavenging intracellular ROS blocked the sensitizing effects of SKN in PTX-induced cytotoxicity and apoptosis in A2780/PTX cells, but not in A2780 cells. Furthermore, SKN/PTX-induced downregulation of PKM2 (a key enzyme in glycolysis) and the suppression of its activity were inhibited by a ROS scavenger N-acetyl cysteine (NAC), suggesting that the synergy of the SKN/PTX combination may be not rely on PKM2 suppression. Conclusions These results reveal a P-gp-independent mechanism through ROS generation for the SKN/PTX combination to overcome MDR in ovarian cancer. Electronic supplementary material The online version of this article (10.1186/s13020-019-0231-3) contains supplementary material, which is available to authorized users.

Helicobacter pylori (H. pylori) is a common human pathogenic bacterium. Once infected, it is difficult for the host to clear this organism using the innate immune system. Increased antibiotic resistance further makes it challenging for effective eradication. However, the mechanisms of immune evasion still remain obscure, and novel strategies should be developed to efficiently eliminate H. pylori infection in stomachs. Here we uncovered desirable anti-H. pylori effect of vitamin D3 both in vitro and in vivo, even against antibiotic-resistant strains. We showed that H. pylori can invade into the gastric epithelium where they became sequestered and survived in autophagosomes with impaired lysosomal acidification. Vitamin D3 treatment caused a restored lysosomal degradation function by activating the PDIA3 receptor, thereby promoting the nuclear translocation of PDIA3-STAT3 protein complex and the subsequent upregulation of MCOLN3 channels, resulting in an enhanced Ca2+ release from lysosomes and normalized lysosomal acidification. The recovered lysosomal degradation function drives H. pylori to be eliminated through the autolysosomal pathway. These findings provide a novel pathogenic mechanism on how H. pylori can survive in the gastric epithelium, and a unique pathway for vitamin D3 to reactivate the autolysosomal degradation function, which is critical for the antibacterial action of vitamin D3 both in cells and in animals, and perhaps further in humans. Abbreviations: 1,25D3: 1α, 25-dihydroxyvitamin D3; ATG5: autophagy related 5; Baf A1: bafilomycin A1; BECN1: beclin 1; CagA: cytotoxin-associated gene A; CFU: colony-forming unit; ChIP-PCR: chromatin immunoprecipitation-polymerase chain reaction; Con A: concanamycin A; CQ: chloroquine; CRISPR: clustered regularly interspaced short palindromic repeats; CTSD: cathepsin D; GPN: Gly-Phe-β-naphthylamide; H. pylori: Helicobacter pylori; LAMP1: lysosomal associated membrane protein 1; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MCOLN1: mucolipin 1; MCOLN3: mucolipin 3; MCU: mitochondrial calcium uniporter; MOI: multiplicity of infection; NAGLU: N-acetyl-alpha-glucosaminidase; PDIA3: protein disulfide isomerase family A member 3; PMA: phorbol 12-myristate 13-acetate; PRKC: protein kinase C; SQSTM1: sequestosome 1; STAT3: signal transducer and activator of transcription 3; SS1: Sydney Strain 1; TRP: transient receptor potential; VacA: vacuolating cytotoxin; VD3: vitamin D3; VDR: vitamin D receptor