Discovery of Urea Derivatives of Celastrol as Selective Peroxiredoxin 1 Inhibitors against Colorectal Cancer Cells.

Peroxiredoxin (PRDX1) is a tumor-overexpressed antioxidant enzyme for eliminating excessive reactive oxygen species (ROS) to protect tumor cells from oxidative damage. Herein, a series of celastrol urea derivatives were developed based on its cocrystal structure with PRDX1, with the aim of pursuing a PRDX1-specific inhibitor. Among them, derivative 15 displayed potent anti-PRDX1 activity (IC50 = 0.35 µM) and antiproliferative potency against colon cancer cells. It covalently bound to Cys-173 of PRDX1 (KD = 0.37 µM), which was secured by the cocrystal structure of PRDX1 with an analogue of 15 while exhibiting weak inhibitory effects on PRDX2-PRDX6 (IC50 > 50 µM), indicating excellent PRDX1 selectivity. Treatment with 15 dose-dependently decreased the mitochondria membrane potential of SW620 cells, probably due to ROS induced by PRDX1 inhibition, leading to cell apoptosis. In colorectal cancer cell xenograft model, it displayed potent antitumor efficacy with superior safety to celastrol. Collectively, 15 represents a promising PRDX1 selective inhibitor for the development of anticolorectal cancer agents.

Natural compounds modulating mitophagy: Implications for cancer therapy.

Cancer is considered as the second leading cause of mortality, and cancer incidence is still growing rapidly worldwide, which poses an increasing global health burden. Although chemotherapy is the most widely used treatment for cancer, its effectiveness is limited by drug resistance and severe side effects. Mitophagy is the principal mechanism that degrades damaged mitochondria via the autophagy/lysosome pathway to maintain mitochondrial homeostasis. Emerging evidence indicates that mitophagy plays crucial roles in tumorigenesis, particularly in cancer therapy. Mitophagy can exhibit dual effects in cancer, with both cancer-inhibiting or cancer-promoting function in a context-dependent manner. A variety of natural compounds have been found to affect cancer cell death and display anticancer properties by modulating mitophagy. In this review, we provide a systematic overview of mitophagy signaling pathways, and examine recent advances in the utilization of natural compounds for cancer therapy through the modulation of mitophagy. Furthermore, we address the inquiries and challenges associated with ongoing investigations concerning the application of natural compounds in cancer therapy based on mitophagy. Overcoming these limitations will provide opportunities to develop novel interventional strategies for cancer treatment.

The effects of hysteroscopy and laparoscopy for scar diverticulum resection and suture on blood loss, operation time and antibiotic time.

To evaluate the effect of hysteroscopy and suture on uterine scar diverticulum (CSD) after caesarean section and its influence on blood loss, operation time and antibiotic time. Eighty-nine patients with CSD were divided into observation group (n = 41 cases) and control group (n = 48 cases). Control group received laparoscopic scar diverticulum resection and suture, while the observation group received hysteroscopic resection of scar diverticulum. The operation time of the observation group was longer, while the bleeding volume and antibiotic administration time were significantly lower. The surgical treatment efficiency of the observation group (97.56%) was significantly higher. After treatment, the observation group's diverticulum repair indexes (width, depth and lower uterine muscular layer thickness) were better than those of the control group (p<.05). Hysteroscopic resection of scar diverticulum in CSD reduces intraoperative blood loss and the risk of complications, shortens time of antibiotic administration, and promotes diverticulum repair.Impact StatementWhat is already known on this subject? Uterine scar diverticulum (CSD) after caesarean section, also called postoperative uterine incision defect (PCSD), is due to poor healing of the uterine incision after caesarean section.What do the results of this study add? Hysteroscopic resection of scar diverticulum in CSD has a significant clinical effect, which can effectively reduce intraoperative blood loss and the risk of complications, shorten the time of antibiotic administration, and promote diverticulum repair.What are the implications of these findings for clinical practice and/or further research? Clinical effect of hysteroscopic resection of scar diverticulum in CSD is significant.

Microbial transformation of pentacyclic triterpenes for anti-inflammatory agents on the HMGB1 stimulated RAW 264.7 cells by Streptomyces olivaceus CICC 23628.

High mobility group box-1 protein (HMGB1) is a typical Damage-Associated Molecular Patterns (DAMPs) released in response to cellular inflammation. The pentacyclic triterpenes (PTs) are considered to be the natural inhibitors against HMGB1-related inflammation. To explore new lead compounds of PTs as anti-inflammatory agents, biotransformation of four PTs by Streptomyces olivaceus CICC 23628 was investigated in this study. As a result, thirteen unique 3,4-seco-triterpenes metabolites were isolated and twelve of them were first identified and reported. Structures of metabolites were determined based on HR-ESI-MS, 1D/2D NMR, and single-crystal X-ray diffraction. Furthermore, all compounds were subjected to the bioassay on the model of HMGB1-stimulated RAW 264.7 cells to evaluate their anti-inflammatory activity through nitric oxide (NO) inhibition activity. Compounds 3b (3,4-seco-olean-12-en-4,21α,22ß,24-tetrahydroxy-ol-3-oic acid) and 2b (3,4-seco-olean-12-en-4,21ß,22ß,24,29-pentahydroxy-ol-3-oic acid) exhibited NO inhibitory activity with IC50 values of 15.94 µM and 36.00 µM, respectively. Thus, indicating their potential as HMGB1 inhibitors and in developing potent anti-inflammatory agents. This work provides an operationally simple, efficient method for the rapid diversification of the PTs scaffold for a variety of distinctive 3,4-seco-triterpenes to facilitate the discovery of potential anti-inflammatory compounds.

Adipose Mesenchymal Stem Cell-Derived Exosomes Enhance PC12 Cell Function through the Activation of the PI3K/AKT Pathway.

Transplantation of mesenchymal stem cells has been considered as an auspicious treatment for repairing nerve injuries. The rat adrenal pheochromocytoma cell line (PC12) is one of the traditional models for the study of neuronal differentiation and neuroregeneration in vitro. However, the effects of adipose mesenchymal stem cell-derived exosomes (ADSC-exo) on PC12 cells remain unclear and to be elucidated. In our study, the effects of ADSC-exo on PC12 cells were investigated. ADSC-exo were isolated by ultracentrifugation and characterized by transmission electron microscopy, flow nanoanalysis, and western blot. The effects of ADSC-exo on PC12 cell proliferation, migration, apoptosis, and the protein levels were analyzed using CCK-8 assay and EdU incorporation assay, transwell migration assay and scratch wound assay, flow cytometry, and western blot, respectively. We successfully isolated and purified exosomes from ADSC supernatant and found that ADSC-exo treatment significantly promoted PC12 cell proliferation and migration, inhibited their apoptosis, and activated the PI3K/AKT pathway, while PI3K/AKT signaling repression using LY294002 exhibited the opposite effects. The results showed that ADSC-exo promoted proliferation and migration and inhibited apoptosis of PC12 through the activation of the PI3K/AKT pathway. Thus, the effect of ADSC-exo on PC12 cells may suggest ADSC-exo may be a promising therapeutic for nerve damage.

In situ Synthesized Monosodium Urate Crystal Enhances Endometrium Decidualization via Sterile Inflammation During Pregnancy.

High level of uric acid (UA) is the major origin of gout, and is highly associated with various pregnant complications, such as preeclampsia and gestational diabetes. However, UA's level and role in the very early stage of pregnancy has not been uncovered. This study aims to investigate the relevance of serum UA and decidualization, an essential process for the establishment and maintenance of pregnancy in women and mice during the early stage of pregnancy. In this study, we first proved that expression level of UA synthase xanthine dehydrogenase (XDH) is highly increased along with decidualization of endometrial stromal cells in both in vitro and in vivo models. Furthermore, serum and endometrial levels of UA are higher in mice with decidualized uterin horn and in vitro decidualized stromal cells. The existence of monosodium urate (MSU) crystal was also confirmed by immunostaining. Next, the roles of MSU on decidualization were explored by both in vitro and in vivo models. Our data shows MSU crystal but not UA enhances the decidualization response of endometrial stromal cells, via the upregulation of inflammatory genes such Ptgs2 and Il11. inhibiting of Cox-2 activity abolishes MSU crystal induced higher expression of decidualization marker Prl8a2. At last, in women, we observed enriched expression of XDH in decidua compare to non-decidualized endometrium, the serum level of UA is significantly increased in women in very early stage of pregnancy, and drop down after elective abortion. In summary, we observed an increased serum UA level in the early stage of women's pregnancy, and proved that the increased level of UA results from the expressed XDH in decidualizing endometrium of both human and mouse, leading to the formation of MSU crystal. MSU crystal can enhance the decidualization response via inflammatory pathways. Our study has uncovered the association between UA, MSU, and decidualization during the early stage of pregnancy.

Carbon phosphide nanosheets and nanoribbons: insights on modulating their electronic properties by first principles calculations.

A carbon phosphide (CP) monolayer, a 2D structure derived from the same 3-fold coordination found both in graphene and phosphorene, has been successfully synthesized in an experiment recently. In this paper, we investigated the modulation of electronic structures and transport characteristics of 2D nanosheets and quasi-1D nanoribbons of CP nanomaterials in the α-phase by using first-principles density functional theory simulation. The calculated band structures show that the band gap of 2D CP nanosheets progressively increases as the uniform biaxial strain changes from compression to stretching. However, the biaxial strain cannot change the indirect band gap behavior of the original 2D CP nanosheet. In addition, the band structures of quasi-1D nanoribbons with different styles of H-passivated zigzag edges have also been studied. The results show that the H-passivated zigzag PC ribbons with two P edges are semiconductors with indirect band gaps, and the gaps decrease with increasing width of ribbons. However, the H-passivated CP nanoribbons with one P-atom terminated edge in combination with one P-atom edge, and H-passivated CC nanoribbons with two C-atom terminated edges display metallic behaviors. The semi-conductive or metallic behaviors of zigzag CP nanoribbons can be explained by presenting the wave function of their energy band around the Fermi level. Finally, the electronic transport properties of different CP nanoribbon based nanojunctions are studied in which arise the interesting negative differential resistance or rectification effects in their current-voltage characteristic curves.

Development and characterization of an Otp conditional loss of function allele.

Orthopedia (Otp) is a homeodomain transcription factor that plays an essential role in the development of hypothalamic neurosecretory systems. Loss of Otp results in the failure of differentiation of key hypothalamic neuroendocrine cell types, and pups die soon after birth. Although the constitutive knockout Otp mouse model (Otp KO ) has significantly expanded our understanding of Otp's function in vivo, a conditional loss of function Otp allele that enables tissue or cell-type specific ablation of Otp has not been developed. Here, we used CRISPR/Cas9 gene-editing technology to generate a conditional Otp knockout mouse line in which exon 2 of the murine Otp gene is flanked by LoxP sites (Otp f/f ). Crossing the Otp f/f mouse with Agrp-Ires-cre mouse, we demonstrate the requirement for Otp in the continuous differentiation of AgRP neurons after cell fate determination. We also show that the residual AgRP neurons in Agrp-Ires-cre;Otp f/f mice project to similar downstream target regions. This newly developed Otp f/f mouse can be used to explore the functions of Otp with cell-type or temporal specificity.

High-efficient and synergetic antibacterial nanocomposite hydrogel with quaternized chitosan/Ag nanoparticles prepared by one-pot UV photochemical synthesis.

Hydrogel dressings have significant advantages such as absorption of tissue exudate, maintenance of proper moist environment, and promotion of cell proliferation. However, facile preparation method and high-efficient antibacterial hydrogel dressings are still a great challenge. In this study, a facile approach to prepare antibacterial nanocomposite hydrogel dressing to accelerate healing was explored. The hydrogels consisted of quaternized chitosan and chemically cross-linked polyacrylamide, as well as silver nanoparticles (AgNPs) stabilized by chitosan. The synthesis of the hydrogels including the formation of AgNPs and polymerization of acrylamide was accomplished simultaneously under UV irradiation in 1 hour without adding initiator. The hydrogels showed favorable tensile strength of ∼100 kPa with elongation at break over 1000% and shear modulus of ∼104 Pa as well as suitable swelling ratio, which were appropriate for wound dressing. The combination of quaternized chitosan and AgNPs exhibited high-efficient and synergetic antibacterial performance with low cytotoxicity. In vivo animal experiments showed that the hydrogel can effectively prevent wound infection and promote wound healing. This study provides a facile method to produce antibacterial hydrogel wound dressing materials.

Microbial transformation of glycyrrhetinic acid derivatives by Bacillus subtilis ATCC 6633 and Bacillus megaterium CGMCC 1.1741.

Glycyrrhetinic acid (GA), the major bioactive pentacyclic triterpene aglycone of licorice root, was known to play a vital role in anti-ulcer, anti-depressant, anti-inflammatory, and anti-allergic. In this study, we semi-synthesized five GA derivatives by a series of chemical reactions. They were selected as substrates for the biotransformation and yielded thirteen metabolites by Bacillus subtilis ATCC 6633 and Bacillus megaterium CGMCC 1.1741. Their structures were identified on the basis of extensive spectroscopic methods and nine of them were found for the first time. Two main types of reactions, regio- and stereo-selective hydroxylation and glycosylation, especially in the unactivated C-H bonds including C-11, C-19 and C-27, were observed in the biotransformation process, which greatly expand the chemical diversities of GA derivatives. All compounds were tested for their inhibitory effects on nitric oxide (NO) generation in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. Among them, olean-12-ene-3ß,7ß,15α,19α,30-pentol (16) and olean-12-ene-3ß,7ß,15α,27,30-pentol (17) showed significant inhibitory effect with IC50 values of 0.64 and 0.07 µM, respectively.

Nucleolar stress regulation of endometrial receptivity in mouse models and human cell lines.

Embryo implantation is essential to the successful establishment of pregnancy. A previous study has demonstrated that actinomycin D (ActD) could initiate the activation of mouse delayed implantation. However, the mechanism underlying this activation remains to be elucidated. A low dose of ActD is an inducer of nucleolar stress. This study was to examine whether nucleolar stress is involved in embryo implantation. We showed that nucleolar stress occurred when delayed implantation was activated by ActD in mice. ActD treatment also stimulated the Lif-STAT3 pathway. During early pregnancy, nucleolar stress was detected in the luminal epithelial cells during the receptive phase. Blastocyst-derived lactate could induce nucleolar stress in cultured luminal epithelial cells. The inhibition of nucleophosmin1 (NPM1), which was a marker of nucleolar stress, compromised uterine receptivity and decreased the implantation rates in pregnant mice. To translate these mouse data into humans, we examined nucleolar stress in human endometrium. Our data demonstrated that ActD-induced nucleolar stress had positive effects on the embryo attachment by upregulating IL32 expression in non-receptive epithelial cells rather than receptive epithelial cells. Our data should be the first to demonstrate that nucleolar stress is present during early pregnancy and is able to induce embryo implantation in both mice and humans.

An ultrasensitive electrochemical aptasensor for the determination of tumor exosomes based on click chemistry.

Exosomes, lipid bilayer membrane vesicles, can guide various pathological and physiological processes. However, reliable, convenient and sensitive methods for exosome determination for early cancer diagnosis are still technically challenging. Herein, an electrochemical aptasensor based on click chemistry and the DNA hybridization chain reaction (HCR) for signal amplification has been developed for the ultrasensitive detection of tumor exosomes. CD63 aptamer was first immobilized on a glassy carbon electrode for capturing exosomes, and 4-oxo-2-nonenal alkyne (alkynyl-4-ONE) molecules, functionalized lipid electrophiles, were conjugated to the exosomes via the reaction of amino and aldehyde groups. Azide-labeled DNA probe as an anchor was then connected to the exosomes by copper (I)-catalyzed click chemistry. Signal amplification was achieved by HCR, and the numerous linked horseradish peroxidase (HRP) molecules could catalyze the reaction of o-phenylenediamine (OPD) and H2O2. The concentration of exosomes could be quantified by monitoring the electrochemical reduction current of 2,3-diaminophenazine (DAP). Under the optimal conditions, this method allowed the sensitive detection of exosomes in the range of 1.12 × 102 to 1.12 × 108 particles/µL with a limit of detection (LOD) of 96 particles/µL. Furthermore, the present assay enabled sensitive and accurate quantification of exosomes in human serum, and it has high potential for exosome analysis in clinical samples.

Comparison of biological characteristics of mesenchymal stem cells derived from the human umbilical cord and decidua parietalis.

Mesenchymal stem cells (MSCs) are derived from the mesoderm and have the self­renewal capacity and multi­directional differentiation potential of adult stem cells. Stem cells from different sources have different molecular and growth characteristics; therefore, the mechanisms and effects of stem cell­mediated repair and tissue regeneration may be different. The aim of the present study was to compare the biological characteristics of MSCs derived from the umbilical cord (UC­MSCs) and MSCs derived from the decidua parietalis (DP­MSCs), and to provide new evidence for the selection of seed cells in regenerative medicine. Growth curves, cell doubling times, colony formation rates, immunophenotypes, differentiation capacities and secretion­factor levels of MSCs derived from the two sources were analysed. UC­MSCs and DP­MSCs exhibited similar properties with regards to morphology, spiral growth, immunophenotype, and potential to differentiate into osteoblasts and adipocytes. For each cell type, the positive rates of the cell surface markers CD73, CD90 and CD105 were >95%, whereas CD34 and CD45 positive rates were <1%. Analyses of in vitro growth kinetics revealed shorter cell­doubling times, and higher proliferative rates and colony formation rates of UC­MSCs compared with DP­MSCs (P<0.05). The concentration of basic fibroblast growth factor in the supernatant from UC­MSCs was higher compared with that from DP­MSCs (P<0.05). However, UC­MSC supernatants exhibited lower levels of of keratinocyte growth factor, vascular endothelial growth factor and stem cell factor compared with DP­MSCs (P<0.05). In conclusion, in vitro characterization of MSCs from these tissue sources revealed a number of common biological properties. However, the results also demonstrated clear biological distinctions and suggested that UC­MSCs may have more effective application prospects.

Overexpression of chloride channel-3 (ClC-3) is associated with human cervical carcinoma development and prognosis.

BACKGROUND: Cervical carcinoma is a major gynecological cancer and causes cancer-related deaths in worldwide, the latent pathogenesis and progress of cervical cancer is still under research. ClC-3 may be an important promoter for aggressive metastasis of malignant tumors. In this research, we explore the ClC-3 expression in cervical carcinoma and its underlying clinical significance, trying to illuminate ClC-3 probable function in the neoplasm malignant behavior, development and prognosis. METHODS: Paraffin-embedded cervical (n = 168) and lymph node (n = 100) tissue specimens were analysed by immunohistochemistry. Fresh human cervical tissue specimens (n = 165) and four human cervical cell lines were tested for ClC-3 mRNA and protein expression levels by quantitative real-time PCR and western blotting. The relationship between the expression levels of ClC-3, the pathological characteristics of the carcinoma, and the clinical prognosis were statistically analysed. RESULTS: In normal and precancerous (LSIL, HSIL) cervical tissues as well as cervical carcinoma tissues, both ClC-3 mRNA and protein expression levels increased significantly (p < 0.05). The expression level of ClC-3 was closely-related to the histological differentiation (p = 0.029), tumour staging (p = 0.016), tumour size (p = 0.039), vascular invasion (p = 0.045), interstitial infiltration depth (p = 0.012), lymphatic metastasis (p = 0.036), and HPV infection (p = 0.022). In an in vitro experiment, ClC-3 mRNA and protein were found to be overexpressed both in the HeLa and SiHa cell lines, but low expression levels were detected in the C-33A and H8 cell lines (p < 0.05). Furthermore, the high expression levels of ClC-3 was significantly correlated to poor survival in cervical carcinoma patients (Log-rank test, p = 0.046). CONCLUSIONS: These data suggest that overexpression of ClC-3 is closely associated with human cervical carcinoma progression and poor prognosis; this suggests that ClC-3 may function as a patent tumour biomarker and a latent therapeutic target for cervical carcinoma patients.

Decidual expression and regulation of fatty acid desaturase 3 during mouse decidualization.

Decidualization is required for the successful establishment of pregnancy in rodents and primates. Fatty acid desaturase 3 (Fads3) belongs to the fatty acid desaturase family, which is a crucial enzyme for highly unsaturated fatty acid biosynthesis. However, the expression, regulation and function of Fads3 during early pregnancy in mice are still unknown. In this study, we examined Fads3 expression, regulation and function during mouse decidualization. The expression of Fads3 is detected in the subluminal stromal cells at implantation site on day 5 of pregnancy, but not at inter-implantation site and in day 5 pseudopregnant uteri. Compared to delayed implantation, Fads3 is strongly expressed after delayed implantation is activated by estrogen treatment. From days 6 to 8, Fads3 mRNA signals are significantly detected in the decidua. In ovariectomized mice, estrogen significantly stimulates Fads3 expression. However, estrogen has no effect on Fads3 expression in ovariectomized ERα-deficient mice, suggesting that estrogen regulation on Fads3 expression is ERα dependent. When ovariectomized mice were treated with progesterone, Fads3 expression is significantly increased by progesterone. Progesterone stimulation on Fads3 expression is also detected in cultured stromal cells, which is abrogated by RU486 treatment. These data indicate that progesterone upregulation on Fads3 expression is progesterone receptor-dependent. Fads3 knockdown by siRNA reduces in vitro decidualization of mouse stromal cells. Taken together, Fads3 may play an important role during mouse decidualization.

The predictive value of interim and final [18F] fluorodeoxyglucose positron emission tomography after rituximab-chemotherapy in the treatment of non-Hodgkin's lymphoma: a meta-analysis.

BACKGROUND AND PURPOSE: The aim of this study is to determine the prognostic value of interim and final FDG-PET in major histotypes of B-cell NHL patients treated with rituximab containing-chemotherapy. METHODS: We searched for articles published in English, limited to lymphoma, rituximab, and FDG-PET, and dedicated to deal with the impact on progression and survival. The log hazard ratios (HR) and their variances were estimated. RESULTS: A PubMed and Scopus review of published trials identified 13 studies of Progression-free survival (PFS) and overall survival (OS) which were set as the main outcome measures. The combined HRs of I-PET for PFS and OS in DLBCL were 4.4 (P = 0.11) and 3.99 (P = 0.46), respectively. The combined HRs of F-PET for PFS and OS in DLBCL were 5.91 (P = 0.39) and 6.75 (P = 0.92), respectively. Regarding to non-DLBCL with F-PET, the combined HRs of F-PET for PFS and OS were 4.05 (P = 0.79) and 5.1 (P = 0.51), respectively. No publication bias existed. CONCLUSION: In DLBCL, both I-PET and F-PET can be performed for survival and progression analysis. But in other B-cell subtypes such as follicular lymphoma (FL) and mantle cell lymphoma (MCL), it would be necessary to perform F-PET for predictive purposes.

Soluble amyloid precursor protein-α modulates ß-secretase activity and amyloid-ß generation.

In sporadic age-related forms of Alzheimer's disease (AD), it is unclear why amyloid-ß (Aß) peptides accumulate. Here we show that soluble amyloid precursor protein-α (sAPP-α) decreases Aß generation by directly associating with ß-site APP-converting enzyme (BACE)1, thereby modulating APP processing. Whereas specifically targeting sAPP-α using antibodies enhances Aß production; in transgenic mice with AD-like pathology, sAPP-α overexpression decreases ß-amyloid plaques and soluble Aß. In support, immunoneutralization of sAPP-α increases APP amyloidogenic processing in these mice. Given our current findings, and because a number of risk factors for sporadic AD serve to lower levels of sAPP-α in brains of AD patients, inadequate sAPP-α levels may be sufficient to polarize APP processing towards the amyloidogenic, Aß-producing route. Therefore, restoration of sAPP-α or enhancement of its association with BACE may be viable strategies to ameliorate imbalances in APP processing that can lead to AD pathogenesis.

Interleukin-10-819 promoter polymorphism in association with gastric cancer risk.

BACKGROUND: Potential functional allele T/C single nucleotide polymorphism (SNP) of Interleukin 10 (IL-10) promoter -819 (rs1800871) has been implicated in gastric cancer risk. We aimed to explore the role of T/C SNP of IL-10 -819 in the susceptibility to gastric cancer through a systematic review and meta-analysis. METHODS: Each initially included article was scored for quality appraisal. Desirable data were extracted and registered into databases. 11 studies were ultimately eligible for the meta-analysis of IL-10 -819 T/C SNP. We adopted the most probably appropriate genetic model (recessive model). Potential sources of heterogeneity were sought out via subgroup and sensitivity analyses, and publication biases were estimated. RESULTS: IL-10 -819 TT genotype is associated with the overall reduced gastric cancer risk among Asians and even apparently observed among high quality subgroup Asians. IL-10-819 TT genotype is not statistically associated with the overall reduced gastric cancer susceptibility in persons with H. pylori infection compared with controls without H. pylori infection. IL-10 -819 TT genotype is reversely associated with diffuse-subtype risk but not in intestinal-subtype risk. IL-10 -819 TT genotype is not reversely associated with non-cardia or cardia subtype gastric cancer susceptibility. CONCLUSIONS: IL-10 -819 TT genotype seems to be more protective from gastric cancer in Asians. Whether IL-10 -819 TT genotype may be protective from gastric cancer susceptibility in persons infected with H. pylori or in diffuse-subtype cancer needs further exploring in the future well-designed high quality studies among different ethnicity populations. Direct sequencing should be more used in the future.