Effect of gradual increase of salt on performance and microbial community during granulation process.

Salinity was considered to have effects on the characteristics, performance microbial communities of aerobic granular sludge. This study investigated granulation process with gradual increase of salt under different gradients. Two identical sequencing batch reactors were operated, while the influent of Ra and Rb was subjected to stepwise increments of NaCl concentrations (0-4 g/L and 0-10 g/L). The presence of filamentous bacteria may contribute to granules formed under lower salinity conditions, potentially leading to granules fragmentation. Excellent removal efficiency achieved in both reactors although there was a small accumulation of nitrite in Rb at later stages. The removal efficiencies of chemical oxygen demand (COD), total nitrogen (TN), and total phosphorus (TP) in Ra were 95.31%, 93.70% and 88.66%, while the corresponding removal efficiencies in Rb were 94.19%, 89.79% and 80.74%. Salinity stimulated extracellular polymeric substances (EPS) secretion and enriched EPS producing bacteria to help maintain the integrity and stability of the aerobic granules. Heterotrophic nitrifying bacteria were responsible for NH4+-N and NO2--N oxidation of salinity systems and large number of denitrifying bacteria were detected, which ensure the high removal efficiency of TN in the systems.

hnRNPA1 promotes the metastasis and proliferation of gastric cancer cells through WISP2-guided Wnt/ß-catenin signaling pathway.

The main cause of gastric cancer (GC)-related death is due to malignant cell unregulated distant metastasis and proliferation. Heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) has been shown to play an important role in carcinogenesis and the development of metastasis in several tumors. However, its downstream regulatory mechanism in GC is not well defined. Our study aims to investigate the function and regulatory mechanism of hnRNPA1 in GC. We analyzed the differential expression of hnRNPA1 in gastric cancer and paired adjacent normal tissues in the TCGA database. Kaplan-Meier analysis was employed for survival assessment. The expressions of hnRNPA1 in GC cells were measured by qRT-PCR and Western blot. Transwell assay, CCK8 and colony formation assay were used to detect the effect of hnRNPA1 on the metastasis and proliferation ability of GC cells. Additionally, Western blotting was performed to examine the expression of proteins related to the Wnt/ß-catenin signaling pathway as well as epithelial-mesenchymal transition (EMT), while further investigations were carried out to explore potential regulatory mechanisms. The results showed that hnRNPA1 was highly expressed differentially in GC over normal gastric tissue. Knocking down hnRNPA1 inhibited the metastasis and proliferation of human gastric cancer cells. Overexpression of hnRNPA1 significantly enhanced the metastatic potential and proliferative capacity of human GC cells. Further mechanism exploration revealed that knocking down hnRNPA1 inhibited the Wnt/ß-catenin signaling pathway and WNT1 inducible signaling pathway protein-2 (WISP2), an activator of the Wnt/ß-catenin signaling pathway. Whereas overexpression of hnRNPA1 had the opposite effects. Our results demonstrated that hnRNPA1 promoted metastasis and proliferation of GC cells by activating Wnt/ß-catenin signaling pathway via WISP2. hnRNPA1 may serve as a potential biomarker and novel therapeutic targets for GC.

Response of aerobic granular sludge to salinity fluctuations in formation, stability and microbial community structures.

Aerobic granular sludge (AGS) exhibits excellent resistance to adverse environment due to its unique layered structure. However, the mechanism about how salinity fluctuations in municipal wastewater impact AGS formation and its physicochemical properties has not been thoroughly revealed. In this study, AGS was cultivated under additional 0 % salinity (R1), additional 1.5 % constant salinity (R2), and additional 0-1.5 % fluctuant salinity (R3), respectively. The results indicate that increased salinity can enhance extracellular polymeric substances (EPS) production and improve sludge settleability, thereby facilitating AGS formation. However, the AGS experienced frequent environmental conversion between dehydration and swell due to salinity fluctuations, resulting in higher content of loosely-bond EPS and low settleability, which delayed the maturation of AGS for over 14 days. Additional salinity significantly inhibited the nitrification process, but the formation of AGS promoted the recovery of ammonia oxidation activity and facilitated the construction of short-range nitrification denitrification processes, resulting in over 16.0 % higher total nitrogen removal efficiency than R1. The microbial community analysis revealed that Thauera played an important role in the granulation process under salinity stress, due to its salt tolerance and EPS secretion abilities. As expected, the formation of AGS enhanced the salt resistance of microorganisms, allowing for the enrichment of functional bacteria, such as Flavobacterium and Candidatus_Competibacter. Generally, microorganisms required extended adaptation periods to cope with salinity fluctuations. Nevertheless, the resulting AGS proved stable and efficient wastewater treatment performance.

Transcriptional upregulation of MMP-9 gene under hyperglycemic conditions in AGS cells: Role of AP-1 transcription factor.

Gastric cancer and diabetes are two complex and interrelated diseases having significant impact on global health. Hyperglycemic condition notably exacerbates cancer by promoting inflammation, angiogenesis, and metastasis. Elevated glucose levels can also upregulate the expression of specific matrix metalloproteinases (MMPs), especially MMP-9, which is associated with cancer cell migration and invasion. However, the molecular mechanism behind such upregulation remains unexplored. In the present study, we have identified the mechanism for hyperglycemia-induced transcriptional activation of MMP-9, in gastric adenocarcinoma (AGS) cells. Using various tools like luciferase-reporter assays with promoter deletion constructs, siRNAs, pharmacological inhibitors, and nuclear translocation experiments, we have identified that the transcriptional activation of MMP-9 under hyperglycemic conditions is predominantly governed by the MAPK pathway, via formation of the AP-1 heterodimer. The p65 NF-κB signaling pathway, although activated, plays no significant role in regulating hyperglycemia-induced MMP-9 expression. Chromatin immunoprecipitation studies indicate that the distal AP-1 binding site is responsible for hyperglycemia-induced MMP-9 transcription; whereas the proximal one accounts for both hyperglycemia-induced and basal MMP-9 transcription. Therefore, binding of AP-1 at both the proximal and distal binding sites on the MMP-9 promoter region is required for hyperglycemia-induced MMP-9 expression. Overall, our study unveils a novel mechanism of MMP-9 transcription under hyperglycemic conditions and also suggests that inhibiting the binding of the AP-1 heterodimer with its distal binding site can potentially reduce the complications developed during gastric cancer-hyperglycemia co-morbidity. A drug designed specifically to inhibit this interaction may prevent hyperglycemia-induced tumor aggressiveness to a considerable extent by impeding MMP-9 transcription.

Anticancer Activity and Mechanism of Action of Couroupita guianensis Bark Decoction in Gastric Adenocarcinoma Cancer Cell Line.

Couroupita guianensis, a medicinal plant autochthonal to South America and South India, is widely used in the ethnomedicine of the indigenous peoples of these regions thanks to its alleged antimicrobial, anti-inflammatory, antioxidant and wound-healing properties. The majority of studies have mainly analyzed organic extracts of the Indian plant's flowers and leaves, with limited research on its bark decoction, traditionally used in Amazonian shamanic medicine. In this study, we investigated the anticancer effects of the bark decoction and its main fractions obtained through chromatographic separation, as well as the underlying molecular mechanisms in AGS gastric cancer cells. Viability, cell proliferation, cell cycle, apoptosis and protein expression related to these processes were evaluated. Both the bark decoction and fraction III significantly inhibited cell viability, and the cytotoxic effect was linked to cell cycle blockade and the induction of apoptosis also through an engulfment of the autophagic flux. Increased expression or activation of the key proteins (p53, p21, cdk2, Bak, caspases, pAMPK, pAkt, beclin, p62 and LC3BII) involved in these processes was observed. The results obtained confirmed an important anticancer effect of C. guianensis bark decoction, providing scientific validation for its use in traditional medicine and highlighting its potential as a therapeutic agent against gastric cancer.

Shatavarin-IV, a steroidal saponin from Asparagus racemosus, inhibits cell cycle progression and epithelial-to-mesenchymal transition in AGS cells under hyperglycemic conditions.

Gastric cancer (GC)-diabetes co-morbidity is nowadays growing into a rising concern. However, no separate treatment procedures have been outlined for such patients. Phytochemicals and their derivatives can therefore be used as therapeutics as they have greater effectiveness, reduced toxicity, and a reduced likelihood of developing multi-drug resistance in cancer treatments. The present study intended to assess the therapeutic efficacy of Shatavarin-IV - a major steroidal saponin from the roots of Asparagus racemosus, in human gastric adenocarcinoma cell line under hyperglycemic conditions and explore its mechanism of action in controlling GC progression. For the present study, AGS cells were incubated in high glucose-containing media and the effects of Shatavarin-IV therein have been evaluated. Cell proliferation, confocal microscopic imaging, flow-cytometric analysis for cell cycle and apoptosis, immunoblotting, zymography, reverse zymography, wound-healing, colony formation, and invasion assays were performed. Shatavarin-IV has a prominent effect on AGS cell proliferation; with IC50 of 2.463 µ M under hyperglycemic conditions. Shatavarin-IV induces cell cycle arrest at the G0/G1 phase, thereby preventing hyperglycemia-induced excessive cell proliferation that later on leads to apoptotic cell death at 36 h of incubation. Shatavarin-IV further inhibits the migratory and invasive potential of AGS cells by altering the expression patterns of different EMT markers. It also inhibits MMP-9 while promoting TIMP-1 activity and expression; thereby regulating ECM turnover. This is the first report demonstrating the therapeutic efficacy of Shatavarin-IV against AGS cells grown in hyperglycemic conditions, implicating new insights into the treatment paradigm of patients with GC-diabetes co-morbidity.

An ADAR1 dsRBD3-PKR kinase domain interaction on dsRNA inhibits PKR activation.

Adar null mutant mouse embryos die with aberrant double-stranded RNA (dsRNA)-driven interferon induction, and Adar Mavs double mutants, in which interferon induction is prevented, die soon after birth. Protein kinase R (Pkr) is aberrantly activated in Adar Mavs mouse pup intestines before death, intestinal crypt cells die, and intestinal villi are lost. Adar Mavs Eifak2 (Pkr) triple mutant mice rescue all defects and have long-term survival. Adenosine deaminase acting on RNA 1 (ADAR1) and PKR co-immunoprecipitate from cells, suggesting PKR inhibition by direct interaction. AlphaFold studies on an inhibitory PKR dsRNA binding domain (dsRBD)-kinase domain interaction before dsRNA binding and on an inhibitory ADAR1 dsRBD3-PKR kinase domain interaction on dsRNA provide a testable model of the inhibition. Wild-type or editing-inactive human ADAR1 expressed in A549 cells inhibits activation of endogenous PKR. ADAR1 dsRNA binding is required for, but is not sufficient for, PKR inhibition. Mutating the ADAR1 dsRBD3-PKR contact prevents co-immunoprecipitation, ADAR1 inhibition of PKR activity, and co-localization of ADAR1 and PKR in cells.

Enhanced aerobic granular sludge by thermally-treated dredged sediment in wastewater treatment under low superficial gas velocity.

The positive contributions of carriers to aerobic granulation have been wildly appreciated. In this study, as a way resource utilization, the dredged sediment was thermally-treated to prepared as carriers to promote aerobic granular sludge (AGS) formation and stability. The system was started under low superficial gas velocity (SGV, 0.6 cm/s)for a lower energy consumption. Two sequencing batch reactors (SBR) labeled R1 (no added carriers) and R2 (carriers added), were used in the experiment. R2 had excellent performance of granulation time (shortened nearly 43%). The maximum mean particle size at the maturity stage of AGS in R2 (0.545 mm) was larger compared to R1 (0.296 mm). The sludge settling performance in R2 was better. The reactors exhibited high chemical oxygen demand (COD) and ammonia nitrogen (NH3-N) removal rates. The total phosphorus (TP) removal rate in R2 was higher than R1 (almost 15% higher) on stage II (93-175d). R2 had a higher microbial abundance and dominant bacteria content. The relative abundance of dominant species was mainly affected by the carrier. However, the enrichment of dominant microorganisms and the evolution of subdominant species were more influenced by the increase of SGV. The results indicated that the addition of carriers induced the secretion of extracellular polymeric substances (EPS) by microorganisms and accelerated the rapid formation of initial microbial aggregates. This work provided a low-cost method and condition to enhance aerobic granulation, which may be helpful in optimizing wastewater treatment processes.

Evaluating the effect of antibiotics on aerobic granular sludge treatment of pharmaceutical wastewater.

Aerobic granular sludge (AGS) has been widely applied in pharmaceutical wastewater treatment due to its advantages such as high biomass and excellent settling performance. However, the influence of commonly found antibiotics in pharmaceutical wastewater on the operational efficiency of AGS has been poorly explored. This study investigated the effects of tetracycline (TE) on AGS treating pharmaceutical wastewater at room temperature and analyzed the related mechanisms. The results demonstrate a dose-dependent relationship between TE's effects on AGS. At concentrations below the threshold of 0.1 mg/L, the effects are considered trivial. In contrast, TE with more than 2.0 mg/L reduces the performance of AGS. In the 6.0 mg/L TE group, COD, TN, and TP removal efficiencies decreased to 72.6-75.5, 54.6-58.9, and 71.6-75.8%, respectively. High concentrations of TE reduced sludge concentration and the proportion of organic matter in AGS, leading to a decline in sludge settling performance. Elevated TE concentrations stimulated extracellular polymeric substance secretion, increasing polymeric nitrogen and polymeric phosphorus content. Intracellular polymer analysis revealed that high TE concentrations reduced polyhydroxyalkanoates but enhanced glycogen metabolism. Enzyme activity analysis disclosed that high TE concentrations decreased the activity of key enzymes associated with nutrient removal.

LOXL3 Silencing Hampers the Metastasis and Angiogenesis of Gastric Cancer Cells Dependent on Ferroptosis Activation.

Gastric cancer (GC) remains a major unmet clinical problem accountable for considerable incidence and fatality rate. Lysyl oxidase-like 3 (LOXL3) has been recognized to be overexpressed in GC. Our work was meant to disclose the significance of LOXL3 in the advancement of GC and the likely action mechanism. LOXL3 expression in GC tissues and its correlation with the outcome of GC patients were investigated through bioinformatics tools. RT-qPCR and western blotting inspected LOXL3 expression in GC cells. CCK-8 method, EDU, as well as colony formation assays assayed cell proliferation. The capacities of cells to migrate and invade were appraised by wound healing and transwell assays, severally. Tube formation assay and ELISA measured angiogenesis. TBARS, C11 BODIPY staining, and FerroOrange estimated ferroptosis. Western blotting examined the expression of proteins implicated in metastasis and ferroptosis. The up-regulation of LOXL3 expression was noticed in GC tissues and cells, which was also associated with the poor outcome of GC patients. When LOXL3 was underexpressed, the proliferation, migration, invasion, epithelial-mesenchymal transition, and angiogenesis of GC cells were all halted. In addition, LOXL3 deletion resulted in the activation of ferroptosis in GC cells, and ferrostatin-1 (Fer-1), the specific ferroptosis inhibitor, compensated the suppressive role of LOXL3 down-regulation in the proliferation, metastasis, and angiogenesis of GC cells in vitro. All in all, knockdown of LOXL3 may serve an activator of ferroptosis to obstruct the aggressive process of GC.

Transplanting mitochondria from gastric epithelial cells reduces the malignancy of gastric cancer.

Mitochondria are essential for energy supplementation and metabolic homeostasis of cancer cells. Using mitochondria transplantation to reduce the malignancy of gastric cancer (GC) cells is herein proposed. In our study normal human gastric mucous epithelium cell line (GES-1) showed a lower mitochondrial membrane potential (MMP) compared to immortalized human vascular endothelial cell line (EAhy 926) and human gastric adenocarcinoma cell line (AGS). The transplantation of GES-1 mitochondria to AGS were confirmed both by confocal microscopy and flow cytometry. After transplanting GES-1 mitochondria, the AGS showed a reduced cell migration, and invasion without affecting cell viability and apoptosis. Investigating the expression of proteins involved in epithelial-mesenchymal-transition (EMT), transplanted GES-1 mitochondria reduced the expression of mesenchymal markers α-SMA, MMP-9, snail, vimentin and N-cadherin, whereas the epithelial markers E-cadherin and clauding-1 were not changed. The proteins implicated in the cell cycle such as cyclin B1 and D1 were decreased. In mice, inoculation with AGS carrying the transplanted GES-1 mitochondria resulted in smaller sized tumors. Further investigating the mitochondrial balance, the transplanted GES-1 mitochondria were more stably preserved compared to endogenous AGS mitochondria. The MMP, ATP production and mitochondrial mass decreased in GES-1 mitochondria and the mitophagic proteins LC3 II and PINK1 were up-regulated. In conclusion the decreased malignancy of AGS was a result of exogenous GES-1 mitochondria transplantation. This suggests for a therapy with low efficiency mitochondria transplantation in the treatment of cancer cells.

Adaptive Changes in Group 2 Metabotropic Glutamate Receptors Underlie the Deficit in Recognition Memory Induced by Methamphetamine in Mice.

Cognitive dysfunction is associated with methamphetamine use disorder (MUD). Here, we used genetic and pharmacological approaches to examine the involvement of either Group 2 metabotropic glutamate (mGlu2) or mGlu3 receptors in memory deficit induced by methamphetamine in mice. Methamphetamine treatment (1 mg/kg, i.p., once a day for 5 d followed by 7 d of withdrawal) caused an impaired performance in the novel object recognition test in wild-type mice, but not in mGlu2-/- or mGlu3-/- mice. Memory deficit in wild-type mice challenged with methamphetamine was corrected by systemic treatment with selectively negative allosteric modulators of mGlu2 or mGlu3 receptors (compounds VU6001966 and VU0650786, respectively). Methamphetamine treatment in wild-type mice caused large increases in levels of mGlu2/3 receptors, the Type 3 activator of G-protein signaling (AGS3), Rab3A, and the vesicular glutamate transporter, vGlut1, in the prefrontal cortex (PFC). Methamphetamine did not alter mGlu2/3-mediated inhibition of cAMP formation but abolished the ability of postsynaptic mGlu3 receptors to boost mGlu5 receptor-mediated inositol phospholipid hydrolysis in PFC slices. Remarkably, activation of presynaptic mGlu2/3 receptors did not inhibit but rather amplified depolarization-induced [3H]-D-aspartate release in synaptosomes prepared from the PFC of methamphetamine-treated mice. These findings demonstrate that exposure to methamphetamine causes changes in the expression and function of mGlu2 and mGlu3 receptors, which might alter excitatory synaptic transmission in the PFC and raise the attractive possibility that selective inhibitors of mGlu2 or mGlu3 receptors (or both) may be used to improve cognitive dysfunction in individuals affected by MUD.

Implications of silver nanoparticles for H. pylori infection: modulation of CagA function and signaling.

Background: Helicobacter pylori infection poses a significant health burden worldwide, and its virulence factor CagA plays a pivotal role in its pathogenesis. Methods: In this study, the interaction between H. pylori-infected AGS cells and silver nanoparticles (AgNPs) was investigated, with a focus on the modulation of CagA-mediated responses, investigated by western blotting. Both, the dose-dependent efficacy against H. pylori (growth curves, CFU assay) and the impact of the nanoparticles on AGS cells (MTT assay) were elucidated. Results: AGS cells infected with H. pylori displayed dramatic morphological changes, characterized by elongation and a migratory phenotype, attributed to CagA activity. Preincubation of H. pylori with AgNPs affected these morphological changes in a concentration-dependent manner, suggesting a correlation between AgNPs concentration and CagA function. Conclusion: Our study highlights the nuanced interplay between host-pathogen interactions and the therapeutic potential of AgNPs in combating H. pylori infection and offers valuable insights into the multifaceted dynamics of CagA mediated responses.

The evolutionary modifications of a GoLoco motif in the AGS protein facilitate micromere formation in the sea urchin embryo.

The evolutionary introduction of asymmetric cell division (ACD) into the developmental program facilitates the formation of a new cell type, contributing to developmental diversity and, eventually, to species diversification. The micromere of the sea urchin embryo may serve as one of those examples: An ACD at the 16-cell stage forms micromeres unique to echinoids among echinoderms. We previously reported that a polarity factor, Activator of G-protein Signaling (AGS), plays a crucial role in micromere formation. However, AGS and its associated ACD factors are present in all echinoderms and across most metazoans, leaving a question of what evolutionary modification of AGS protein or its surrounding molecular environment contributed to the evolutionary acquisition of micromeres only in echinoids. In this study, we learned that the GoLoco motifs at the AGS C-terminus play critical roles in regulating micromere formation in sea urchin embryos. Further, other echinoderms' AGS or chimeric AGS that contain the C-terminus of AGS orthologs from various organisms showed varied localization and function in micromere formation. In contrast, the sea star or the pencil urchin orthologs of other ACD factors were consistently localized at the vegetal cortex in the sea urchin embryo, suggesting that AGS may be a unique variable factor that facilitates ACD diversity among echinoderms. Consistently, sea urchin AGS appears to facilitate micromere-like cell formation and accelerate the enrichment timing of the germline factor Vasa during early embryogenesis of the pencil urchin, an ancestral type of sea urchin. Based on these observations, we propose that the molecular evolution of a single polarity factor facilitates ACD diversity while preserving the core ACD machinery among echinoderms and beyond during evolution.

The role of ayahuasca in cell viability and oxidative stress in gastric adenocarcinoma cell line.

Ayahuasca, a psychoactive beverage native to the Amazon, originally derived from Banisteriopsis caapi stem scrapings and Psychotria viridis leaves, exhibits hallucinogenic properties due to N,N-dimethyltryptamine. When combined with ß-carbolines, it enters the bloodstream and central nervous system, inhibiting monoamine oxidase-A. Over time, therapeutic effects have been associated to ayahuasca consumption. This study assessed the impact of extracts from three plant decoctions used in ayahuasca preparation on the gastric adenocarcinoma cell line (AGS). MTT reduction assays selected B. caapi, Mimosa hostilis, and Peganum harmala samples as most effective. Lactate dehydrogenase activity evaluated membrane integrity loss, while oxidative stress induction was measured using dihydroethidium and 2',7'-dichlorodihydrofluorescein diacetate probes. Results revealed apoptosis induction in AGS cells, with all three samples significantly reducing oxidative stress.

Potentially Inappropriate Use of Medication and Its Determinants Among Ambulatory Older Adults in Six Community Chain Pharmacies in Asmara, Eritrea: A Cross-Sectional Study Using the 2023 American Geriatric Society Beers Criteria®.

Background: Potentially inappropriate medication (PIM) use is one of the main drug-related problems encountered in older adults. It is associated with adverse drug events, morbidity, mortality, increased economic costs, and negative effects on the quality of life that requires strict monitoring of prescriptions in older adults. Thus, the study aimed to assess potentially inappropriate medication use and its determinants among older adults. Methods: A cross-sectional study was conducted among all outpatient prescriptions dispensed to older adults (aged 65 years and above) in six community chain pharmacies in Asmara, Eritrea. Data were collected retrospectively, between June 16 and July 16, 2023. PIMs were detected using the 2023 American Geriatric Society (AGS) Beers Criteria®. Descriptive statistics and logistic regression analysis were performed using IBM SPSS® (Version-26.0). Results: A total of 2680 outpatient prescriptions dispensed to older adults were included in this study. The prevalence of PIM among prescriptions was 18.1% (95% CI: 16.7, 19.6). Moreover, a total of 470 medications were found to be avoided in older adults. The most commonly prescribed PIMs were sulfonylureas (27.2%) and substituted alkylamines (16.2%). The prevalence of prescriptions containing medications to be used with caution in older adults was 13.2% (95% CI: 12.0, 14.5). Age (Adjusted Odds Ratio (AOR))=0.98, 95% CI: 0.97, 0.99), polypharmacy (AOR=2.77, 95% CI: 1.49, 5.15), and general practitioner prescriber (AOR=1.38, 95% CI: 1.11, 1.70) were significantly associated with PIMs. Conclusion: A considerable number of ambulatory older adults were exposed to PIMs which require a close attention by policymakers, program managers, and healthcare professionals.

Alpha-Gal Syndrome: An Underrated Serious Disease and a Potential Future Challenge.

Over the past decades, red meat allergy, also known as mammalian meat allergy, which manifests differently from classic food allergies, has been reported in different countries and regions, including China. The allergen of this disease is not a protein but an oligosaccharide: galactose-α-1,3-galactose, i.e., alpha-gal or α-gal. Therefore, this clinical syndrome is also called α-gal syndrome (AGS). It clinically manifests as delayed anaphylaxis, i.e., patients generally develop allergic symptoms 2-6 h after ingesting red meat. This clinical manifestation is believed to be related to sensitization to α-gal after tick bites. Sensitized individuals may also develop anaphylaxis after ingesting food and medicine or being exposed to medical equipment containing α-gal, such as cetuximab and gelatin. Here, the literature on AGS is reviewed for a better understanding of its pathogenesis, clinical diagnosis, and treatment.

The Sixth Sense: Self-nucleic acid sensing in the brain.

Our innate immune system uses pattern recognition receptors (PRRs) as a first line of defense to detect microbial ligands and initiate an immune response. Viral nucleic acids are key ligands for the activation of many PRRs and the induction of downstream inflammatory and antiviral effects. Initially it was thought that endogenous (self) nucleic acids rarely activated these PRRs, however emerging evidence indicates that endogenous nucleic acids are able to activate host PRRs in homeostasis and disease. In fact, many regulatory mechanisms are in place to finely control and regulate sensing of self-nucleic acids by PRRs. Sensing of self-nucleic acids is particularly important in the brain, as perturbations to nucleic acid sensing commonly leads to neuropathology. This review will highlight the role of nucleic acid sensors in the brain, both in disease and homeostasis. We also indicate the source of endogenous stimulatory nucleic acids where known and summarize future directions for the study of this growing field.

Biosynthesized BiFe2O4@Ag nanoparticles mediated Scenedesmus obliquus induce apoptosis in AGS gastric cancer cell line.

The use of magnetic metal nanoparticles has been considered in cancer treatment studies. In this study, BiFe2O4@Ag nanoparticles were synthesized biologically by Scenedesmus obliquus for the first time and their anticancer mechanism in a gastric cancer cell line was characterized. The physicochemical properties of the nanoparticles were evaluated by fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), energy-dispersive X-ray spectroscopy (EDS), scanning electron microscopy (SEM), transmission electron microscopy (TEM), dynamic Light Scattering (DLS), and zeta potential analyses. Cell viability and nuclear damage were investigated by the MTT and Hoechst staining assays, respectively. Flow cytometry analysis was performed to determine the frequency of the necrotic and apoptotic cells as well as cell cycle analysis of the nanoparticles-treated cells. Physicochemical characterization showed that the synthesized particles were spherical, without impurities, in a size range of 38-83 nm, with DLS size and zeta potential of 295.7 nm and -27.7 mV, respectively. BiFe2O4@Ag nanoparticles were considerably more toxic for the gastric cancer cells (AGS cell line) than HEK293 normal cells with IC50 of 67 and 117 µg/ml, respectively. Treatment of AGS cells with the nanoparticles led to a remarkable increase in the percentage of late apoptosis (38.5 folds) and cell necrosis (13.4 folds) and caused cell cycle arrest, mainly at the S phase. Also, nuclear fragmentation and apoptotic bodies were observed in the gastric cancer cells treated with the nanoparticles. This study represents BiFe2O4@Ag as a novel anticancer candidate against gastric cancer that can induce cell apoptosis through DNA damage and inhibition of cell cycle progression.

Knock down of APE1 suppressed gastric cancer metastasis via improving immune disorders caused by myeloid-derived suppressor cells.

Gastric cancer is a highly immunogenic malignancy. Immune tolerance facilitated by myeloid-derived suppressor cells (MDSCs) has been implicated in gastric cancer resistance mechanisms. The potential role of APE1 in regulating gastric cancer metastasis by targeting MDSCs remains uncertain. In this study, the plasmid Plxpsp-mGM-CSF was used to induce high expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) in GES-1 cells. For tumor transplantation experiments, AGS, AGS+GM-CSF and AGS+GM-CSF-siAPE1 cell lines were established by transfection, followed by subcutaneous implantation of tumor cells. MDSCs, Treg cells, IgG, CD3 and CD8 levels were assessed. Transfection with siAPE1 significantly inhibited tumor growth compared to the AGS+GM-CSF group. APE1 gene knockdown modulated the immune system in gastric cancer mice, characterized by a decrease in MDSCs and an increase in Treg cells, IgG, CD3 and CD8. In addition, APE1 gene knockdown resulted in decreased levels of pro-MDSC cytokines (HGF, CCL5, IL-6, CCL12). Furthermore, APE1 gene knockdown inhibited proliferation, migration and invasion of AGS and MKN45 cells. AGS-GM-CSF cell transplantation increased MDSC levels and accelerated tumor growth, whereas APE1 knockdown reduced MDSC levels, inhibited tumor growth and attenuated inflammatory infiltration in gastric cancer tissues. Strategies targeting the APE1/MDSC axis offer a promising approach to the prevention and treatment of gastric cancer, providing new insights into its management.