CS12192, a novel JAK3/JAK1/TBK1 inhibitor, attenuates autoimmune dermatoses in murine models.

OBJECTIVE: Autoimmune dermatosis (AID) occurs when the body's immune system attacks skin or tissue, leading to various types of skin disorders or injuries. Recent studies show that Janus kinases (JAKs) play critical roles in autoimmune diseases including AID by regulating multiple cytokine signaling pathways. CS12192, a novel JAK3/JAK1/TBK1 inhibitor, has been reported to exert ameliorative effects in rheumatoid arthritis. However, the efficacy of CS12192 on AID is undetermined. This study aims to investigate the therapeutic efficacy of CS12192 on psoriasis (PSO), systemic lupus erythematosus (SLE) and atopic dermatitis (AD) in mouse models. METHODS: Interleukin-23 (IL-23)-induced PSO model, spontaneous SLE model of MRL/MpJ-Faslpr/J (MRL/lpr) mice, and oxazolone (OXA) and dinitrochlorobenzene (DNCB)-induced murine AD models were used for the evaluation of curative effects of CS12192, respectively. The skin lesion, biochemical parameters, ear thickness, ear weight and histopathology were assessed accordingly. RESULTS: In PSO model, mice treated with CS12192 show reduced ear thickness and ear weight as compared with vehicle. In SLE model, CS12192 ameliorates cutaneous parameters such as lymphadenectasis and skin lesion but not systematic parameters such as proteinuria concentration and score, serum dsDNA and BUN concentration. In AD models, CS12192 dose-dependently improves ear swelling and reduces histological scores, exerting equivalent efficacy with baricitinib, a marketed JAK1/JAK2 inhibitor. CONCLUSION: Our findings suggest that the novel JAK3/JAK1/TBK1 inhibitor CS12192 is potentially to alleviate autoimmune dermatosis.

Application of MALDI-TOF MS to rapid identification of anaerobic bacteria.

BACKGROUND: Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) has been rapidly developed and widely used as an analytical technique in clinical laboratories with high accuracy in microorganism identification. OBJECTIVE: To validate the efficacy of MALDI-TOF MS in identification of clinical pathogenic anaerobes. METHODS: Twenty-eight studies covering 6685 strains of anaerobic bacteria were included in this meta-analysis. Fixed-effects models based on the P-value and the I-squared were used for meta-analysis to consider the possibility of heterogeneity between studies. Statistical analyses were performed by using STATA 12.0. RESULTS: The identification accuracy of MALDI-TOF MS was 84% for species (I2 = 98.0%, P < 0.1), and 92% for genus (I2 = 96.6%, P < 0.1). Thereinto, the identification accuracy of Bacteroides was the highest at 96% with a 95% CI of 95-97%, followed by Lactobacillus spp., Parabacteroides spp., Clostridium spp., Propionibacterium spp., Prevotella spp., Veillonella spp. and Peptostreptococcus spp., and their correct identification rates were all above 90%, while the accuracy of rare anaerobic bacteria was relatively low. Meanwhile, the overall capabilities of two MALDI-TOF MS systems were different. The identification accuracy rate was 90% for VITEK MS vs. 86% for MALDI biotyper system. CONCLUSIONS: Our research showed that MALDI-TOF-MS was satisfactory in genus identification of clinical pathogenic anaerobic bacteria. However, this method still suffers from different drawbacks in precise identification of rare anaerobe and species levels of common anaerobic bacteria.

Functional variations of the TLR4 gene in association with chronic obstructive pulmonary disease and pulmonary tuberculosis.

OBJECTIVE: Chronic obstructive pulmonary disease (COPD) and pulmonary tuberculosis (PTB) share a number of common risk factors, including innate immunity-related genetic factors. In the present study, we compared the role of genetic variations of the TLR4 gene in susceptibility to COPD and PTB and illuminated the underlying molecular mechanism of functional single-nucleotide polymorphisms (SNPs). METHODS: A population-based case control study was performed in a Chinese Han population and included 152 COPD cases, 1601 PTB cases and 1727 controls. Five SNPs in the TLR4 gene (rs10759932, rs2737190, rs7873784, rs11536889, and rs10983755) were genotyped using TaqMan allelic discrimination technology. We estimated the effects of SNPs using the odds ratio (OR) together with 95% confidence interval (CI). Dual-luciferase reporter vectors expressing different genotypes of SNPs were constructed and transfected into the human HEK 293 T cell line to explore their effects on potential transcription activity. RESULTS: After Bonferroni correction, the genetic polymorphisms of all five SNPs remained significantly associated with COPD, while rs10759932 and rs2737190 were also associated with PTB. Compared with rs10759932-TT, individuals carrying TC (OR: 0.42, 95% CI: 0.28-0.64) or CC (OR: 0.24, 95% CI: 0.09-0.63) had a significantly reduced risk of COPD. However, individuals carrying TC (OR: 1.28, 95% CI: 1.11-1.49) or CC (OR: 1.26, 95% CI: 0.98-1.62) had an increased risk of PTB. The OR (95% CI) for allele rs10759932-C was 0.45 (0.32-0.62) for COPD and 1.18 (1.07-1.32) for PTB. For rs2737190, heterozygous AG was related to a decreased risk of COPD (OR: 0.32, 95% CI: 0.21-0.49) and an increased risk of PTB (OR: 1.30, 95% CI: 1.11-1.52). The dual-luciferase reporter assay showed decreased transcription activity caused by rs10759932-C and rs2737190-G. CONCLUSION: Genetic polymorphisms of rs10759932 and rs2737190 in TLR4 are significantly related to both COPD and PTB but with inverse effects. The altered transcription activity caused by mutations in these two loci may partly explain the observed relationship.

MicroRNA-21 regulates the ERK/NF-κB signaling pathway to affect the proliferation, migration, and apoptosis of human melanoma A375 cells by targeting SPRY1, PDCD4, and PTEN.

This study aims to explore the effects of microRNA-21 (miR-21) and ERK/NF-κB signaling pathway on human melanoma A375 cells. The melanoma tissues and adjacent normal tissues were obtained from 45 melanoma patients. qRT-PCR was conducted to quantify the expression of miR-21 and the gene mRNA expressions. Human melanoma A375 cells were divided into the Mock, negative control (NC), miR-21 inhibitors, miR-21 inhibitors + siRNA-SPRY1, miR-21 inhibitors + siRNA-PDCD4, and miR-21 inhibitors + siRNA-PTEN groups. Western blotting was used to determine protein expressions. CCK8 assay and Transwell assay were performed to evaluate the proliferation, migration, and invasion of A375 cells. Annexin V/propidium iodide double staining was adopted to detect cell apoptosis. MiR-21 expression was higher in melanoma tissues than in adjacent tissues, while the mRNA and protein expressions of SPRY1, PDCD4, and PTEN were lower in melanoma tissues than in adjacent tissues. Compared with the Mock and NC groups, the miR-21 inhibitors group exhibited increased expressions of SPRY1, PDCD4, and PTEN and decreased expressions of ERK, p-ERK, NF-κB p65, and p-NF-κB p65. After transfection of miR-21 inhibitors, the proliferation, migration, and invasion of A375 cells were inhibited, while the apoptosis of A375 cells was promoted. However, the effects of miR-21 inhibitors on the growth, migration, invasion, and apoptosis of A375 cells were reversed after transfection of siRNA-SPRY1, siRNA-PDCD4, or siRNA-PTEN. MiR-21 can promote the proliferation, migration, and inhibit the apoptosis of human melanoma A375 cells by inhibiting SPRY1, PDCD4, and PTEN via ERK/NF-κB signaling pathway. © 2016 Wiley Periodicals, Inc.

The prognostic role of MAC30 in advanced gastric cancer patients receiving platinum-based chemotherapy.

AIM: We aimed to investigate a practical profile of MAC30 on chemotherapeutic response in gastric cancer (GC). PATIENTS & METHODS: We elected 87 GC patients receiving platinum-based chemotherapy in this study. MAC30 levels in tumor and adjuvant nontumor tissues were confirmed via reverse transcription-PCR to identify the clinical profile in GC and the correlation with therapeutic response. RESULTS: We found elevated MAC30 in GC compared with the matched adjacent nontumor tissues. GC with enhanced MAC30 exhibited poorer survival by Kaplan-Meier analysis and poor response to adjuvant platinum-based chemotherapy. A multivariate analysis showed that MAC30 was an independent prognostic factor of overall survival in GC receiving platinum-based chemotherapy. CONCLUSION: MAC30 could play as a potential biomarker for prognosis of GC with platinum-based chemotherapy.

Apoptosis Induction and Imaging of Cadmium-Telluride Quantum Dots with Wogonin in Multidrug-Resistant Leukemia K562/A02 Cell.

Wogonin (5,7-dihydroxy-8-methoxyflavone) is one of the active components of flavonoids isolated from Scutellariae radix and possesses antitumor effect against leukemia. Cadmium-telluride quantum dots (CdTe-QDs) are a kind of nanoparticles with great potential in functioning as an efficient drug delivery vector in biomedical research. In this study, we investigated the synergistic effect of CdTe-QDs with Wogonin on the induction of apoptosis using drug-resistant human leukemia KA cells. Flow cytometry analysis, assay of morphology under electron microscope, quantitative analysis of tumor volume and micro-CT imaging demonstrated that compared with that by pure CdTe-QDs or wogonin, the apoptosis rate increased sharply when treated wirh CdTe-QDs together with wogonin on KA cells. These results proved that the nanocomposites readily overcame the barrier of drug-resistance and provoked cell apoptosis in vitro and in vivo by facilitating the interaction between wogonin and KA cells. As known to all, it is an inevitable tendency that new effective therapies will take the place of conventional chemotherapy and radiotherapy presenting significant disadvantages. According to this article, CdTe-QD combined with wogonin is a possible alternative for some cancer treatments.

The changes of HRV in refractory epilepsy: The potential index to predict the onset of epilepsy in children.

In this study, we examine the potential of heart rate variability (HRV) as an efficient tool for predicting the onset of epilepsy in children. We totally collected 53 seizures EEG and ECG data using Video - EEG - ECG monitoring system. We then separated the ECG data into three segments: ten-minute before onset of each seizure, five-minute before onset of each seizure, and five-minute from the onset of each seizure. After the HRV parameters in all segments were calculated, we compared the differences between pre-ictal period and ictal period. We found that the values of meanHR, LF and LF/HF were greater in onset period. And the values of meanRR and the HF were less in ictal period. And it presented the similar changes when seizures occurred in the daytime and seizures occurred in the nighttime. In brief, we found that the sympathetic nervous system was under a more active status during onset period. We speculated that the HRV parameters such as the LF, HF or LF/HF could have potential to predict the seizures in children with epilepsy.

Serum miR-21 is a diagnostic and prognostic marker of primary central nervous system lymphoma.

The standard of care for primary central nervous system lymphoma (PCNSL) is systemic chemotherapy with or without whole brain radiotherapy or intrathecal chemotherapy. In contrast to treatment for other brain tumors, efforts at resection are discouraged. However, it is difficult to distinguish PCNSL from other central nervous system tumors which need aggressive surgery in both CT and MRI images. In this study, we assessed whether measurement of miR-21 in the serum could improve diagnostic accuracy for PCNSL. We found that serum miR-21 significantly increased in PCNSL when compared with other brain tumors and normal controls in both test and validation cohort. Further, serum miR-21 could discriminate PCNSL from all controls with an area under the curve of 0.930 for the test cohort and 0.916 for the validation cohort in ROC analysis. Similar results were also obtained in the validation cohort. Besides, raised concentrations of miR-21 in serum could differentiate PCNSL from glioblastoma under the curve of 0.883 for the test cohort and 0.851 for the validation cohort in ROC analysis. Furthermore, Kaplan-Meier curve analysis (p = 0.03 for test cohort and 0.02 for validation cohort) and Multivariable Cox regression (p = 0.03 for test cohort and 0.01 for validation cohort) revealed serum miR-21 as an independent and powerful predictor of overall survival. Taken together, our results demonstrate that serum miR-21 may represent a diagnostic and prognostic marker for PCNSL.

Communication molecules (ncRNAs) mediate tumor-associated macrophage polarization and tumor progression.

Non-coding RNAs play important roles in tumor cells and macrophages and participate in their communication as messengers. Non-coding RNAs have an impact in tumor cell proliferation, migration, and apoptosis, and they also regulate the differentiation and regulation of immune cells. In macrophages, they stimulate the polarization of macrophages into M1 or M2 by regulating proteins related to signaling pathways; in tumor cells, non-coding RNAs can enter macrophages through exosomes and affect the latter polarization. The polarization of macrophages further regulates the biological functions of cancer cells. The direction of macrophage polarization determines tumor progression, angiogenesis and drug resistance. This often creates a feedback loop. Non-coding RNAs act as bridges between tumor cells and macrophages to regulate the balance of the tumor microenvironment. We reviewed the signaling pathways related to macrophage polarization and the regulatory mechanisms of non-coding RNA in tumor-associated macrophages M1 and M2, and discussed the potential applications and prospects of exosome engineering.

Bifidobacterium animalis subsp. lactis boosts neonatal immunity: unravelling systemic defences against Salmonella.

Bifidobacterium animalis subsp. lactis may be a useful probiotic intervention for regulating neonatal intestinal immune responses and counteracting Salmonella infection. However, recent research has focused on intestinal immunity, leaving uncertainties regarding the central, peripheral, and neural immune responses in neonates. Therefore, this study investigated the role and mechanisms of B. animalis subsp. lactis in the systemic immune responses of neonatal rats following Salmonella infection. Through extremely early pretreatment with B. animalis subsp. lactis (6 hours postnatal), the neonatal rat gut microbiota was effectively reshaped, especially the Bifidobacterium community. In the rats pretreated with B. animalis subsp. lactis, Salmonella was less prevalent in the blood, liver, spleen, and intestines following infection. The intervention promoted T lymphocyte subset balance in the spleen and thymus and fostered neurodevelopment and neuroimmune balance in the brain. Furthermore, metabolic profiling showed a strong correlation between the metabolites in the serum and colon, supporting the view that B. animalis subsp. lactis pretreatment influences the systemic immune response by modifying the composition and metabolism of the gut microbiota. Overall, the results imply that B. animalis subsp. lactis pretreatment, through the coordinated regulation of colonic and serum metabolites, influences the systemic immune responses of neonatal rats against Salmonella infection.

Targeting ASK1 by CS17919 alleviates kidney- and liver-related diseases in murine models.

BACKGROUND: Apoptosis signal-regulating kinase 1 (ASK1) is a MAP3K kinase in the MAPK signaling pathway activated by stressors and triggers downstream biological effects such as inflammation and apoptosis; therefore, inhibition of ASK1 kinase activity can protect cells from pathological injury. In this study, we designed and synthesized a novel selective ASK1 inhibitor, CS17919, and investigated its pharmacological effects in various animal models of metabolic injury. METHODS: First, we validated the ability of CS17919 to inhibit ASK1 in vitro and then tested the safety profile of CS17919 in cell lines compared with Selonsertib (GS-4997), a phase III ASK1 inhibitor. We then conducted pharmacokinetic (PK) studies in mice. Finally, we tested the in vivo efficacy of CS17919 in murine models of chronic kidney disease (CKD) and non-alcoholic steatohepatitis (NASH). RESULTS: Compared to GS-4997, CS17919 demonstrated comparable inhibition of ASK1 in vitro, exhibited lower toxicity, and provided greater protection in palmitic acid-treated LO2 cells. CS17919 also showed pronounced pharmacokinetic properties such as a high plasma concentration. In the unilateral ureteral obstruction model (UUO), CS17919 and GS-4997 preserved kidney function and showed a non-significant tendency to alleviate kidney fibrosis. In the diabetic kidney disease (DKD) model, CS17919 significantly improved serum creatinine and glomerular sclerosis. In the NASH model, the combination of CS17919 and a THRß agonist (CS27109) was found to significantly improve liver inflammation and substantially reduced liver fibrosis. CONCLUSIONS: CS17919 showed cell protective, anti-inflammatory, and antifibrotic effects in vitro and in vivo, suggesting its therapeutic potential for metabolic-related kidney and liver diseases.

Clinical efficacy of Fufang Yinhua Jiedu (FFYH) granules in mild COVID-19 and its anti-SARS-CoV-2 mechanism by blocking autophagy through inhibiting the AKT/mTOR signaling pathway.

Background: Fufang Yinhua Jiedu (FFYH) granules are recommended for treating coronavirus pneumonia (COVID-19) in China. However, its anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) activity and clinical efficacy against COVID-19 remain to be confirmed. Aims: Our study aimed to investigate the anti-SARS-CoV-2 effect and potential mechanism of FFYH. Materials and Methods: The activity of FFYH against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was evaluated via cell pathogenic effects, immunoblotting, immunofluorescence staining, and qRT-PCR. The potential mechanism of FFYH against SARS-CoV-2 was investigated by immunoblotting. One head-to-head randomized controlled trial was designed to evaluate the clinical efficacy of FFYH in mild COVID-19. Two hundred patients were randomly recruited to receive either FFYH or LHQW (Lianhua Qingwen) granules. Results: The in vitro results indicated that FFYH effectively inhibited SARS-CoV-2 replication by suppressing CPE and decreasing viral RNA and protein expression. A time-of-drug-addition assay confirmed that FFYH mainly targeted the binding and replication stages of the SARS-CoV-2 life cycle. Mechanistic studies revealed that blocking SARS-CoV-2-triggered autophagy may be the primary mechanism by which FFYH protects against SARS-CoV-2 infection by regulating the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway. Clinical results confirmed that FFYH effectively shortened the recovery time of clinical symptoms and viral nucleic acid negativity, improved abnormal hematology parameters, and controlled excessive cytokine responses in mild COVID-19 patients. Subgroup analysis revealed that FFYH improved the recovery time of clinical symptoms, improved hematological parameters, and controlled excessive cytokine storms to a greater extent in the mild COVID-19 male subgroup, abnormal hematology subgroup, and 32-42-year-old subgroup than in the corresponding LHQW subgroup (P < 0.05). No patients progressed to severe or critical cases. Conclusion: Our results indicate that FFYH not only has good anti-viral activity against SARS-CoV-2 but also has significant efficacy against COVID-19, indicating that FFYH may be a novel complementary option for treating COVID-19.

Bifidobacterium breve CCFM1025 Improves Sleep Quality via Regulating the Activity of the HPA Axis: A Randomized Clinical Trial.

Psychobiotics, a newly identified category of probiotics primarily targeting the gut-brain axis, exhibit tremendous potential in improving sleep quality. In this study, the clinical trial was registered in advance (identifier: NO. ChiCTR2300067806). Forty participants who were diagnosed with stress-induced insomnia were chosen and randomly divided into two groups: one received CCFM1025 at a dose of 5 × 109 CFU (n = 20), while the other was administered a placebo (n = 20), over a period of four weeks. The results revealed that compared to the placebo group (pre: M = 10.10, SD = 2.292; post: M = 8.650, SD = 2.793; pre vs. post: F (1, 38) = 15.41, p = 0.4316), the CCFM1025-treated group exhibited a significant decrease in Pittsburgh Sleep Quality Index (PSQI) scores from baseline (pre: M = 11.60, SD = 3.169; post: M = 7.750, SD = 3.697, F (1, 38) = 15.41, p = 0.0007). Furthermore, the administration of CCFM1025 was associated with a more pronounced reduction in stress marker concentrations. This effect could potentially be linked to changes in serum metabolites induced by the probiotic treatment, notably daidzein. In conclusion, B. breve CCFM1025 demonstrates promise as a psychobiotic strain for enhancing sleep quality.

Tumor-derived CircRNA_102191 promotes gastric cancer and facilitates M2 macrophage polarization.

BACKGROUND: Gastric cancer is a common malignant tumor of the digestive tract and the fourth leading cause of death from cancer-related diseases. In recent years, many studies have found that circular RNAs play an important role in cancer. Tumor-associated macrophages (TAMs) are also critical for tumor progression. OBJECTIVE: This study examined the role of circRNA_102191 in gastric cancer progression. METHODS: The relative mRNA levels were determined by qRT-PCR. Western blotting and ELISA were used to detect the protein levels. In vitro proliferation was assessed using CCK8 and clonogenic assays. The migration and invasion of cell lines were assessed by transwell-based assays. The interactions between molecules were detected using a luciferase reporter assay. M0 macrophages were induced with PMA. M1 macrophages were induced with LPS and IFN-γ, and M2 macrophages were induced with IL-4. RESULTS: The expression of circRNA_102191 was enhanced significantly in gastric cancer cell lines and clinical tumor tissues. CircRNA_102191 promotes gastric cancer cell progression by regulating miR-493-3p and its downstream target gene XPR1. CircRNA_102191 can enhance the EMT process of gastric cancer cells by promoting the M2 polarization of macrophages. CONCLUSION: CircRNA_102191 promotes the biological function of gastric cancer cells by regulating the miR-493-3p/XPR1 axis and M2 macrophage polarization.

Molecular features, biological behaviors and clinical implications of m5C RNA methylation modification regulators in gastrointestinal cancers.

Epitranscriptome studies have shown that critical RNA modifications drive tumorigenicity; however, the role of 5-methylcytosine (m5C) RNA methylation remains poorly understood. We extracted 17 m5C regulators and clustered distinct m5C modification patterns by consensus clustering analysis. Gene set variation and single-sample gene set enrichment analysis were applied to quantify functional analysis and immune infiltration. The least absolute shrinkage and selection operator was employed to develop a prognostic risk score. Kaplan-Meier with log-rank test was used for survival analysis. Differential expression analysis was performed with the "limma" R package. Wilcoxon signed ranked test or Kruskal-Wallis test was used to compare groups. We observed that m5C RNA methylation was commonly upregulated in gastrointestinal cancer and related to prognosis. Clusters were identified for m5C patterns, with distinct immune infiltrations and functional pathways. The risk scores of m5C regulators were independent risk factors. Differentially expressed mRNAs (DEmRNAs) in m5C clusters were involved in cancer-related pathways. The methylation-based m5Cscore showed a significant effect on the prognosis. Patients with a lower m5Cscore exhibited more therapeutic efficiency on anti-CTLA4 therapy in liver cancer, while the combination of anti-CTLA4 therapy and pd1 was more efficient for patients with a lower m5Cscore in pancreatic cancer. We uncovered dysregulations of m5C-related regulators in gastrointestinal cancer and their associations with overall survival. Some immune cells were differently infiltrated in distinct m5C modification patterns, indicating their potential impacts on gastrointestinal cancer cell-immune. Moreover, an m5Cscore, derived from DEmRNAs in specific clusters, can serve as a classifier for immunotherapy.

Effects of short-term PM2.5 exposure on blood lipids among 197,957 people in eastern China.

Globally, air pollution is amongst the most significant causes of premature death. Nevertheless, studies on the relationship between fine particulate matter (PM2.5) exposure and blood lipids have typically not been population-based. In a large, community-based sample of residents in Yixing city, we assessed the relationship between short-term outdoor PM2.5 exposure and blood lipid concentrations. Participants who attended the physical examination were enrolled from Yixing People's hospital from 2015 to 2020. We collected general characteristics of participants, including gender and age, as well as test results of indicators of blood lipids. Data on daily meteorological factors were collected from the National Meteorological Data Sharing Center ( http://data.cma.cn/ ) and air pollutant concentrations were collected from the China Air Quality Online Monitoring and Analysis Platform ( https://www.aqistudy.cn/ ) during this period. We applied generalized additive models to estimate short-term effects of ambient PM2.5 exposure on each measured blood lipid-related indicators and converted these indicators into dichotomous variables (non- hyperlipidemia and hyperlipidemia) to calculate risks of hyperlipidemia associated with PM2.5 exposure. A total of 197,957 participants were included in the analysis with mean age 47.90 years (± SD, 14.28). The increase in PM2.5 was significantly associated with hyperlipidemia (odds ratio (OR) 1.003, 95% CI 1.001-1.004), and it was still significant in subgroups of males and age < 60 years. For every 10 µg/m3 increase in PM2.5, triglyceride levels decreased by 0.5447% (95% CI - 0.7873, - 0.3015), the low-density lipoprotein cholesterol concentration increased by 0.0127 mmol/L (95% CI 0.0099, 0.0156), the total cholesterol concentration increased by 0.0095 mmol/L (95% CI 0.0053, 0.0136), and no significant association was observed between PM2.5 and the high-density lipoprotein cholesterol concentration. After excluding people with abnormal blood lipid concentrations, the associations remained significant except for the high-density lipoprotein cholesterol concentration. PM2.5 was positively correlated with low-density lipoprotein cholesterol and total cholesterol, and negatively correlated with triglyceride, indicating PM2.5 can potentially affect health through blood lipid levels.

CS27109, A Selective Thyroid Hormone Receptor-ß Agonist Alleviates Metabolic-Associated Fatty Liver Disease in Murine Models.

Background/Aim: Thyroid hormone receptor-ß (THR-ß) agonists play crucial roles in dyslipidemia and metabolic associated fatty liver disease (MAFLD). We developed a novel oral and liver-targeted THR-ß agonist, CS27109, and evaluated its efficacy in the treatment of metabolic disorders. Materials and Methods: We evaluated in vitro and in vivo efficacy and/or safety of CS27109 along with MGL3196 (a phase III THR-ß agonist). Results: CS27109 showed pronounced activity and selectivity to THR-ß and favorable PK properties, which was equivalent to MGL3196. In the hamster model, animals treated with a high dose of CS27109 showed equivalent reductions in serum TC and LDL-c with groups treated with MGL3196. In the rat model, CS27109 and MGL3196 reduced serum ALT, TC, TG, LDL-c, liver weight ratio, and liver steatosis. CS27109 simultaneously decreased liver TG and TC, and MGL3196 additionally reduced AST. In the mouse model, CS27109 dose-dependently reduced serum AST, ALT, liver inflammation, and NAS score, and also downregulated TC, LDL-c, liver steatosis, and fibrosis, but not in a dose-dependent manner. MGL3196 revealed an equivalent effect with CS27109 in that model. CS27109 also exhibited tolerable toxicity to the heart. Conclusions: CS27109 shows comparative in vitro and in vivo efficacy with MGL3196, suggesting its potential therapeutic application in the treatment of MAFLD such as dyslipidemia and steatohepatitis.

Helicobacter pylori regulates stomach diseases by activating cell pathways and DNA methylation of host cells.

One of the most prevalent malignant tumors of the digestive tract is gastric cancer (GC). Age, high salt intake, Helicobacter pylori (H. pylori) infection, and a diet deficient in fruits and vegetables are risk factors for the illness. A significant risk factor for gastric cancer is infection with H. pylori. Infecting gastric epithelial cells with virulence agents secreted by H. pylori can cause methylation of tumor genes or carcinogenic signaling pathways to be activated. Regulate downstream genes' aberrant expression, albeit the precise mechanism by which this happens is unclear. Oncogene, oncosuppressor, and other gene modifications, as well as a number of different gene change types, are all directly associated to the carcinogenesis of gastric cancer. In this review, we describe comprehensive H. pylori and its virulence factors, as well as the activation of the NF-κB, MAPK, JAK/STAT signaling pathways, and DNA methylation following infection with host cells via virulence factors, resulting in abnormal gene expression. As a result, host-related proteins are regulated, and gastric cancer progression is influenced. This review provides insight into the H. pylori infection, summarizes a series of relevant papers, discusses the complex signaling pathways underlying molecular mechanisms, and proposes new approach to immunotherapy of this important disease.

Bifidobacterium longum CCFM1077 Ameliorated Neurotransmitter Disorder and Neuroinflammation Closely Linked to Regulation in the Kynurenine Pathway of Autistic-like Rats.

The kynurenine pathway (KP) is abnormal in autistic patients and model animals. According to studies on the brain-gut axis, probiotics can help ameliorate the metabolic abnormalities of the KP in patients and model animals with neurological diseases. This study was aimed at evaluating the ability of Bifidobacterium longum (B. longum) CCFM077 to enhance the gut microbiome and KP metabolism and regulate the neurotransmitter levels and neuroinflammation of autistic rats. The KP metabolism of autistic rats was significantly disordered and significantly related to the regulation of neurotransmitter (excitation and inhibition) and neuroglia states. B. longum CCFM1077 could effectively alleviate autistic-like behaviours (repetitive stereotyped behaviour, learning and memory ability, and despair mood) and regulate the KP metabolism in the periphery system (gut and blood) and brain. In particular, B. longum CCFM1077 could significant regulate the quinolinic acid (QUIN) level in the brain and markedly regulate glutamic acid (Glu) and Glu/γ-aminobutyric acid (GABA) levels in the brain while alleviating microglia activity in the cerebellum. Through a correlation analysis, the QUIN level in the brain was strongly related with autistic-like behaviours and neurotransmitter levels (GABA and Glu). The QUIN level may thus be a potential therapeutic marker for treating autism through the intestinal and neural pathways.