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To explore the effect of long non-coding RNA cancer susceptibility 19 (lncRNA CASC19) on the activity, apoptosis, and oxidative stress response of cardiomyocytes, so as to assess the clinical relevance and molecular mechanism of CASC19 in myocardial infarction (MI). CASC19 level was determined by using real-time quantitative polymerase chain reaction (RT-qPCR). MI model was constructed using hypoxia induction, and rat cardiomyocytes H9c2 were divided into control group, MI group, MI small interference negative control (MI-si-NC) group, MI-si-CASC19 group, MI-si-CASC19+microRNA-NC (miR-NC) group, and MI-si-CASC19+miR-218-5p inhibitor group. Tetramethylazolium salt colorimetric method and flow cytometry were used to evaluate cell activity and apoptotic capacity. Cellular oxidative stress was evaluated using malondialdehyde and superoxide dismutase kits. The relationship between CASC19 and miR-218-5p was confirmed by using dual-luciferase activity assay. CASC19 levels were enhanced in MI patients and hypoxia-induced cardiomyocytes. Downregulating CASC19 promoted the proliferation, while suppressed apoptosis and oxidative stress in the MI cell model. Moreover, low expression of miR-218-5p reversed the promotion of proliferation and inhibition of apoptosis and oxidative stress in MI cell models by silencing CASC19. Briefly, CASC19 may serve as a diagnostic marker for MI by sponging miR-218-5p to inhibit apoptosis and oxidative stress in cardiomyocytes and promote cell survival.
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Objective: This study aimed to investigate the efficacy of postpartum nursing guidance in the treatment of early pelvic floor dysfunction (PFD) in women of advanced maternal age. Methods: A total of 146 patients of advanced maternal age admitted to our hospital between January and December 2021 were enrolled in this study and randomly divided into two groups: the control group and the experimental group, with 73 patients in each group. Parturients in the control group received routine pelvic floor rehabilitation treatment, whereas those in the experimental group were given individualized postpartum nursing guidance alongside routine pelvic floor rehabilitation treatment. The recovery of pelvic floor muscle (PFM) strength, the incidence of PFD diseases and nursing satisfaction were compared between the two groups after 3 months of treatment. Results: The enhancement of PFM strength in the experimental group significantly surpassed that in the control group. Furthermore, the experimental group exhibited a notably lower overall occurrence of PFD and significantly greater maternal satisfaction compared with the control group, and the difference was statistically significant (p < 0.05). Conclusion: Combining postpartum nursing guidance with pelvic floor rehabilitation for women of advanced maternal age represents a treatment regimen deserving of clinical endorsement, as it offers numerous advantages, including substantial improvement in PFM strength, decreased incidence of PFD and enhanced patient satisfaction.
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As emerging environmental contaminants, nanoplastics (NPs) are progressively accumulating in terrestrial and aquatic ecosystems worldwide, posing a potential threat to human health. The liver is considered as one of the primary organs targeted by NPs accumulation in living organisms. However, there remains a large knowledge gap concerning NPs-induced hepatotoxicity. In this study, we examined the impact of chronic exposure to environmentally relevant doses of polystyrene (PS) NPs on hepatic pyroptosis in mice. The results demonstrated that both particle sizes of PS-NPs (100 nm and 500 nm) significantly triggered pyroptosis in the mouse liver, as evidenced by the upregulation of GSDMD-N protein levels; moreover, this pyroptotic effect induced by 100 nm PS-NPs was more pronounced compared to that of 500 nm PS-NPs. Mechanistically, exposure to 100 nm and 500 nm PS-NPs resulted in an upregulation of TXNIP protein expression, thereby activating NLRP3 inflammasome and subsequently inducing inflammatory responses and pyroptosis. Notably, following the termination of PS-NPs exposure and a subsequent recovery period of 50 days, PS-NPs-mediated inflammation and pyroptosis via TXNIP/NLRP3 pathway were effectively ameliorated, even returning to levels close to the baseline. Collectively, our findings provide novel evidence for the size-dependence and reversibility of NPs-induced hepatic pyroptosis through TXNIP/NLRP3/GSDMD pathway in vivo.
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Tissue-resident memory T cells (TRMs) play a critical role in cancer immunity by offering quick and effective immune responses. However, the cellular heterogeneity of TRMs and their significance in cervical cancer (CC) remain unknown. In this study, we generated and analyzed single-cell RNA sequencing data from 12,945 TRMs (ITGAE+ CD3D+) and 25,627 non-TRMs (ITGAE- CD3D+), derived from 11 CC tissues and 5 normal cervical tissues. We found that TRMs were more immunoreactive than non-TRMs, and TRMs in CC tissues were more activated than those in normal cervical tissues. Six CD8+ TRM subclusters and one CD4+ TRM subcluster were identified. Among them, CXCL13+ CD8+ TRMs were more abundant in CC tissues than in normal cervical tissues, had both cytotoxic and inhibitory features, and were enriched in pathways related to defense responses to the virus. Meanwhile, PLAC8+ CD8+ TRMs were less abundant in CC tissues than in normal cervical tissues but had highly cytotoxic features. The signature gene set scores of both cell subclusters were positively correlated with the overall survival and progression-free survival of patients with CC following radiotherapy. Of note, the association between HLA-E and NKG2A, either alone or in a complex with CD94, was enriched in CXCL13+ CD8+ TRMs interacting with epithelial cells at CC tissues. The in-depth characterization of TRMs heterogeneity in the microenvironment of CC could have important implications for advancing treatment and improving the prognosis of patients with CC.
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Biomarcadores de Tumor , Neoplasias de la Mama , Neoplasias de los Genitales Femeninos , Inmunoterapia , Humanos , Femenino , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/terapia , Inmunoterapia/métodos , Neoplasias de los Genitales Femeninos/inmunología , Neoplasias de los Genitales Femeninos/terapia , Neoplasias de los Genitales Femeninos/diagnóstico , PronósticoRESUMEN
Accumulating evidence indicates that plasma metal levels may be associated with Type 2 diabetes mellitus (T2DM) incident risk. Mitochondrial function such as mitochondrial DNA copy number (mtDNA-CN) might be linked to metal exposure and physiological metabolism. Mediation analysis was conducted to determine the mediating roles of mtDNA-CN in the association between plasma metals and diabetes risk. In the present study, we investigated associations between plasma metals levels, mtDNA-CN, and T2DM incident in the elderly population with a 6-year follow-up (two times) study. Ten plasma metals [i.e. manganese, aluminum, calcium, iron, barium (Ba), arsenic, copper, selenium, titanium, and strontium] were measured using inductively coupled plasma mass spectrometry. mtDNA-CN was measured by real-time polymerase chain reaction. Multivariable linear regression and logistic regression analyses were carried out to estimate the relationship between plasma metal concentrations, mtDNA-CN, and T2DM incident risk in the current work. Plasma Ba deficiency and mtDNA-CN decline were associated with T2DM incident risk during the aging process. Meanwhile, plasma Ba was found to be positively associated with mtDNA-CN. Mitochondrial function mtDNA-CN demonstrated mediating effects in the association between plasma Ba deficiency and T2DM incident risk, and 49.8% of the association was mediated by mtDNA-CN. These findings extend the knowledge of T2DM incident risk factors and highlight the point that mtDNA-CN may be linked to plasma metal elements and T2DM incident risk.
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Bario , Variaciones en el Número de Copia de ADN , ADN Mitocondrial , Diabetes Mellitus Tipo 2 , Humanos , ADN Mitocondrial/genética , ADN Mitocondrial/sangre , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/sangre , Masculino , Femenino , Anciano , Estudios de Seguimiento , Bario/sangre , Factores de Riesgo , Persona de Mediana Edad , IncidenciaRESUMEN
The global prevalence of nonalcoholic fatty liver disease (NAFLD) has reached 30â¯%, with an annual increase. The incidence of NAFLD-induced cirrhosis is rapidly rising and has become the leading indicator for liver transplantation in the US. However, there are currently no US Food and Drug Administration-approved drugs for NAFLD. Increasing evidence underscores the close association between NAFLD and bile acid metabolism disorder, highlighting the feasibility of targeting the bile acid signaling pathway for NAFLD treatment. The farnesoid X receptor (FXR) is an endogenous receptor for bile acids that exhibits favorable effects in ameliorating the metabolic imbalance of bile acids, lipid disorders, and disruption of intestinal homeostasis, all of which are key characteristics of NAFLD, making FXR a promising therapeutic target for NAFLD. The present review provides a comprehensive overview of the diverse mechanisms through which FXR improves NAFLD, with particular emphasis on its involvement in regulating bile acid homeostasis and the recent advancements in drug development targeting FXR for NAFLD treatment.
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Ácidos y Sales Biliares , Desarrollo de Medicamentos , Enfermedad del Hígado Graso no Alcohólico , Receptores Citoplasmáticos y Nucleares , Humanos , Receptores Citoplasmáticos y Nucleares/metabolismo , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Animales , Ácidos y Sales Biliares/metabolismo , Desarrollo de Medicamentos/métodos , Descubrimiento de Drogas/métodos , Transducción de Señal/efectos de los fármacos , Homeostasis/efectos de los fármacos , Metabolismo de los Lípidos/efectos de los fármacosRESUMEN
BACKGROUND: Diabetic cardiomyopathy (DCM), a serious complication of diabetes, leads to structural and functional abnormalities of the heart and ultimately evolves to heart failure. IL-37 exerts a substantial influence on the regulation of inflammation and metabolism. Whether IL-37 is involved in DCM is unknown. METHODS: The plasma samples were collected from healthy controls, diabetic patients and DCM patients, and the level of IL-37 and its relationship with heart function were observed. The changes in cardiac function, myocardial fibrosis and mitochondrial injury in DCM mice with or without IL-37 intervention were investigated in vivo. By an in vitro co-culture approach involving HG challenge of cardiomyocytes and fibroblasts, the interaction carried out by cardiomyocytes on fibroblast profibrotic activation was studied. Finally, the possible interactive mediator between cardiomyocytes and fibroblasts was explored, and the intervention role of IL-37 and its relevant molecular mechanisms. RESULTS: We showed that the level of plasma IL-37 in DCM patients was upregulated compared to that in healthy controls and diabetic patients. Both recombinant IL-37 administration or inducing IL-37 expression alleviated cardiac dysfunction and myocardial fibrosis in DCM mice. Mechanically, hyperglycemia impaired mitochondria through SIRT1/AMPK/PGC1α signaling, resulting in significant cardiomyocyte apoptosis and the release of extracellular vesicles containing mtDNA. Fibroblasts then engulfed these mtDNA-enriched vesicles, thereby activating TLR9 signaling and the cGAS-STING pathway to initiate pro-fibrotic process and adverse remodeling. However, the presence of IL-37 ameliorated mitochondrial injury by preserving the activity of SIRT1-AMPK-PGC1α axis, resulting in a reduction in release of mtDNA-enriched vesicle and ultimately attenuating the progression of DCM. CONCLUSIONS: Collectively, our study demonstrates a protective role of IL-37 in DCM, offering a promising therapeutic agent for this disease.
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ADN Mitocondrial , Cardiomiopatías Diabéticas , Fibrosis , Interleucina-1 , Miocitos Cardíacos , Animales , Femenino , Humanos , Masculino , Ratones , Persona de Mediana Edad , Apoptosis/efectos de los fármacos , Cardiomiopatías Diabéticas/patología , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/tratamiento farmacológico , ADN Mitocondrial/metabolismo , Fibroblastos/metabolismo , Fibroblastos/efectos de los fármacos , Interleucina-1/metabolismo , Ratones Endogámicos C57BL , Miocardio/patología , Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patología , Transducción de Señal/efectos de los fármacos , Sirtuina 1/metabolismoRESUMEN
Arsenic (As) is widely present in the natural environment, and exposure to it can lead to learning and memory impairment. However, the underlying epigenetic mechanisms are still largely unclear. This study aimed to reveal the role of histone modifications in environmental levels of arsenic (sodium arsenite) exposure-induced learning and memory dysfunction in male rats, and the inter/transgenerational effects of paternal arsenic exposure were also investigated. It was found that arsenic exposure impaired the learning and memory ability of F0 rats and down-regulated the expression of cognition-related genes Bdnf, c-Fos, mGlur1, Nmdar1, and Gria2 in the hippocampus. We also observed that inorganic arsenite was methylated to DMA and histone modification-related metabolites were altered, contributing to the dysregulation of H3K4me1/2/3, H3K9me1/2/3, and H3K4ac in rat hippocampus after exposure. Therefore, it is suggested that arsenic methylation and hippocampal metabolism changes attenuated H3K4me1/2/3 and H3K4ac while enhancing H3K9me1/2/3, which repressed the key gene expressions, leading to cognitive impairment in rats exposed to arsenic. In addition, paternal arsenic exposure induced transgenerational effects of learning and memory disorder in F2 male rats through the regulation of H3K4me2 and H3K9me1/2/3, which inhibited c-Fos, mGlur1, and Nmdar1 expression. These results provide novel insights into the molecular mechanism of arsenic-induced neurotoxicity and highlight the risk of neurological deficits in offspring with paternal exposure to arsenic.
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Arsénico , Ratas , Animales , Masculino , Arsénico/toxicidad , Código de Histonas , Hipocampo , MetilaciónRESUMEN
As a widely used alternative to perfluorooctanoic acid (PFOA), hexafluoropropylene oxide trimer acid (HFPO-TA) has been detected in the environment and humans; however, little is known regarding its male reproductive toxicity. To compare the effects of HFPO-TA on steroid hormone synthesis with PFOA, we exposed Leydig cells (MLTC-1) to non-lethal doses (0.1, 1, and 10 µM) of PFOA and HFPO-TA for 48 h. It was found that the levels of steroid hormones, 17α-hydroxyprogesterone (OHP), androstenedione (ASD), and testosterone (T) were significantly increased in 1 and 10 µM of PFOA and HFPO-TA groups, with greater elevation being observed in the HFPO-TA groups than in the PFOA groups at 10 µM. We further showed that the two rate-limiting steroidogenic genes (Star and Cyp11a1) were up-regulated, while Hsd3b, Cyp17a1, and Hsd17b were down-regulated or unchanged after PFOA/HFPO-TA exposure. Moreover, PFOA exposure significantly up-regulated histone H3K4me1/3 and H3K9me1, while down-regulated H3K4me2 and H3K9me2/3 levels. By contrast, H3K4me2/3 and H3K9me2/3 were enhanced, while H3K4me1 and H3K9me1 were repressed after HFPO-TA treatment. It was further confirmed that H3K4me1/3 were increased and H3K9me2 was decreased in Star and Cyp11a1 promoters by PFOA, while HFPO-TA increased H3K4me2/3 and decreased H3K9me1 in the two gene promoters. Therefore, we propose that low levels of PFOA/HFPO-TA enhance the expression of Star and Cyp11a1 by regulating H3K4 and H3K9 methylation, thus stimulating the production of steroid hormones in MLTC-1 cells. Collectively, HFPO-TA exhibits stronger effects on steroidogenesis compared to PFOA, which may be ascribed to the distinct regulation of histone modifications. These data suggest that HFPO-TA does not appear to be a safer alternative to PFOA on the aspect of male reproductive toxicity.
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Caprilatos , Fluorocarburos , Fluorocarburos/toxicidad , Caprilatos/toxicidad , Animales , Masculino , Código de Histonas/efectos de los fármacos , Células Intersticiales del Testículo/efectos de los fármacos , Células Intersticiales del Testículo/metabolismo , Testosterona/metabolismo , Histonas/metabolismo , RatonesRESUMEN
Haloacetic acids (HAAs) are ubiquitous in drinking water and have been associated with impaired male reproductive health. However, epidemiological evidence exploring the associations between HAA exposure and reproductive hormones among males is scarce. In the current study, the urinary concentrations of dichloroacetic acid (DCAA) and trichloroacetic acid (TCAA), the internal exposure markers of HAAs, as well as sex hormones (testosterone [T], progesterone [P], and estradiol [E2]) were measured among 449 Chinese men. Moreover, in vitro experiments, designed to simulate the real-world scenarios of human exposure, were conducted to assess testosterone synthesis in the Leydig cell line MLTC-1 and testosterone metabolism in the hepatic cell line HepG2 in response to low-dose HAA exposure. The DCAA and TCAA urinary concentrations were found to be positively associated with urinary T, P, and E2 levels (all p < 0.001), but negatively associated with the ratio of urinary T to E2 (p < 0.05). Combined with in vitro experiments, the results suggest that environmentally-relevant doses of HAA stimulate sex hormone synthesis and steroidogenesis pathway gene expression in MLTC-1 cells. In addition, the inhibition of the key gene CYP3A4 involved in the testosterone phase â catabolism, and induction of the gene UGT2B15 involved in testosterone phase â ¡ glucuronide conjugation metabolism along with the ATP-binding cassette (ABC) transport genes (ABCC4 and ABCG2) in HepG2 cells could play a role in elevation of urinary hormone excretion upon low-dose exposure to HAAs. Our novel findings highlight that exposure to HAAs at environmentally-relevant concentrations is associated with increased synthesis and excretion of sex hormones in males, which potentially provides an alternative approach involving urinary hormones for the noninvasive evaluation of male reproductive health following exposure to DBPs.
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Desinfección , Agua Potable , Humanos , Masculino , Ácido Tricloroacético/toxicidad , Ácido Dicloroacético/análisis , Ácido Dicloroacético/orina , Esteroides , TestosteronaRESUMEN
Nanoplastics (NPs) continue to accumulate in global aquatic and terrestrial systems, posing a potential threat to human health through the food chain and/or other pathways. Both in vivo and in vitro studies have confirmed that the liver is one of the main organs targeted for the accumulation of NPs in living organisms. However, whether exposure to NPs induces size-dependent disorders of liver lipid metabolism remains controversial, and the reversibility of NPs-induced hepatotoxicity is largely unknown. In this study, the effects of long-term exposure to environmentally relevant doses of polystyrene nanoplastics (PS-NPs) on lipid accumulation were investigated in terms of autophagy and lysosomal mechanisms. The findings indicated that hepatic lipid accumulation was more pronounced in mice exposed to 100 nm PS-NPs compared to 500 nm PS-NPs. This effect was effectively alleviated after 50 days of self-recovery for 100 nm and 500 nm PS-NPs exposure. Mechanistically, although PS-NPs exposure activated autophagosome formation through ERK (mitogen-activated protein kinase 1)/mTOR (mechanistic target of rapamycin kinase) signaling pathway, the inhibition of Rab7 (RAB7, member RAS oncogene family), CTSB (cathepsin B), and CTSD (cathepsin D) expression impaired lysosomal function, thereby blocking autophagic flux and contributing to hepatic lipid accumulation. After termination of PS-NPs exposure, lysosomal exocytosis was responsible for the clearance of PS-NPs accumulated in lysosomes. Furthermore, impaired lysosomal function and autophagic flux inhibition were effectively alleviated. This might be the main reason for the alleviation of PS-NPs-induced lipid accumulation after recovery. Collectively, we demonstrate for the first time that lysosomes play a dual role in the persistence and reversibility of hepatotoxicity induced by environmental relevant doses of NPs, which provide novel evidence for the prevention and intervention of liver injury associated with nanoplastics exposure.
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Enfermedad Hepática Inducida por Sustancias y Drogas , Nanopartículas , Contaminantes Químicos del Agua , Humanos , Animales , Ratones , Microplásticos , Poliestirenos/toxicidad , Lisosomas , LípidosRESUMEN
Per- and polyfluoroalkyl substances (PFAS) can pass through the placental barrier and pose health risks to fetuses. However, exposure and transplacental transfer patterns of emerging PFAS remain unclear. Here, 24 PFAS were measured in paired maternal whole blood (n = 228), umbilical cord whole blood (n = 119) and serum (n = 120). Orthogonal partial least-squares discriminant analysis (OPLS-DA) was used to differentiate PFAS between different matrices. The transplacental transfer (TPT) of PFAS was calculated using cord to maternal whole blood concentration ratios. PFOS and PFOA were still the dominant PFAS in maternal samples. The emerging PFAS had higher TPT than PFOS and PFOA. Moreover, PFAS with the same chain length but different functional groups and C-F bonds showed different TPT, such as PFOS and PFOSA (C8, median: 0.090 vs. 0.305, p < 0.05) and PFHxS and 4:2 FTS (C6, median: 0.220 vs. 1.190, p < 0.05). A significant sex difference in 4:2 FTS (median: boys 1.250, girls 1.010, p < 0.05) were found. Furthermore, we observed a significant U-shaped trend for the TPT of carboxylates with increasing carbon chain length. PFAS showed a compound-specific transfer through placental barrier and a compound-specific distribution between different matrices in this study.
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Ácidos Alcanesulfónicos , Contaminantes Ambientales , Fluorocarburos , Humanos , Masculino , Embarazo , Femenino , Estudios de Cohortes , Placenta , Sangre Fetal/química , Fluorocarburos/análisis , China , Ácidos Alcanesulfónicos/análisis , Contaminantes Ambientales/análisisRESUMEN
Dendritic cells (DCs) serve as a pivotal link connecting innate and adaptive immunity by processing tumor-derived antigens and activating T cells. The advent of single-cell sequencing has revolutionized the categorization of DCs, enabling a high-resolution characterization of the previously unrecognized diversity of DC populations infiltrating the intricate tumor microenvironment (TME). The application of single-cell sequencing technologies has effectively elucidated the heterogeneity of DCs present in the tumor milieu, yielding invaluable insights into their subpopulation structures and functional diversity. This review provides a comprehensive summary of the current state of knowledge regarding DC subtypes in the TME, drawing from single-cell studies conducted across various human tumors. We focused on the categorization, functions, and interactions of distinct DC subsets, emphasizing their crucial roles in orchestrating tumor-related immune responses. Additionally, we delve into the potential implications of these findings for the identification of predictive biomarkers and therapeutic targets. Enhanced insight into the intricate interplay between DCs and the TME promises to advance our comprehension of tumor immunity and, in turn, pave the way for the development of more efficacious cancer immunotherapies.
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Gestational diabetes mellitus (GDM) is one of the most common complications of pregnancy. Metal exposure is an emerging factor affecting the risk of GDM. However, the effects of metal mixture on GDM and key metals within the mixture remain unclear. This study was aimed at investigating the association between metal mixture during early pregnancy and the risk of GDM using four statistical methods and further at identifying the key metals within the mixture associated with GDM. A nested case-control study including 128 GDM cases and 318 controls was conducted in Beijing, China. Urine samples were collected before 13 gestational weeks and the concentrations of 13 metals were measured. Single-metal analysis (unconditional logistic regression) and mixture analyses (Bayesian kernel machine regression (BKMR), quantile g-computation, and elastic-net regression (ENET) models) were applied to estimate the associations between exposure to multiple metals and GDM. Single-metal analysis showed that Ni was associated with lower risk of GDM, while positive associations of Sr and Sb with GDM were observed. Compared with the lowest quartile of Ni, the ORs of GDM in the highest quartiles were 0.49 (95% CI 0.24, 0.98). In mixture analyses, Ni and Mg showed negative associations with GDM, while Co and Sb were positively associated with GDM in BKMR and quantile g-computation models. No significant joint effect of metal mixture on GDM was observed. However, interestingly, Ni was identified as a key metal within the mixture associated with decreased risk of GDM by all three mixture methods. Our study emphasized that metal exposure during early pregnancy was associated with GDM, and Ni might have important association with decreased GDM risk.
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Diabetes Gestacional , Embarazo , Femenino , Humanos , Diabetes Gestacional/inducido químicamente , Diabetes Gestacional/epidemiología , Estudios de Casos y Controles , Teorema de Bayes , Metales , Modelos LogísticosRESUMEN
Fine particulate matter (PM2.5) and high-fat diet (HFD) are known to contribute to blood glucose metabolic disorders. However, limited research has investigated the combined impact of PM2.5 and HFD on blood glucose metabolism. This study aimed to explore the joint effects of PM2.5 and HFD on blood glucose metabolism in rats using serum metabolomics and to identify involved metabolites and metabolic pathways. The 32 male Wistar rats were exposed to filtered air (FA) or PM2.5 (real-world inhaled, concentrated PM2.5, 8 times the ambient level, ranging from 131.42 to 773.44 µg/m3) and fed normal diet (ND) or HFD for 8 weeks. The rats were divided into four groups (n = 8/group): ND-FA, ND-PM2.5, HFD-FA and HFD-PM2.5 groups. Blood samples were collected to determine fasting glucose (FBG), plasma insulin and glucose tolerance test and HOMA Insulin Resistance (HOMA-IR) index was calculated. Finally, the serum metabolism of rats was analyzed by ultra-high performance liquid chromatography/mass spectrometry (UHPLC-MS). Then we constructed the partial least squares discriminant analysis (PLS-DA) model to screen the differential metabolites, and performed pathway analysis to screen the main metabolic pathways. Results showed that combined effect of PM2.5 and HFD caused changes in glucose tolerance, increased FBG levels and HOMA-IR in rats and there were interactions between PM2.5 and HFD in FBG and insulin. By metabonomic analysis, the serum differential metabolites pregnenolone and progesterone, which involved in steroid hormone biosynthesis, were two different metabolites in the ND groups. In the HFD groups, the serum differential metabolites were L-tyrosine and phosphorylcholine, which involved in glycerophospholipid metabolism, and phenylalanine, tyrosine, and tryptophan biosynthesis. When PM2.5 and HFD coexist, they may lead to more severe and complex effects on glucose metabolism by affecting lipid metabolism and amino acid metabolism. Therefore, reducing PM2.5 exposure and controlling dietary structure are important measures for preventing and reducing glucose metabolism disorders.
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BACKGROUND: Bile duct obstruction is a common issue for patients with advanced cholangiocarcinoma (CCA). Percutaneous transhepatic cholangial drainage (PTCD) is often required to relieve the obstruction. However, PTCD may alter the intestinal microbiota, which can affect the efficacy of immunotherapy. Antibiotics (ATB) can also have significant immunomodulatory effects by perturbing the gut microbiota. Therefore, this study aimed to investigate whether PTCD or ATB therapy is associated with overall survival (OS) or progression-free survival (PFS) in patients with advanced CCA receiving first-line chemotherapy plus immune checkpoint blockade (ICB) in clinical practice. We also explored whether the gut microbiota changes after receiving PTCD. METHODS: We conducted a single-center retrospective analysis of PTCD and ATB therapy in patients with advanced CCA. PTCD was performed before ICB initiation, and ATB was administered within 1 month before and 6 weeks after ICB initiation. Our primary outcomes were PFS and OS. Moreover, we used 16s rRNA sequencing to analyze fecal and bile samples obtained from patients who underwent PTCD. RESULTS: In total, 107 patients with CCA were included. Among patients who did not undergo PTCD, ICB plus chemotherapy significantly improved OS vs. chemotherapy alone (hazard ratio [HR] 0.21, 95% confidence interval [CI] 0.09-0.45, p < 0.0001). PFS was also significantly improved in patients who received ICB plus chemotherapy compared with chemotherapy alone (HR 0.36, 95% CI 0.16-0.80, p = 0.0024). However, ICB plus chemotherapy did not improve survival compared with chemotherapy alone among patients who received PTCD. Overall changes in the fecal microbiota of patients after PTCD involved significant reductions in which Escherichia - Shigella. CONCLUSIONS: The use of ATB or PTCD in patients with CCA receiving ICB was associated with worse OS compared with chemotherapy alone, and PTCD affects the gut microbiota. Escherichia - Shigella was significantly reduced in feces of patients after PTCD.
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Neoplasias de los Conductos Biliares , Colangiocarcinoma , Humanos , Antibacterianos/efectos adversos , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Conductos Biliares Intrahepáticos , Colangiocarcinoma/tratamiento farmacológico , Drenaje , Inmunoterapia , Estudios Retrospectivos , ARN Ribosómico 16SRESUMEN
Chronic exposure to very low ambient PM2.5 has been linked to cardiovascular risks in epidemiological observation, which also brought doubts on its safety threshold. In this study, we approached this question by chronic exposure of AC16 to the non-observable acute effect level (NOAEL) PM2.5 5 µg/mL and its positive reference 50 µg/mL, respectively. The doses were respectively defined on the cell viabilities >95% (p = 0.354) and >90% (p = 0.004) when treated acutely (24 h). To mimic the long-term exposure, AC16 was cultured from the 1st to 30th generations and treated with PM2.5 24 h in every three generations. The integration of proteomic and metabolomic analysis was applied, and 212 proteins and 172 metabolites were significantly altered during the experiments. The NOAEL PM2.5 induced both dose- and time-dependent disruption, which showed the dynamic cellular proteomic response and oxidation accumulation, the main metabolomics changes were ribonucleotide, amino acid, and lipid metabolism that have involved in stressed gene expression, and starving for energy metabolism and lipid oxidation. In summary, these pathways interacted with the monotonically increasing oxidative stress and led to the accumulated damage in AC16 and implied that the safe threshold of PM2.5 may be non-existent when a long-term exposure occurred.
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BACKGROUND: The combined infection of actinomyces odontolyticus sepsis and cryptococcal encephalitis is rare in routine clinical practice. Thus, we presented this case report and literature review to provide clues to improve such patients' diagnoses and treatment processes. CASE PRESENTATION: The main clinical manifestations of the patient were high fever and intracranial hypertension. Then, we completed the routine cerebrospinal fluid examination, biochemical detection, cytological examination, bacterial culture, and India ink staining. Firstly, the blood culture suggested actinomyces odontolyticus infection, considering the possibility of actinomyces odontolyticus sepsis and intracranial actinomyces odontolyticus infection. Accordingly, the patient was administered penicillin for treatment. Although the fever was slightly relieved, the symptoms of intracranial hypertension did not relieve. After 7 days, the characteristics of brain magnetic resonance imaging and the results of pathogenic metagenomics sequencing and cryptococcal capsular polysaccharide antigen suggested that cryptococcal infection. Based on the above results, the patient was diagnosed with a combined infection of cryptococcal meningoencephalitis and actinomyces odontolyticus sepsis. Anti-infection therapy with 'penicillin, amphotericin, and fluconazole' was provided, improving the clinical manifestations and objective indexes. CONCLUSION: The combined infection of Actinomyces odontolyticus sepsis and cryptococcal encephalitis is first reported in this case report, and combined antibiotics with 'penicillin, amphotericin, and fluconazole' are effective.
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Actinomicosis , Cryptococcus neoformans , Hipertensión Intracraneal , Meningitis Criptocócica , Meningoencefalitis , Sepsis , Humanos , Fluconazol/uso terapéutico , Anfotericina B/uso terapéutico , Actinomicosis/diagnóstico , Actinomicosis/tratamiento farmacológico , Actinomicosis/microbiología , Penicilinas/uso terapéutico , Sepsis/diagnóstico , Sepsis/tratamiento farmacológico , Meningoencefalitis/diagnóstico , Meningoencefalitis/tratamiento farmacológico , Actinomyces , Hipertensión Intracraneal/tratamiento farmacológico , Antifúngicos/uso terapéutico , Antifúngicos/farmacología , Meningitis Criptocócica/diagnósticoRESUMEN
Environmental arsenic (As) exposure has been associated with gestational diabetes mellitus (GDM) risk. Our recent study found that GDM was positively associated with urinary As3+ level while negatively correlated to As5+. However, the mechanisms underlying the association between arsenic species and GDM remain largely unknown. In the present study, through the measurement of urinary arsenic species and metabolome analysis in 399 pregnant women, we aimed to identify the metabolic biomarkers that may link arsenic exposure to GDM based on a novel systems epidemiology strategy termed meet-in-metabolite-analysis (MIMA). The metabolomics analysis revealed that 20 and 16 urinary metabolites were relevant to arsenic exposure and GDM, respectively. Among them, 12 metabolites were identified to be both arsenic- and GDM-related, which are mainly involved in purine metabolism, onecarbon metabolism (OCM) and glycometabolism. Moreover, it was further showed that the regulation of thiosulfate (AOR: 2.52; 95 % CI: 1.33, 4.77) and phosphoroselenoic acid (AOR: 2.35; 95 % CI: 1.31, 4.22) could significantly contribute to the negative association between As5+ and GDM. Considering the biological functions of these metabolites, it is suggested that As5+ may reduce GDM risk by disturbing OCM in the pregnant women. These data will provide novel insights into the mechanism of action of environmental arsenic exposure on GDM incidence from the aspect of metabolism disorder.