The Effect of Aflatoxin B1 on Tumor-Related Genes and Phenotypic Characters of MCF7 and MCF10A Cells.

The fungal toxin aflatoxin B1 (AB1) and its reactive intermediate, aflatoxin B1-8, 9 epoxide, could cause liver cancer by inducing DNA adducts. AB1 exposure can induce changes in the expression of several cancer-related genes. In this study, the effect of AB1 exposure on breast cancer MCF7 and normal breast MCF10A cell lines at the phenotypic and epigenetic levels was investigated to evaluate its potential in increasing the risk of breast cancer development. We hypothesized that, even at low concentrations, AB1 can cause changes in the expression of important genes involved in four pathways, i.e., p53, cancer, cell cycle, and apoptosis. The transcriptomic levels of BRCA1, BRCA2, p53, HER1, HER2, cMyc, BCL2, MCL1, CCND1, WNT3A, MAPK1, MAPK3, DAPK1, Casp8, and Casp9 were determined in MCF7 and MCF10A cells. Our results illustrate that treating both cells with AB1 induced cytotoxicity and apoptosis with reduction in cell viability in a concentration-dependent manner. Additionally, AB1 reduced reactive oxygen species levels. Phenotypically, AB1 caused cell-cycle arrest at G1, hypertrophy, and increased cell migration rates. There were changes in the expression levels of several tumor-related genes, which are known to contribute to activating cancer pathways. The effects of AB1 on the phenotype and epigenetics of both MCF7 and MCF10A cells associated with cancer development observed in this study suggest that AB1 is a potential risk factor for developing breast cancer.

Transcriptomic and proteomic profiling revealed reprogramming of carbon metabolism in acetate-grown human pathogen Candida glabrata.

BACKGROUND: Emergence of Candida glabrata, which causes potential life-threatening invasive candidiasis, has been widely associated with high morbidity and mortality. In order to cause disease in vivo, a robust and highly efficient metabolic adaptation is crucial for the survival of this fungal pathogen in human host. In fact, reprogramming of the carbon metabolism is believed to be indispensable for phagocytosed C. glabrata within glucose deprivation condition during infection. METHODS: In this study, the metabolic responses of C. glabrata under acetate growth condition was explored using high-throughput transcriptomic and proteomic approaches. RESULTS: Collectively, a total of 1482 transcripts (26.96%) and 242 proteins (24.69%) were significantly up- or down-regulated. Both transcriptome and proteome data revealed that the regulation of alternative carbon metabolism in C. glabrata resembled other fungal pathogens such as Candida albicans and Cryptococcus neoformans, with up-regulation of many proteins and transcripts from the glyoxylate cycle and gluconeogenesis, namely isocitrate lyase (ICL1), malate synthase (MLS1), phosphoenolpyruvate carboxykinase (PCK1) and fructose 1,6-biphosphatase (FBP1). In the absence of glucose, C. glabrata shifted its metabolism from glucose catabolism to anabolism of glucose intermediates from the available carbon source. This observation essentially suggests that the glyoxylate cycle and gluconeogenesis are potentially critical for the survival of phagocytosed C. glabrata within the glucose-deficient macrophages. CONCLUSION: Here, we presented the first global metabolic responses of C. glabrata to alternative carbon source using transcriptomic and proteomic approaches. These findings implicated that reprogramming of the alternative carbon metabolism during glucose deprivation could enhance the survival and persistence of C. glabrata within the host.

The assimilation of different carbon sources in Candida albicans: Fitness and pathogenicity.

Candida albicans is a commensal yeast commonly found on the skin and in the body. However, in immunocompromised individuals, the fungi could cause local and systemic infections. The carbon source available plays an important role in the establishment of C. albicans infections. The fungi's ability to assimilate a variety of carbon sources plays a vital role in its colonization, and by extension, its fitness and pathogenicity, as it often inhabits niches that are glucose-limited but rich in alternative carbon sources. A difference in carbon sources affect the growth and mating of C. albicans, which contributes to its pathogenicity as proliferation helps the fungi colonize its environment. The carbon source also affects its metabolism and signaling pathways, which are integral parts of the fungi's fitness and pathogenicity. As a big percentage of the carbon assimilated by C. albicans goes to cell wall biogenesis, the availability of different carbon sources will result in cell walls with variations in rigidity, adhesion, and surface hydrophobicity. In addition to the biofilm formation of the fungi, the carbon source also influences whether the fungi grow in yeast- or mycelial-form. Both forms play different roles in C. albicans's infection process. A better understanding of the role of the carbon sources in C. albicans's pathogenicity would contribute to more effective treatment solutions for fungal infections.

Identification of Alkaloid Compounds Arborinine and Graveoline from Ruta angustifolia (L.) Pers for their Antifungal Potential against Isocitrate lyase (ICL1) gene of Candida albicans.

Candida albicans has been reported globally as the most widespread pathogenic species contributing candidiasis from superficial to systemic infections in immunocompromised individuals. Their metabolic adaptation depends on glyoxylate cycle to survive in nutrient-limited host. The long term usage of fungistatic drugs and the lack of cidal drugs frequently result in strains that could resist commonly used antifungals and display multidrug resistance (MDR). In search of potential therapeutic intervention and novel fungicidals, we have explored a plant alkaloids, namely arborinine and graveoline for its antifungal potential. Alkaloids belongs to Rutaceae family have been reported with numerous antimicrobial activities. In this study, we aimed to isolate and identify the antifungal active alkaloids of R. angustifolia and assess antifungal effect targeting C. albicans isocitrate lyase (ICL) gene which regulates isocitrate lyase, key enzyme in glyoxylate cycle contributing to the virulence potential of C. albicans. Alkaloids were extracted by bioassay guided isolation technique which further identified by TLC profile and compared with the standard through HPLC and NMR analysis. The antifungal activities of the extracted alkaloids were quantified by means of MIC (Minimum Inhibitory Concentration). The gene expression of the targeted gene upon treatment was analysed using RT-qPCR and western blot. Additionally, this study looked at the drug-likeness and potential toxicity effect of the active alkaloid compounds in silico analysis. Spectroscopic analysis showed that the isolated active alkaloids were characterized as acridone, furoquinoline, 4-quinolone known as arborinine and graveoline. Results showed that each compound significantly inhibited the growth of C. albicans at the dose of 250 to 500 µg/mL which confirm its antifungal activity. Each alkaloid was found to successfully downregulate the expression of both ICL1 gene CaIcl1 protein. Finally, ADMET analysis suggests a good prediction of chemical properties, namely absorption, distribution, metabolism, excretion and toxicity (ADMET) that will contribute in drug discovery and development later on.

ß-Caryophyllene Induces Apoptosis and Inhibits Angiogenesis in Colorectal Cancer Models.

Beta-Caryophyllene (BCP), a naturally occurring sesquiterpene abundantly found in cloves, hops, and cannabis, is the active candidate of a relatively new group of vascular-inhibiting compounds that aim to block existing tumor blood vessels. Previously, we have reported the anti-cancer properties of BCP by utilizing a series of in-vitro anti-tumor-related assays using human colorectal carcinoma cells. The present study aimed to investigate the effects of BCP on in-vitro, ex-vivo, and in-vivo models of anti-angiogenic assays and evaluate its anti-cancer activity in xenograft tumor (both ectopic and orthotopic) mice models of human colorectal cancer. Computational structural analysis and an apoptosis antibody array were also performed to understand the molecular players underlying this effect. BCP exhibited strong anti-angiogenic activity by blocking the migration of endothelial cells, tube-like network formation, suppression of vascular endothelial growth factor (VEGF) secretion from human umbilical vein endothelial cells and sprouting of rat aorta microvessels. BCP has a probable binding at Site#0 on the surface of VEGFR2. Moreover, BCP significantly deformed the vascularization architecture compared to the negative control in a chick embryo chorioallantoic membrane assay. BCP showed a remarkable reduction in tumor size and fluorescence molecular tomography signal intensity in all the mice treated with BCP, in a dose-dependent relationship, in ectopic and orthotopic tumor xenograft models, respectively. The histological analysis of the tumor from BCP-treated mice revealed a clear reduction of the density of vascularization. In addition, BCP induced apoptosis through downregulation of HSP60, HTRA, survivin, and XIAP, along with the upregulation of p21 expressions. These results suggest that BCP acts at multiple stages of angiogenesis and could be used as a promising therapeutic candidate to halt the growth of colorectal tumor cells.

Physiologically Relevant Alternative Carbon Sources Modulate Biofilm Formation, Cell Wall Architecture, and the Stress and Antifungal Resistance of Candida glabrata.

Flexibility in carbon metabolism is pivotal for the survival and propagation of many human fungal pathogens within host niches. Indeed, flexible carbon assimilation enhances pathogenicity and affects the immunogenicity of Candida albicans. Over the last decade, Candida glabrata has emerged as one of the most common and problematic causes of invasive candidiasis. Despite this, the links between carbon metabolism, fitness, and pathogenicity in C. glabrata are largely unexplored. Therefore, this study has investigated the impact of alternative carbon metabolism on the fitness and pathogenic attributes of C. glabrata. We confirm our previous observation that growth on carbon sources other than glucose, namely acetate, lactate, ethanol, or oleate, attenuates both the planktonic and biofilm growth of C. glabrata, but that biofilms are not significantly affected by growth on glycerol. We extend this by showing that C. glabrata cells grown on these alternative carbon sources undergo cell wall remodeling, which reduces the thickness of their ß-glucan and chitin inner layer while increasing their outer mannan layer. Furthermore, alternative carbon sources modulated the oxidative stress resistance of C. glabrata as well as the resistance of C. glabrata to an antifungal drug. In short, key fitness and pathogenic attributes of C. glabrata are shown to be dependent on carbon source. This reaffirms the perspective that the nature of the carbon sources available within specific host niches is crucial for C. glabrata pathogenicity during infection.

Pleurotus sajor-caju can be used to synthesize silver nanoparticles with antifungal activity against Candida albicans.

BACKGROUND: Green synthesis of silver nanoparticles (AgNPs) has become widely practiced worldwide. In this study, AgNPs were synthesized using a hot-water extract of the edible mushroom Pleurotus sajor-caju. The product, PSC-AgNPs, was characterized by using UV-visible spectra, dynamic light scattering analysis, transmission electron microscopy (TEM), X-ray diffraction (XRD) and Fourier transform infrared (FTIR) spectrometry. To assess its antifungal activity against Candida albicans, gene transcription and protein expression analyses were conducted for CaICL1 and its product, ICL, using real-time quantitative polymerase chain reaction and western blot, respectively. RESULTS: PSC-AgNPs with an average particle size of 11.68 nm inhibited the growth of the pathogenic yeast C. albicans. Values for minimum inhibitory concentration and minimum fungicidal concentration were 250 and 500 mg L-1 , respectively. TEM images revealed that the average particle size of PSC-AgNPs was 16.8 nm, with the values for zeta potential and the polydispersity index being -8.54 mV and 0.137, respectively. XRD and FTIR spectra showed PSC-AgNPs to have a face-centered cubic crystalline structure. The polysaccharides and amino acid residues present in P. sajor-caju extract were found to be involved in reducing Ag+ to AgNP. Both CaICL1 transcription and ICL protein expression were found to be suppressed in the cells treated with PSC-AgNPs as compared with the control. CONCLUSION: Our PSC-AgNP preparation makes for a promising antifungal agent that can downregulate isocitrate lyase. © 2017 Society of Chemical Industry.

Construction and Cloning of Reporter-Tagged Replicon cDNA for an In Vitro Replication Study of Murine Norovirus-1 (MNV-1).

BACKGROUND: A norovirus maintains its viability, infectivity and virulence by its ability to replicate. However, the biological mechanisms of the process remain to be explored. In this work, the NanoLuc™ Luciferase gene was used to develop a reporter-tagged replicon system to study norovirus replication. METHODS: The NanoLuc™ Luciferase reporter protein was engineered to be expressed as a fusion protein for MNV-1 minor capsid protein, VP2. The foot-and-mouth disease virus 2A (FMDV2A) sequence was inserted between the 3'end of the reporter gene and the VP2 start sequence to allow co-translational 'cleavage' of fusion proteins during intracellular transcript expression. Amplification of the fusion gene was performed using a series of standard and overlapping polymerase chain reactions. The resulting amplicon was then cloned into three readily available backbones of MNV-1 cDNA clones. RESULTS: Restriction enzyme analysis indicated that the NanoLucTM Luciferase gene was successfully inserted into the parental MNV-1 cDNA clone. The insertion was further confirmed by using DNA sequencing. CONCLUSION: NanoLuc™ Luciferase-tagged MNV-1 cDNA clones were successfully engineered. Such clones can be exploited to develop robust experimental assays for in vitro assessments of viral RNA replication.

Scopoletin, an active principle of tree tobacco (Nicotiana glauca) inhibits human tumor vascularization in xenograft models and modulates ERK1, VEGF-A, and FGF-2 in computer model.

We recently reported the antineovascularization effect of scopoletin on rat aorta and identified its potential anti-angiogenic activity. Scopoletin could be useful as a systemic chemotherapeutic agent against angiogenesis-dependent malignancies if its antitumorigenic activity is investigated and scientifically proven using a suitable human tumor xenograft model. In the present study, bioassay-guided (anti-angiogenesis) phytochemical investigation was conducted on Nicotiana glauca extract which led to the isolation of scopoletin. Further, anti-angiogenic activity of scopoletin was characterized using ex vivo, in vivo and in silico angiogenesis models. Finally, the antitumorigenic efficacy of scopoletin was studied in human colorectal tumor xenograft model using athymic nude mice. For the first time, an in vivo anticancer activity of scopoletin was reported and characterized using xenograft models. Scopoletin caused significant suppression of sprouting of microvessels in rat aortic explants with IC50 (median inhibitory concentration) 0.06µM. Scopoletin (100 and 200mg/kg) strongly inhibited (59.72 and 89.4%, respectively) vascularization in matrigel plugs implanted in nude mice. In the tumor xenograft model, scopoletin showed remarkable inhibition on tumor growth (34.2 and 94.7% at 100 and 200mg/kg, respectively). Tumor histology revealed drastic reduction of the extent of vascularization. Further, immunostaining of CD31 and NG2 receptors in the histological sections confirmed the antivascular effect of scopoletin in tumor vasculature. In computer modeling, scopoletin showed strong ligand affinity and binding energies toward the following angiogenic factors: protein kinase (ERK1), vascular endothelial growth factor A (VEGF-A), and fibroblast growth factor 2 (FGF-2). These results suggest that the antitumor activity of scopoletin may be due to its strong anti-angiogenic effect, which may be mediated by its effective inhibition of ERK1, VEGF-A, and FGF-2.

Cat's whiskers (Orthosiphon stamineus) tea modulates arthritis pathogenesis via the angiogenesis and inflammatory cascade.

BACKGROUND: Orthosiphon stamineus is used traditionally to treat gout, arthritis, and inflammatory related conditions. The in vitro anti-inflammatory effects of the plant have been scientifically investigated. The goal of the present study was to evaluate the potential of the 50% ethanol extract of O. stamineus (EOS) to treat rheumatoid arthritis. METHODS: Anti-arthritic activity was assessed using the in vitro heat denaturation test and the (FCA)-induced arthritis model. Efficacy was assessed by measurements of paw edema and granulation, X-ray radiography, fluorescence molecular tomography (FMT), and histological evaluation. Levels of (TNF-α), interleukin-1 (IL-1), and (COX-1 and COX-2) were analyzed in vitro in lipopolysaccharide (LPS)-stimulated human macrophage (U937). TNF-α and IL-1 levels in the serum samples of arthritic rats were also measured using an ELISA kit. RESULTS: Treatment with EOS resulted in dose-dependent inhibition of paw edema in acute and chronic models of inflammation. It also inhibited significantly the production of TNF-α, IL-1 COX-1, and COX-2 in the LPS-stimulated U937 macrophages. EOS significantly suppressed FCA-induced paw edema as well as the serum levels of TNF-α and IL-1. X-rays of the synovial joint of the hind leg showed considerable improvement in joint integrity and recovery of tibia-talus bones from degeneration and osteoporotic lesions. Histology of proximal interphalangeal joints of EOS-treated animals showed obvious protection of cartilage and soft tissue. Finally, FMT analysis strongly supported the anti-arthritic effect of EOS. EOS had high phenolic and total flavonoid content as well as strong antioxidant activity. CONCLUSIONS: Results illustrated that the anti-arthritic properties of O. stamineus could be beneficial for prevention and management of rheumatoid arthritis and other chronic inflammatory disorders. Illustration of the Anti- arthritis efficacy of Orthosiphon Stamineus standardized extract.

Mutagenicity and preclinical safety assessment of the aqueous extract of Clinacanthus nutans leaves.

CONTEXT: Clinacanthus nutans (CN) is used traditionally for treating various illnesses. Robust safety data to support its use is lacking. OBJECTIVE: To evaluate the adverse effects of aqueous extract of CN leaves (AECNL). MATERIALS AND METHODS: The oral toxicity of the AECNL was tested following Organisation for Economic Co-operation and Development (OECD) guidelines. Mutagenicity (Ames test) of AECNL was evaluated using TA98 and TA100 Salmonella typhimurium strains. RESULTS: No mortality or morbidity was found in the animals upon single and repeated dose administration. However, significant body weight loss was observed at 2000 mg/kg during sub-chronic (90 d) exposure. In addition, increased eosinophil at 500 mg/kg and decreased serum alkaline phosphatase levels at 2000 mg/kg were observed in male rats. Variations in glucose and lipid profiles in treated groups were also observed compared to control. Ames test revealed no evidence of mutagenic or carcinogenic effects at 500 µg/well of AECNL. CONCLUSION: The median lethal dose (LD50) of the AECNL is >5000 mg/kg and the no-observed-adverse-effect level is identified to be greater than 2000 mg/kg/day in 90-d study.

Yeast Infection and Diabetes Mellitus among Pregnant Mother in Malaysia.

BACKGROUND: Vaginal yeast infection refers to irritation of the vagina due to the presence of opportunistic yeast of the genus Candida (mostly Candida albicans). About 75% of women will have at least one episode of vaginal yeast infection during their lifetime. Several studies have shown that pregnancy and uncontrolled diabetes increase the infection risk. Reproductive hormone fluctuations during pregnancy and elevated glucose levels characteristic of diabetes provide the carbon needed for Candida overgrowth and infection. The goal of this study was to determine the prevalence of vaginal yeast infection among pregnant women with and without diabetes. METHODS: This was a case-control study using cases reports from Kepala Batas Health Clinic, Penang State, Malaysia from 2006 to 2012. In total, 740 pregnant ladies were chosen as sample of which 370 were diabetic and 370 were non-diabetic cases. RESULTS: No relationship between diabetes and the occurrence of vaginal yeast infection in pregnant women was detected, and there was no significant association between infection and age group, race or education level. CONCLUSION: In conclusion, within radius of this study, vaginal yeast infection can occur randomly in pregnant women.

In vitro modulation of probiotic bacteria on the biofilm of Candida glabrata.

A conspicuous new concept of pathogens living as the microbial societies in the human host rather than free planktonic cells has raised considerable concerns among scientists and clinicians. Fungal biofilms are communities of cells that possess distinct characteristic such as increased resistance to the immune defence and antimycotic agents in comparison to their planktonic cells counterpart. Therefore, inhibition of the biofilm may represent a new paradigm for antifungal development. In this study, we aim to evaluate the in vitro modulation of vulvovaginal candidiasis (VVC)-causing Candida glabrata biofilms using probiotic lactobacilli strains. Probiotic Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 were shown to have completely inhibited C. glabrata biofilms and the results were corroborated by scanning electron microscopy (SEM), which revealed scanty structures of the mixed biofilms of C. glabrata and probiotic lactobacilli strains. In addition, biofilm-related C. glabrata genes EPA6 and YAK1 were downregulated in response to the probiotic lactobacilli challenges. The present study suggested that probiotic L. rhamnosus GR-1 and L. reuteri RC-14 strains inhibited C. glabrata biofilm by partially impeding the adherence of yeast cells and the effect might be contributed by the secretory compounds produced by these probiotic lactobacilli strains. Further investigations are required to examine and identify the biofilm inhibitory compounds and the mechanism of probiotic actions of these lactobacilli strains.

Stress adaptation in a pathogenic fungus.

Candida albicans is a major fungal pathogen of humans. This yeast is carried by many individuals as a harmless commensal, but when immune defences are perturbed it causes mucosal infections (thrush). Additionally, when the immune system becomes severely compromised, C. albicans often causes life-threatening systemic infections. A battery of virulence factors and fitness attributes promote the pathogenicity of C. albicans. Fitness attributes include robust responses to local environmental stresses, the inactivation of which attenuates virulence. Stress signalling pathways in C. albicans include evolutionarily conserved modules. However, there has been rewiring of some stress regulatory circuitry such that the roles of a number of regulators in C. albicans have diverged relative to the benign model yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe. This reflects the specific evolution of C. albicans as an opportunistic pathogen obligately associated with warm-blooded animals, compared with other yeasts that are found across diverse environmental niches. Our understanding of C. albicans stress signalling is based primarily on the in vitro responses of glucose-grown cells to individual stresses. However, in vivo this pathogen occupies complex and dynamic host niches characterised by alternative carbon sources and simultaneous exposure to combinations of stresses (rather than individual stresses). It has become apparent that changes in carbon source strongly influence stress resistance, and that some combinatorial stresses exert non-additive effects upon C. albicans. These effects, which are relevant to fungus-host interactions during disease progression, are mediated by multiple mechanisms that include signalling and chemical crosstalk, stress pathway interference and a biological transistor.

Prevalence of Bacterial Contamination when using a Diversion Pouch during Blood Collection: A Single Center Study in Malaysia.

BACKGROUND: The implementation of diversion pouches is to minimise the risk of bacterial contamination as the initial blood flow is prevented from entering primary bag collections as it is diverted into a pouch. This study was carried out to determine the prevalence of bacterial contamination in the diversion pouches used during blood collections in the Transfusion Department of Hospital Seberang Jaya, Penang, Malaysia. METHODS: BD Bactec™ Fx instrument detection system was performed on 702 samples of 20 mL of diverting blood in diversion pouch. The inocullum volume was 10 mL for both aerobic and anaerobic bottles cultures and incubated for 5 days in the BD Bactec™ Fx instrument. Positive sample was flagged by BD Bactec™ Fx instrument and subculture to identify the species of organism. RESULTS: The results showed that of 702 samples, 12 (1.7%) were contaminated. The bacterial species identified were coagulase negative Staphylococcus, Staphylococcus aureus and Gram positive Bacilli. CONCLUSION: The results strongly suggest that the usage of diversion pouch is of significant importance in reducing bacterial contamination during blood collection.

Potential shared pathogenic mechanisms between endometriosis and inflammatory bowel disease indicate a strong initial effect of immune factors.

Introduction: Over the past decades, immune dysregulation has been consistently demonstrated being common charactoristics of endometriosis (EM) and Inflammatory Bowel Disease (IBD) in numerous studies. However, the underlying pathological mechanisms remain unknown. In this study, bioinformatics techniques were used to screen large-scale gene expression data for plausible correlations at the molecular level in order to identify common pathogenic pathways between EM and IBD. Methods: Based on the EM transcriptomic datasets GSE7305 and GSE23339, as well as the IBD transcriptomic datasets GSE87466 and GSE126124, differential gene analysis was performed using the limma package in the R environment. Co-expressed differentially expressed genes were identified, and a protein-protein interaction (PPI) network for the differentially expressed genes was constructed using the 11.5 version of the STRING database. The MCODE tool in Cytoscape facilitated filtering out protein interaction subnetworks. Key genes in the PPI network were identified through two topological analysis algorithms (MCC and Degree) from the CytoHubba plugin. Upset was used for visualization of these key genes. The diagnostic value of gene expression levels for these key genes was assessed using the Receiver Operating Characteristic (ROC) curve and Area Under the Curve (AUC) The CIBERSORT algorithm determined the infiltration status of 22 immune cell subtypes, exploring differences between EM and IBD patients in both control and disease groups. Finally, different gene expression trends shared by EM and IBD were input into CMap to identify small molecule compounds with potential therapeutic effects. Results: 113 differentially expressed genes (DEGs) that were co-expressed in EM and IBD have been identified, comprising 28 down-regulated genes and 86 up-regulated genes. The co-expression differential gene of EM and IBD in the functional enrichment analyses focused on immune response activation, circulating immunoglobulin-mediated humoral immune response and humoral immune response. Five hub genes (SERPING1、VCAM1、CLU、C3、CD55) were identified through the Protein-protein Interaction network and MCODE.High Area Under the Curve (AUC) values of Receiver Operating Characteristic (ROC) curves for 5hub genes indicate the predictive ability for disease occurrence.These hub genes could be used as potential biomarkers for the development of EM and IBD. Furthermore, the CMap database identified a total of 9 small molecule compounds (TTNPB、CAY-10577、PD-0325901 etc.) targeting therapeutic genes for EM and IBD. Discussion: Our research revealed common pathogenic mechanisms between EM and IBD, particularly emphasizing immune regulation and cell signalling, indicating the significance of immune factors in the occurence and progression of both diseases. By elucidating shared mechanisms, our study provides novel avenues for the prevention and treatment of EM and IBD.

Machine learning-based integrated identification of predictive combined diagnostic biomarkers for endometriosis.

Background: Endometriosis (EM) is a common gynecological condition in women of reproductive age, with diverse causes and a not yet fully understood pathogenesis. Traditional diagnostics rely on single diagnostic biomarkers and does not integrate a variety of different biomarkers. This study introduces multiple machine learning techniques, enhancing the accuracy of predictive models. A novel diagnostic approach that combines various biomarkers provides a new clinical perspective for improving the diagnostic efficiency of endometriosis, holding significant potential for clinical application. Methods: In this study, GSE51981 was used as a test set, and 11 machine learning algorithms (Lasso, Stepglm, glmBoost, Support Vector Machine, Ridge, Enet, plsRglm, Random Forest, LDA, XGBoost, and NaiveBayes) were employed to construct 113 predictive models for endometriosis. The optimal model was determined based on the AUC values derived from various algorithms. These genes were then evaluated using nine machine learning algorithms (Random Forest, SVM, Gradient Boosting Machine, LASSO, XGB, NNET, Generalized Linear Model, KNN, and Decision Tree) to assess significance scores and identify diagnostic genes for each algorithm. The diagnostic value of these genes was further validated in external datasets from GSE7305, GSE11691, and GSE120103. Results: Analysis of the GSE51981 dataset revealed 62 DEGs. The Stepglm [Both] and plsRglm algorithms identified 30 genes with the most potential using the AUC evaluation. Subsequently, nine machine learning algorithms were applied to select diagnostic genes, leading to the identification of five key diagnostic genes using the LASSO algorithm. The ADAT1 gene exhibited the best single-gene predictive performance, with an AUC of 0.785. A combination of genes (FOS, EPHX1, DLGAP5, PCSK5, and ADAT1) achieves an AUC of 0.836 in the test dataset. Moreover, these genes consistently exhibited an AUC exceeding 0.78 in all validation datasets, demonstrating superior predictive performance. Furthermore, correlation analysis with immune infiltration strengthened their predictive value by demonstrating the close relationship of the diagnostic genes with immune infiltrating cells. Conclusion: A combination of biomarkers consisting of FOS, EPHX1, DLGAP5, PCSK5, and ADAT1 can serve as a diagnostic tool for endometriosis, enhancing diagnostic efficiency. The association of these genes with immune infiltrating cells reveals their potential role in the pathogenesis of endometriosis, providing new insights for early detection and treatment.

The Anticancer Potential of Psidium guajava (Guava) Extracts.

The fruits, leaves, and bark of the guava (Psidium guajava) tree have traditionally been used to treat a myriad of ailments, especially in the tropical and subtropical regions. The various parts of the plant have been shown to exhibit medicinal properties, such as antimicrobial, antioxidant, anti-inflammatory, and antidiabetic activities. Recent studies have shown that the bioactive phytochemicals of several parts of the P. guajava plant exhibit anticancer activity. This review aims to present a concise summary of the in vitro and in vivo studies investigating the anticancer activity of the plant against various human cancer cell lines and animal models, including the identified phytochemicals that contributes to their activity via the different mechanisms. In vitro growth and cell viability studies, such as the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, the sulforhodamine B (SRB) assay, and the trypan blue exclusion test, were conducted using P. guajava extracts and their biomolecules to assess their effects on human cancer cell lines. Numerous studies have showcased that the P. guajava plant and its bioactive molecules, especially those extracted from its leaves, selectively suppress the growth of human cancer cells without cytotoxicity against the normal cells. This review presents the potential of the extracts of P. guajava and the bioactive molecules derived from it, to be utilized as a feasible alternative or adjuvant treatment for human cancers. The availability of the plant also contributes towards its viability as a cancer treatment in developing countries.

ATP-induced cell death: a novel hypothesis for osteoporosis.

ATP-induced cell death has emerged as a captivating realm of inquiry with profound ramifications in the context of osteoporosis. This study unveils a paradigm-shifting hypothesis that illuminates the prospective involvement of ATP-induced cellular demise in the etiology of osteoporosis. Initially, we explicate the morphological attributes of ATP-induced cell death and delve into the intricacies of the molecular machinery and regulatory networks governing ATP homeostasis and ATP-induced cell death. Subsequently, our focus pivots towards the multifaceted interplay between ATP-induced cellular demise and pivotal cellular protagonists, such as bone marrow-derived mesenchymal stem cells, osteoblasts, and osteoclasts, accentuating their potential contributions to secondary osteoporosis phenotypes, encompassing diabetic osteoporosis, glucocorticoid-induced osteoporosis, and postmenopausal osteoporosis. Furthermore, we probe the captivating interplay between ATP-induced cellular demise and alternative modalities of cellular demise, encompassing apoptosis, autophagy, and necroptosis. Through an all-encompassing inquiry into the intricate nexus connecting ATP-induced cellular demise and osteoporosis, our primary goal is to deepen our comprehension of the underlying mechanisms propelling this malady and establish a theoretical bedrock to underpin the development of pioneering therapeutic strategies.

Adenosine triphosphate induced cell death: Mechanisms and implications in cancer biology and therapy.

Adenosine triphosphate (ATP) induced cell death (AICD) is a critical cellular process that has garnered substantial scientific interest for its profound relevance to cancer biology and to therapeutic interventions. This comprehensive review unveils the intricate web of AICD mechanisms and their intricate connections with cancer biology. This review offers a comprehensive framework for comprehending the multifaceted role of AICD in the context of cancer. This is achieved by elucidating the dynamic interplay between systemic and cellular ATP homeostasis, deciphering the intricate mechanisms governing AICD, elucidating its intricate involvement in cancer signaling pathways, and scrutinizing validated key genes. Moreover, the exploration of AICD as a potential avenue for cancer treatment underscores its essential role in shaping the future landscape of cancer therapeutics.