Kefir peptides mitigate bleomycin-induced pulmonary fibrosis in mice through modulating oxidative stress, inflammation and gut microbiota.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive and life-threatening lung disease with high mortality rates. The limited availability of effective drugs for IPF treatment, coupled with concerns regarding adverse effects and restricted responsiveness, underscores the need for alternative approaches. Kefir peptides (KPs) have demonstrated antioxidative, anti-inflammatory, and antifibrotic properties, along with the capability to modulate gut microbiota. This study aims to investigate the impact of KPs on bleomycin-induced pulmonary fibrosis. METHODS: Mice were treated with KPs for four days, followed by intratracheal injection of bleomycin for 21 days. Comprehensive assessments included pulmonary functional tests, micro-computed tomography (µ-CT), in vivo image analysis using MMPsense750, evaluation of inflammation- and fibrosis-related gene expression in lung tissue, and histopathological examinations. Furthermore, a detailed investigation of the gut microbiota community was performed using full-length 16 S rRNA sequencing in control mice, bleomycin-induced fibrotic mice, and KPs-pretreated fibrotic mice. RESULTS: In KPs-pretreated bleomycin-induced lung fibrotic mice, notable outcomes included the absence of significant bodyweight loss, enhanced pulmonary functions, restored lung tissue architecture, and diminished thickening of inter-alveolar septa, as elucidated by morphological and histopathological analyses. Concurrently, a reduction in the expression levels of oxidative biomarkers, inflammatory factors, and fibrotic indicators was observed. Moreover, 16 S rRNA sequencing demonstrated that KPs pretreatment induced alterations in the relative abundances of gut microbiota, notably affecting Barnesiella_intestinihominis, Kineothrix_alysoides, and Clostridium_viride. CONCLUSIONS: Kefir peptides exerted preventive effects, protecting mice against bleomycin-induced lung oxidative stress, inflammation, and fibrosis. These effects are likely linked to modifications in the gut microbiota community. The findings highlight the therapeutic potential of KPs in mitigating pulmonary fibrosis and advocate for additional exploration in clinical settings.

In Utero Cell Treatment of Hemophilia A Mice via Human Amniotic Fluid Mesenchymal Stromal Cell Engraftment.

Hemophilia is a genetic disorder linked to the sex chromosomes, resulting in impaired blood clotting due to insufficient intrinsic coagulation factors. There are approximately one million individuals worldwide with hemophilia, with hemophilia A being the most prevalent form. The current treatment for hemophilia A involves the administration of clotting factor VIII (FVIII) through regular and costly injections, which only provide temporary relief and pose inconveniences to patients. In utero transplantation (IUT) is an innovative method for addressing genetic disorders, taking advantage of the underdeveloped immune system of the fetus. This allows mesenchymal stromal cells to play a role in fetal development and potentially correct genetic abnormalities. The objective of this study was to assess the potential recovery of coagulation disorders in FVIII knockout hemophilia A mice through the administration of human amniotic fluid mesenchymal stromal cells (hAFMSCs) via IUT at the D14.5 fetal stage. The findings revealed that the transplanted human cells exhibited fusion with the recipient liver, with a ratio of approximately one human cell per 10,000 mouse cells and produced human FVIII protein in the livers of IUT-treated mice. Hemophilia A pups born to IUT recipients demonstrated substantial improvement in their coagulation issues from birth throughout the growth period of up to 12 weeks of age. Moreover, FVIII activity reached its peak at 6 weeks of age, while the levels of FVIII inhibitors remained relatively low during the 12-week testing period in mice with hemophilia. In conclusion, the results indicated that prenatal intrahepatic therapy using hAFMSCs has the potential to improve clotting issues in FVIII knockout mice, suggesting it as a potential clinical treatment for individuals with hemophilia A.

Coating-Free Culture Medium for Establishing and Maintaining Human Induced Pluripotent Stem Cells.

Cell expansion of human pluripotent stem cells (hPSCs) commonly depends on Matrigel as a coating matrix on two-dimensional (2D) culture plates and 3D microcarriers. However, the xenogenic Matrigel requires sophisticated quality-assurance processes to meet clinical requirements. In this study, we develop an innovative coating-free medium for expanding hPSCs. The xenofree medium supports the weekend-free culture and competitive growth of hPSCs on several cell culture plastics without an additional pre-coating process. The pluripotent stemness of the expanded cells is stably sustained for more than 10 passages, featured with high pluripotent marker expressions, normal karyotyping, and differentiating capacity for three germ layers. The expression levels of some integrins are reduced, compared with those of the hPSCs on Matrigel. This medium also successfully supports the clonal expansion and induced pluripotent stem cell establishment from mitochondrial-defective MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) patient's peripheral blood mononuclear cells. This innovative hPSC medium provides a straightforward scale-up process for producing clinical-orientated hPSCs by excluding the conventional coating procedure.

Kefir peptides attenuate atherosclerotic vascular calcification and osteoporosis in atherogenic diet-fed ApoE -/- knockout mice.

Aims: Vascular calcification (VC) and osteoporosis were previously considered two distinct diseases. However, current understanding indicates that they share common pathogenetic mechanisms. The available medicines for treating VC and osteoporosis are limited. We previously demonstrated that kefir peptides (KPs) alleviated atherosclerosis in high-fat diet (HFD)-induced apolipoprotein E knockout (ApoE -/- ) mice. The present study further addressed the preventive effects of KPs on VC and osteoporosis in ApoE -/- mice fed a high-cholesterol atherogenic diet (AD). Main methods: Seven-week-old ApoE -/- and wild-type C57BL/6 mice were randomly divided into five groups (n = 6). The development of VC and osteoporosis was evaluated after AD feeding for 13 weeks in KP-treated ApoE -/- mice and compared to C57BL/6 and ApoE -/- mice fed a standard chow diet (CD). Key findings: The results indicated that KP-treated ApoE -/- mice exhibited lower serum total cholesterol, oxidized low-density lipoprotein (ox-LDL), malondialdehyde (MDA) levels, and serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and creatine kinase (CK) activities, which suggested that KPs prevented hyperlipidemia and possible damages to the liver and muscle in ApoE -/- mice. KPs reduced serum tumor necrosis factor-α (TNF-α) and the local expression of TNF-α, IL-1ß, and macrophage-specific CD68 markers in aortic tissues, which suggested that KPs inhibited inflammatory responses in AD-fed ApoE -/- mice. KPs reduced the deposition of lipid, collagen, and calcium minerals in the aortic roots of AD-fed ApoE -/- mice, which suggested that KPs inhibited the calcific progression of atherosclerotic plaques. KPs exerted osteoprotective effects in AD-fed ApoE -/- mice, which was evidenced by lower levels of the bone resorption marker CTX-1 and higher levels of the bone formation marker P1NP. KPs improved cortical bone mineral density and bone volume and reduced trabecular bone loss in femurs. Significance: The present data suggested that KPs attenuated VC and osteoporosis by reducing oxidative stress and inflammatory responses in AD-fed ApoE -/- mice. Our findings contribute to the application of KPs as preventive medicines for the treatment of hyperlipidemia-induced vascular and bone degeneration.

Kefir peptides ameliorate osteoporosis in AKR1A1 knockout mice with vitamin C deficiency by promoting osteoblastogenesis and inhibiting osteoclastogenesis.

The AKR1A1 protein is a member of the aldo-keto reductase superfamily that catalyzes the transformation of D-glucuronate to L-gulonate in the synthesis of L-ascorbic acid (vitamin C, Vit C). We previously demonstrated that AKR1A1 knockout mice (AKR1A1eGFP/eGFP) with Vit C deficiency exhibited aberrant bone formation and osteoporosis. In this study, we aimed to evaluate the osteoprotective effects of kefir peptides (KPs) in AKR1A1eGFP/eGFP mice and uncover the underlying mechanism of KPs in the modulation of bone remodeling. Six male CD-1 mice and 24 male AKR1A1eGFP/eGFP mice were used in this study, in which the AKR1A1eGFP/eGFP mice were randomly divided into four groups (n = 6). KPs treatment for 12 weeks exerted several effects in AKR1A1eGFP/eGFP mice including the reduction of serum proinflammatory cytokines (IL-1ß, IL-6, TNF-α), bone resorption markers (CTX-1, RANKL), and the increase of serum bone formation markers (P1NP, OPG, OC). µ-CT analysis indicated that KPs prevented the bone loss in the femurs of AKR1A1eGFP/eGFP mice by significantly increasing the trabecular parameters of bone mineral density, bone volume and bone number. Nanoindentation analysis demonstrated that KPs enhanced the elasticity and hardness of femoral cortical bones in AKR1A1eGFP/eGFP mice. KPs promoted bone marrow mesenchymal stem cells (BMMSCs)-derived osteoblast differentiation and mineralization by upregulating positive regulators of osteoblastogenesis (Runx2, ß-catenin, BMP-2, NFATc1). Conversely, KPs inhibited bone marrow macrophages (BMMs)-derived osteoclast differentiation and bone resorption, which was demonstrated by the facts that KPs suppressed RANKL-induced p38, NF-κB, Akt, PLCγ2 and CREB-1 phosphorylation, decreased the nuclear translocation of NFATc1 and c-Fos. Our findings demonstrate the efficacy of KPs in the prevention of osteoporosis in AKR1A1eGFP/eGFP mice and also unveil the dual effects of KPs in osteogenic promotion and osteoclastic inhibition. This study supports the use of KPs as nutritional supplements for the prevention of osteoporosis.

Telomeres and Cancer.

Telomeres cap the ends of eukaryotic chromosomes and are indispensable chromatin structures for genome protection and replication. Telomere length maintenance has been attributed to several functional modulators, including telomerase, the shelterin complex, and the CST complex, synergizing with DNA replication, repair, and the RNA metabolism pathway components. As dysfunctional telomere maintenance and telomerase activation are associated with several human diseases, including cancer, the molecular mechanisms behind telomere length regulation and protection need particular emphasis. Cancer cells exhibit telomerase activation, enabling replicative immortality. Telomerase reverse transcriptase (TERT) activation is involved in cancer development through diverse activities other than mediating telomere elongation. This review describes the telomere functions, the role of functional modulators, the implications in cancer development, and the future therapeutic opportunities.

Using IVIM Parameters to Differentiate Prostate Cancer and Contralateral Normal Tissue through Fusion of MRI Images with Whole-Mount Pathology Specimen Images by Control Point Registration Method.

The intravoxel incoherent motion (IVIM) model may enhance the clinical value of multiparametric magnetic resonance imaging (mpMRI) in the detection of prostate cancer (PCa). However, while past IVIM modeling studies have shown promise, they have also reported inconsistent results and limitations, underscoring the need to further enhance the accuracy of IVIM modeling for PCa detection. Therefore, this study utilized the control point registration toolbox function in MATLAB to fuse T2-weighted imaging (T2WI) and diffusion-weighted imaging (DWI) MRI images with whole-mount pathology specimen images in order to eliminate potential bias in IVIM calculations. Sixteen PCa patients underwent prostate MRI scans before undergoing radical prostatectomies. The image fusion method was then applied in calculating the patients' IVIM parameters. Furthermore, MRI scans were also performed on 22 healthy young volunteers in order to evaluate the changes in IVIM parameters with aging. Among the full study cohort, the f parameter was significantly increased with age, while the D* parameter was significantly decreased. Among the PCa patients, the D and ADC parameters could differentiate PCa tissue from contralateral normal tissue, while the f and D* parameters could not. The presented image fusion method also provided improved precision when comparing regions of interest side by side. However, further studies with more standardized methods are needed to further clarify the benefits of the presented approach and the different IVIM parameters in PCa characterization.

KFP-1, a Novel Calcium-Binding Peptide Isolated from Kefir, Promotes Calcium Influx Through TRPV6 Channels.

INTRODUCTION: Kefir is an acidic and alcoholic fermented milk product with multiple health-promoting benefits. A previous study demonstrated that kefir enhanced calcium absorption in intestinal Caco-2 cells. In this study, kefir-fermented peptide-1 (KFP-1) is isolated from the kefir peptide fraction, and its function as a calcium-binding peptide is characterized. METHODS AND RESULTS: KFP-1 was identified as a 17-residue peptide with a sequence identical to that of κ-casein (residues 138-154) in milk protein. KFP-1 is demonstrated to promote calcium influx in Caco-2 and IEC-6 small intestinal cells in a concentration-dependent manner. TRPV6, but not L-type voltage-gated calcium channels, is associated with the calcium influx induced by KFP-1. An in vitro calcium binding assay indicates that the full-length KFP-1 peptide has a higher calcium-binding capacity than the two truncated KFP-1 peptides, KFP-1∆C5 and KFP-1C5. Alexa Fluor 594 labeling shows that KFP-1 is taken up by Caco-2 cells and interacts with calcium ions and TRPV6 protein. Moreover, KFP-1 is found moderately resistant to pepsin and pancreatin digestions and enhanced calcium uptake by intestinal enterocytes in vivo. CONCLUSION: These data suggest that KFP-1, a novel calcium-binding peptide, binds extracellular calcium ions and enters Caco-2 and IEC-6 cells, and promotes calcium uptake through TRPV6 calcium channels. The present study is of great importance for developing kefir-derived metal ion-binding peptides as functional nutraceutical additives.

Dehydroxyhispolon Methyl Ether, A Hispolon Derivative, Inhibits WNT/ß-Catenin Signaling to Elicit Human Colorectal Carcinoma Cell Apoptosis.

Colorectal cancer (CRC) is the fourth leading cause of cancer mortality worldwide. Aberrant activation of WNT/ß-catenin signaling present in the vast majority of CRC cases is indispensable for CRC initiation and progression, and thus is a promising target for CRC therapeutics. Hispolon is a fungal-derived polyphenol with a pronounced anticancer effect. Several hispolon derivatives, including dehydroxyhispolon methyl ether (DHME), have been chemically synthesized for developing lead molecules with stronger anticancer activity. Herein, a DHME-elicited anti-CRC effect with the underlying mechanism is reported for the first time. Specifically, DHME was found to be more cytotoxic than hispolon against a panel of human CRC cell lines, while exerting limited toxicity to normal human colon cell line CCD 841 CoN. Additionally, the cytotoxic effect of DHME appeared to rely on inducing apoptosis. This notion was evidenced by DHME-elicited upregulation of poly (ADP-ribose) polymerase (PARP) cleavage and a cell population positively stained by annexin V, alongside the downregulation of antiapoptotic B-cell lymphoma 2 (BCL-2), whereas the blockade of apoptosis by the pan-caspase inhibitor z-VAD-fmk attenuated DHME-induced cytotoxicity. Further mechanistic inquiry revealed the inhibitory action of DHME on ß-catenin-mediated, T-cell factor (TCF)-dependent transcription activity, suggesting that DHME thwarted the aberrantly active WNT/ß-catenin signaling in CRC cells. Notably, ectopic expression of a dominant-active ß-catenin mutant (∆N90-ß-catenin) abolished DHME-induced apoptosis while also restoring BCL-2 expression. Collectively, we identified DHME as a selective proapoptotic agent against CRC cells, exerting more potent cytotoxicity than hispolon, and provoking CRC cell apoptosis via suppression of the WNT/ß-catenin signaling axis.

Gene Modified CAR-T Cellular Therapy for Hematologic Malignancies.

With advances in the understanding of characteristics of molecules, specific antigens on the surface of hematological malignant cells were identified and multiple therapies targeting these antigens as neoplasm treatments were developed. Among them, chimeric antigen receptor (CAR) T-cell therapy, which got United States Food and Drug Administration (FDA) approval for relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) as well as for recurrent acute lymphoblastic leukemia (ALL) within the past five years, and for r/r mantle cell lymphoma (MCL) this year, represents one of the most rapidly evolving immunotherapies. Nevertheless, its applicability to other hematological malignancies, as well as its efficacy and persistence are fraught with clinical challenges. Currently, more than one thousand clinical trials in CAR T-cell therapy are ongoing and its development is changing rapidly. This review introduces the current status of CAR T-cell therapy in terms of the basic molecular aspects of CAR T-cell therapy, its application in hematological malignancies, adverse reactions during clinical use, remaining challenges, and future utilization.

Kefir peptides alleviate particulate matter <4 µm (PM4.0)-induced pulmonary inflammation by inhibiting the NF-κB pathway using luciferase transgenic mice.

Kefir peptides, generated by kefir grain fermentation of milk proteins, showed positive antioxidant effects, lowered blood pressure and modulated the immune response. In this study, kefir peptide was evaluated regarding their anti-inflammatory effects on particulate matter <4 µm (PM4.0)-induced lung inflammation in NF-κB-luciferase+/+ transgenic mice. The lungs of mice under 20 mg/kg or 10 mg/kg PM4.0 treatments, both increased significantly the generation of reactive oxygen species (ROS) and inflammatory cytokines; increased the protein expression levels of p-NF-κB, NLRP3, caspase-1, IL-1ß, TNF-α, IL-6, IL-4 and α-SMA. Thus, we choose the 10 mg/kg of PM4.0 for animal trials; the mice were assigned to four treatment groups, including control group (saline treatment), PM4.0 + Mock group (only PM4.0 administration), PM4.0 + KL group (PM4.0 + 150 mg/kg low-dose kefir peptide) and PM4.0 + KH group (PM4.0 + 500 mg/kg high-dose kefir peptide). Data showed that treatment with both doses of kefir peptides decreased the PM4.0-induced inflammatory cell infiltration and the expression of the inflammatory mediators IL-lß, IL-4 and TNF-α in lung tissue by inactivating NF-κB signaling. The oral administrations of kefir peptides decrease the PM4.0-induced lung inflammation process through the inhibition of NF-κB pathway in transgenic luciferase mice, proposing a new clinical application to particulate matter air pollution-induced pulmonary inflammation.

A mini-pig model for evaluating the efficacy of autologous platelet patches on induced acute full thickness wound healing.

BACKGROUND: Autologous platelet concentrates are currently widely used across different areas of regenerative medicine in order to enhance the wound healing process. Although several protocols for platelet concentrates are available, their application remains difficult due to different protocols leading to distinct products with vary potential biological uses. In this study, we attempted to make a platelet patch (PP) using mixtures of platelet rich plasma (PRP) injection and platelet rich fibrin (PRF) to promote wound repair and regeneration. RESULTS: Experiments were performed using a full-thickness wound model in mini-pigs. Autologous PRP, PRF and PP were prepared immediately before creating four full-thickness skin wounds in pigs. We quantified concentrations of platelets, thrombin and various growth factors to ensure that the desired effect can be produced. After surgery, hydrocolloid dressing, PRP injection, PRF and PP was applied to experimentally induced wounds. Application efficacy was evaluated by measurement of wound sizes and histological examination. The results indicated that all wounds showed a significant size reduction. Wound repair efficacy in response to PP treatment exhibited enhanced re-epithelialization compared to PRP and PRF (P < 0.05) and higher wound contraction than did PRF application (P < 0.05). Another aspect, experiment using DsRed transgenic pigs as blood donors demonstrated that leucocytes in PP were incorporated into the wound bed at the end of the study, suggesting that leucocytes activity is stimulated in response to PP application. Safety of the experimental processes was also confirmed by examination of organ biopsies. CONCLUSIONS: We used a mini-pig model to evaluate the efficacy of lab-made PP on induced full-thickness wound healing. Results demonstrated that application of one piece of PP was enough to obtain comparable efficacy versus general utilization of PRP or PRF for wound care. We also demonstrated that leucocytes in PP were incorporated into the wound bed and no safety concerns have been found in the whole experiment. This study provides a novel and feasible method for veterinary or clinical wound care.

Targeting Telomerase and ATRX/DAXX Inducing Tumor Senescence and Apoptosis in the Malignant Glioma.

Glioblastoma multiforme (GBM) is a type of brain tumor that is notorious for its aggressiveness and invasiveness, and the complete removal of GBM is still not possible, even with advanced diagnostic strategies and extensive therapeutic plans. Its dismal prognosis and short survival time after diagnosis make it a crucial public health issue. Understanding the molecular mechanisms underlying GBM may inspire novel and effective treatments against this type of cancer. At a molecular level, almost all tumor cells exhibit telomerase activity (TA), which is a major means by which they achieve immortalization. Further studies show that promoter mutations are associated with increased TA and stable telomere length. Moreover, some tumors and immortalized cells maintain their telomeres with a telomerase-independent mechanism termed the "alternative lengthening of telomeres" (ALT), which relates to the mutations of the α-thalassemia/mental retardation syndrome X-linked protein (ATRX), the death-domain associated protein (DAXX) and H3.3. By means of the mutations of the telomerase reverse transcriptase (TERT) promoter and ATRX/DAXX, cancers can immortalize and escape cell senescence and apoptosis. In this article, we review the evidence for triggering GBM cell death by targeting telomerase and the ALT pathway, with an extra focus on a plant-derived compound, butylidene phthalide (BP), which may be a promising novel anticancer compound with good potential for clinical applications.

Prolonged length of stay for acute hospital admissions as the increasing of age: A nationwide population study for Taiwan's patients with cerebral palsy.

BACKGROUND: Studies investigating reasons for the admission and the associated lengths of stay (LOSs) among cerebral palsy (CP) patients are limited. This study determined common reasons for acute hospitalizations and the LOSs among children, adolescents, and young adults with CP. METHODS: We performed a secondary analysis of data. CP patients aged 4-32.9 years were identified by CP registry in the catastrophic illness patient registry of the 2010 Taiwan National Health Insurance Research Database. Data of admission claims from 2010 to 2011 were analyzed. Reasons for admissions were identified according to International Classification of Diseases codes. Common reasons, frequencies of admissions for each reason, and LOSs were reported. RESULTS: Pneumonia, other respiratory problems, and epilepsy were the top three reasons for admissions in all groups. Other common reasons in all groups were sepsis, other respiratory infections, and gastrointestinal problems. The reasons specific to children included orthopedic issues; ear, nose, and throat problems; and urinary tract infections (UTIs). In youths, scoliosis, and contractures, were unique reasons. In young adults, UTIs, blood problems, and mental illness, were special reasons. Most admission reasons appeared to prolong LOS, and the LOS exhibited an increasing trend as age increased. CONCLUSION: The results implied that patients with CP are more susceptible to most disease invasions. Our results also suggest that the current care system in Taiwan is unsuitable for patients with CP. These results can be used as guidance for planning effective multidisciplinary assessments in the future.

Increased risk of incident nasopharyngeal carcinoma with exposure to air pollution.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a race-specific malignancy. The nasal cavity is the main entry point for air pollutants or poisonous gases into the human body. However, the risk of NPC in populations exposed to air pollution remains unknown. METHODS: We combined data from the Taiwan Air Quality Monitoring Database (TAQMD) and the Longitudinal Health Insurance Database (LHID) to assess the risk of NPC in a population exposed to air pollution. RESULTS: Multivariate analysis revealed positive trends for the association between the risk of NPC and exposure to air pollution. After adjusting for potential covariates, the risk of developing NPC increased with the increase in nitrogen dioxide (NO2) and fine particulate matter (PM2.5) exposure concentrations from 1.39 to 2.28 and 2.01 to 1.97, respectively, compared to the risks at the lowest concentration levels. CONCLUSIONS: We identified a significant risk of NPC in a population exposed to air pollution. However, this study had several limitations. Moreover, additional experimental and clinical studies on the associations between environmental factors and NPC risk are warranted.

The Molecular Mechanisms of Plant-Derived Compounds Targeting Brain Cancer.

Glioblastoma multiforme (GBM) is one of the most aggressive and malignant forms of brain tumors. Despite recent advances in operative and postoperative treatments, it is almost impossible to perform complete resection of these tumors owing to their invasive and diffuse nature. Several natural plant-derived products, however, have been demonstrated to have promising therapeutic effects, such that they may serve as resources for anticancer drug discovery. The therapeutic effects of one such plant product, n-butylidenephthalide (BP), are wide-ranging in nature, including impacts on cancer cell apoptosis, cell cycle arrest, and cancer cell senescence. The compound also exhibits a relatively high level of penetration through the blood-brain barrier (BBB). Taken together, its actions have been shown to have anti-proliferative, anti-chemoresistance, anti-invasion, anti-migration, and anti-dissemination effects against GBM. In addition, a local drug delivery system for the subcutaneous and intracranial implantation of BP wafers that significantly reduce tumor size in xenograft models, as well as orthotopic and spontaneous brain tumors in animal models, has been developed. Isochaihulactone (ICL), another kind of plant product, possesses a broad spectrum of pharmacological activities, including impacts on cancer cell apoptosis and cell cycle arrest, as well as anti-proliferative and anti-chemoresistance effects. Furthermore, these actions have been specifically shown to have cancer-fighting effects on GBM. In short, the results of various studies reviewed herein have provided substantial evidence indicating that BP and ICH are promising novel anticancer compounds with good potential for clinical applications.

The impact of prenatal group B streptococcus screening as a national health policy in Taiwan.

OBJECTIVE: There was no national data on group B streptococcus (GBS) infections in Taiwan. Until 2012, when prenatal GBS screening was introduced to obstetric practices as a national health policy aimed at reducing neonatal GBS infections. The purpose of this study was to examine the impact of this national health policy on the incidence of maternal GBS colonization and neonatal GBS infection rate. Relatedly, the clinical characteristics of neonatal GBS infection were investigated to determine the correlations between the incidence of maternal GBS colonization and the neonatal GBS infection rate. MATERIALS AND METHODS: This population-based nationwide study used data for 2012-2013 from the National Health Insurance Research Database of Taiwan. A total of 789 newly diagnosed pregnant women with genital GBS infection were recruited. RESULTS: The maternal GBS screening rate was 93.2%. The maternal colonization rate of GBS was around 8.2%, and the incidence of neonatal GBS infection was 22.6%. The data indicate that no sepsis was developed in any of the cases, while fever was found in 3 cases (3/179, 1.7%) and UTI was found in 1 case (1/179, 0.6%). CONCLUSIONS: We conclude that a policy calling for universal maternal rectovaginal cultures for GBS with intrapartum antibiotic prophylaxis is a good national policy for reducing morbidity due to GBS infections in neonates in Taiwan.

The identification of the TRPM8 channel on primary culture of human nasal epithelial cells and its response to cooling.

BACKGROUND: It has been proposed that the transient receptor potential (TRP) channel Melastatin 8 (TRPM8) is a cold-sensing TRP channel. However, its presence and its role in the nasal cavity have not yet been fully studied. METHODS: Immunohistology was used to study TRPM8 receptors in both the nasal mucosa tissue and the primary cultures of human nasal cells. Cells from primary cultures were immunostained with antibodies to TRPM8, mucin, cytokeratin (CK)-14, CK-18, and vimentin. Western blotting and real-time polymerase chain reaction (PCR) were used to determine the physiological role of TRPM8 in mucus production in the nasal cavity, with and without its agonist and antagonist. RESULTS: The TRPM8 is clearly present in the epithelium, mucous glands, and vessels. No obvious TRPM8-immunoreactive cells were detected in the connective tissue. Immunostaining of cytospin preparations showed that epithelial cells test positive for CK-14, CK-18, TRPM8, and mucin 5AC (MUC5AC). Fibroblastic cells are stained negative for TRPM8. Secreted mucins in the cultured supernatant are detected after exposure to menthol and moderate cooling to 24°C. Both induce a statistically significant increase in the level of MUC5AC mRNA and mucin production. BCTC, a TRPM8 antagonist, has a statistically significant inhibitory effect on MUC5AC mRNA expression and MUC5AC protein production that is induced by menthol and moderate cooling to 24°C. CONCLUSIONS: The study demonstrates that TRPM8 is present in the nasal epithelium. When it is activated by moderate cooling to 24°C or menthol, TRPM8 induces the secretion of mucin. This study shows that TRPM8 channels are important regulators of mucin production. Therefore, TRPM8 antagonists could be used to treat refractory rhinitis.

Risk analysis of colorectal cancer incidence by gene expression analysis.

BACKGROUND: Colorectal cancer (CRC) is one of the leading cancers worldwide. Several studies have performed microarray data analyses for cancer classification and prognostic analyses. Microarray assays also enable the identification of gene signatures for molecular characterization and treatment prediction. OBJECTIVE: Microarray gene expression data from the online Gene Expression Omnibus (GEO) database were used to to distinguish colorectal cancer from normal colon tissue samples. METHODS: We collected microarray data from the GEO database to establish colorectal cancer microarray gene expression datasets for a combined analysis. Using the Prediction Analysis for Microarrays (PAM) method and the GSEA MSigDB resource, we analyzed the 14,698 genes that were identified through an examination of their expression values between normal and tumor tissues. RESULTS: Ten genes (ABCG2, AQP8, SPIB, CA7, CLDN8, SCNN1B, SLC30A10, CD177, PADI2, and TGFBI) were found to be good indicators of the candidate genes that correlate with CRC. From these selected genes, an average of six significant genes were obtained using the PAM method, with an accuracy rate of 95%. The results demonstrate the potential of utilizing a model with the PAM method for data mining. After a detailed review of the published reports, the results confirmed that the screened candidate genes are good indicators for cancer risk analysis using the PAM method. CONCLUSIONS: Six genes were selected with 95% accuracy to effectively classify normal and colorectal cancer tissues. We hope that these results will provide the basis for new research projects in clinical practice that aim to rapidly assess colorectal cancer risk using microarray gene expression analysis.

Estrogen Enhances the Expression of the Multidrug Transporter Gene ABCG2-Increasing Drug Resistance of Breast Cancer Cells through Estrogen Receptors.

BACKGROUND: Multidrug resistance is a major obstacle in the successful therapy of breast cancer. Studies have proved that this kind of drug resistance happens in both human cancers and cultured cancer cell lines. Understanding the molecular mechanisms of drug resistance is important for the reasonable design and use of new treatment strategies to effectively confront cancers. RESULTS: In our study, ATP-binding cassette sub-family G member 2 (ABCG2), adenosine triphosphate (ATP) synthase and cytochrome c oxidase subunit VIc (COX6C) were over-expressed more in the MCF-7/MX cell line than in the normal MCF7 cell line. Therefore, we believe that these three genes increase the tolerance of MCF7 to mitoxantrone (MX). The data showed that the high expression of COX6C made MCF-7/MX have more stable on mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) expression than normal MCF7 cells under hypoxic conditions. The accumulation of MX was greater in the ATP-depleted treatment MCF7/MX cells than in normal MCF7/MX cells. Furthermore, E2 increased the tolerance of MCF7 cells to MX through inducing the expression of ABCG2. However, E2 could not increase the expression of ABCG2 after the inhibition of estrogen receptor α (ERα) in MCF7 cells. According to the above data, under the E2 treatment, MDA-MB231, which lacks ER, had a higher sensitivity to MX than MCF7 cells. CONCLUSIONS: E2 induced the expression of ABCG2 through ERα and the over-expressed ABCG2 made MCF7 more tolerant to MX. Moreover, the over-expressed ATP synthase and COX6c affected mitochondrial genes and function causing the over-expressed ABCG2 cells pumped out MX in a concentration gradient from the cell matrix. Finally lead to chemoresistance.