Gut-Derived Trimethylamine N-Oxide Promotes CCR2-Mediated Macrophage Infiltration in acute kidney injury.

BACKGROUND: Inflammation is crucial in the development of AKI and subsequent CKD following renal ischemia-reperfusion (IR) injury. Gut microbiota metabolites trigger inflammation and affect IR-induced renal damage. Yet, the driving factors and mechanisms are unclear. Trimethylamine N-oxide (TMAO), a gut-derived choline metabolite, is a strong pro-inflammatory factor that increases in patients with AKI and CKD. We hypothesized that TMAO can promote renal injury caused by IR. METHODS: Mice subjected to unilateral renal IR to induce AKI and CKD were fed a high-choline diet to observe the effects of TMAO on kidney inflammation, fibrosis, and macrophage dynamics. RESULTS: A choline-rich diet altered the gut microbiota and elevated TMAO levels, which exacerbated IR-induced AKI and subsequent CKD. Single-cell analysis identified a distinct subset of CCR2+ macrophages derived from monocytes as key responders to TMAO, intensifying immune cell interactions and worsening renal injury. TMAO promoted sustained CCR2 expression after IR, increasing macrophage infiltration. CCR2 deletion and antagonist RS-102895 improved TMAO-induced inflammation and fibrosis, alleviated renal injury induced by IR. CONCLUSIONS: Our study provides valuable insights into the link between TMAO and IR-incited renal inflammation and fibrosis, emphasizing the critical role of TMAO-mediated macrophage infiltration via CCR2 as a key therapeutic target in the acute and chronic phase after IR.

The effect of reactive oxygen species (ROS) in immunity and WSSV infection of Scylla paramamosain.

Reactive oxygen species (ROS) are typically regarded as being generated by the cellular respiratory chain or by cells under pathological damage, which play a crucial role as signaling molecules in promoting hemocytes circulation and normal cellular physiological functions. In this study, the antioxidant N-acetylcysteine (NAC) was used to reduce ROS in vivo and in vitro, which to analyze the effect of ROS on innate immunity and viral infection of mud crab. The total hemocyte count (THC), phenoloxidase (PO), superoxide dismutase (SOD) activity, immune-relative genes were analyzed, respectively. Moreover, the effect of ROS on WSSV infection was analyzed by THC and hemocytes apoptosis. The data showed that NAC could effectively remove and inhibit intracellular ROS. The THC of NAC group was reduced at 12 h and 24 h compared with that of control. And the inhibition of ROS by NAC could increase the SOD activity with control group, while increased the PO activity caused by early WSSV infection. And NAC could up-regulate the expression of MCM7, JAK, TLR and proPO significantly, while down-regulate the expression of Astakine, proPO, caspase and p53. Similarly, NAC could inhibit WSSV-induced apoptosis of S. paramamosain hemocytes. The data illustrated that ROS participates in the interaction between hemocytes and virus infection by regulating innate immunity. Especially, after NAC inhibited ROS, the expression of hemocytes proliferation gene Astakine was also inhibited, which may indicate that ROS is related to the process of hemocytes proliferation. The data will show a preliminary exploration on the regulatory role of ROS in crustacean immune system.

Finasteride Alleviates High Fat Associated Protein-Overload Nephropathy by Inhibiting Trimethylamine N-Oxide Synthesis and Regulating Gut Microbiota.

Unhealthy diet especially high-fat diet (HFD) is the major cause of hyperlipidemia leading to deterioration of chronic kidney diseases (CKD) in patients. Trimethylamine N-oxide (TMAO) is a gut-derived uremic toxin. Our previous clinical study demonstrated that the elevation of TMAO was positively correlated with CKD progression. Finasteride, a competitive and specific inhibitor of type II 5a-reductase, has been reported recently to be able to downregulate plasma TMAO level thus preventing the onset of atherosclerosis by our research group. In this study, we established a protein-overload nephropathy CKD mouse model by bovine serum albumin (BSA) injection to investigate whether hyperlipidemia could accelerate CKD progression and the underlying mechanisms. Finasteride was administrated to explore its potential therapeutic effects. The results of biochemical analyses and pathological examination showed that HFD-induced hyperlipidemia led to aggravated protein-overload nephropathy in mice along with an elevated level of circulating TMAO, which can be alleviated by finasteride treatment possibly through inhibition of Fmo3 in liver. The 16 S rRNA sequencing results indicated that HFD feeding altered the composition and distribution of gut microbiota in CKD mice contributing to the enhanced level of TMAO precursor TMA, while finasteride could exert beneficial effects via promoting the abundance of Alistipes_senegalensis and Akkermansia_muciniphila. Immunofluorescence staining (IF) and qRT-PCR results demonstrated the disruption of intestinal barrier by decreased expression of tight junction proteins including Claudin-1 and Zo-1 in HFD-fed CKD mice, which can be rescued by finasteride treatment. Cytokine arrays and redox status analyses revealed an upregulated inflammatory level and oxidative stress after HFD feeding in CKO mice, and finasteride-treatment could alleviate these lesions. To summarize, our study suggested that finasteride could alleviate HFD-associated deterioration of protein-overload nephropathy in mice by inhibition of TMAO synthesis and regulation of gut microbiota.

[Gut-derived uremic toxin trimethylamine-N-oxide in cardiovascular disease under end-stage renal disease: an injury mechanism and therapeutic target].

The main cause of death in patients with end-stage renal disease (ESRD) is cardiovascular disease, and trimethylamine-N-oxide (TMAO) has been found to be one of the specific risk factors in the pathogenic process in recent years. TMAO is derived from intestinal bacterial metabolism of dietary choline, carnitine and other substances and subsequently catalyzed by flavin monooxygenase enzymes in the liver. The changes of intestinal bacteria in ESRD patients have contributed to the accumulation of gut-derived uremic toxins such as TMAO, indoxyl sulfate and indole-3-acetic acid. While elevated TMAO concentration accelerates atherosclerosis through mechanisms such as inflammation, increased scavenger receptor expression, and inhibition of reverse cholesterol transport. In this review, this research introduces the biological function, metabolic processes of TMAO and mechanisms by which TMAO promotes the progression of cardiovascular disease in ESRD patients and summarizes current interventions that may be used to reverse gut microbiota disturbances, such as activated carbon, fecal microbial transplantation, dietary improvement, probiotic and probiotic introduction. It also focuses on exploring intervention targets to reduce the gut-derived uremic toxin TMAO in order to explore the possibility of more cardiovascular disease treatments for ESRD patients.

Association between TGF-ß gene polymorphism and myopia: A systematic review and meta-analysis.

INTRODUCTION: The present study was conducted to determine the association of transforming growth factor-beta (TGF-ß) gene polymorphism and myopia. METHOD: Four hundred twelve articles were identified, of which 11 articles with 5213 participants in 4 countries were included in the final analysis. Review Manager software (RevMan, version 5.4) was used for data analysis. RESULT: Odds ratio (OR) value of TGF-ß1 rs1800469 is 1.33 (95% confidence interval [CI] = 1.15-1.54) in the allelic model; in the dominant model is 1.76 (95% CI = 1.16-2.67); in homozygous model is 5.98 (95% CI = 4.31-8.06). OR value of TGF-ß1 rs4803455 is 0.62 (95% CI = 0.43-0.88) in recessive model. TGF-ß2 is not associated with myopia. Relevant study on TGF-ß3 is scarce. CONCLUSION: Our systematic review and meta-analysis found that TGF-ß1 rs4803455 and rs1800469 were correlated with myopia.

Qualitative and Quantitative Evaluation of Chemical Constituents from Shuanghuanglian Injection Using Nuclear Magnetic Resonance Spectroscopy.

By employing nuclear magnetic resonance (NMR), we implemented a chemical research on Shuanghuanglian injection (SHLI) and identified 17 components, including eight primary metabolites and nine secondary metabolites. Guided by the approach of network pharmacology, the potential activities were briefly predicted for seven primary metabolites except for formic acid, such as anti-inflammation, antioxidation, and cardiovascular protection. The focused primary metabolites were quantified by a proton nuclear magnetic resonance (1H-NMR) method, which was verified with good linearity and satisfactory precision, repeatability, stability, and accuracy (except for myo-inositol with mean recovery at 135.78%). Based on the successfully established method, seven primary metabolites were effectively quantified with a slight fluctuation in 20 batches of SHLIs. The average total content of these compounds was 6.85 mg/mL, accounting for 24.84% in total solid of SHLI. This research provides an alternative method for analysis of primary metabolites and contributes to the quality control of SHLI.

The exploration of new therapeutic targets for HPV-negative head and neck squamous cell cancer through the construction of a ceRNA network and immune microenvironment analysis.

Previous studies have shown that human papillomavirus (HPV)-negative patients with head and neck squamous cell cancer (HNSCC) suffer from an unsatisfactory prognosis. Long noncoding RNAs (lncRNAs) have been verified to participate in many biological processes, including regulating gene expression as competing endogenous RNAs (ceRNAs), while few studies focused the ceRNA network regulation mechanism in patients with HPV-negative HNSCC tumor. Meanwhile, the immune microenvironment may be critical in the development and prognosis of HPV-negative tumors. Our study aimed to further investigate the pathogenesis and potential biomarkers for the diagnosis, therapy and prognosis of HPV-negative HNSCC through a ceRNA network. Comprehensively analyzing the sequencing data of lncRNAs, microRNAs (miRNAs), and messenger RNAs (mRNAs) in The Cancer Genome Atlas HNSCC dataset, we constructed a differentially expressed ceRNA network containing 131 lncRNAs, 35 miRNAs and 162 mRNAs. Then, survival analysis in the network was cited to explore the prognostic biomarkers. Eight mRNAs, nine lncRNAs, and one miRNA were identified to be associated with prognosis. Neuropilin (NRP) binding function, retinoid X receptor (RXR) binding, and the vascular endothelial growth factor (VEGF) signaling pathway were associated with the enrichment analysis, and they also related to the immune microenvironment. Combined with the analysis of the immune microenvironment differences, we obtained new targeted therapies using an RXR agonist, or a combination of the VEGF monoclonal antibody and an NRP antagonist, which may provide a promising future for HPV-negative HNSCC patients.

Deconvolution and network analysis of IDH-mutant lower grade glioma predict recurrence and indicate therapeutic targets.

Aim: IDH-mutant lower grade glioma (LGG) has been proven to have a good prognosis. However, its high recurrence rate has become a major therapeutic difficulty. Materials & methods: We combined epigenomic deconvolution and a network analysis on The Cancer Genome Atlas IDH-mutant LGG data. Results: Cell type compositions between recurrent and primary gliomas are significantly different, and the key cell type that determines the prognosis and recurrence risk was identified. A scoring model consisting of four gene expression levels predicts the recurrence risk (area under the receiver operating characteristic curve = 0.84). Transcription factor PPAR-α explains the difference between recurrent and primary gliomas. A cell cycle-related module controls prognosis in recurrent tumors. Conclusion: Comprehensive deconvolution and network analysis predict the recurrence risk and reveal therapeutic targets for recurrent IDH-mutant LGG.

Follow-up study of a pregnant woman 16 years after exposure in the Xinzhou radiation accident.

To investigate the late effects of radiation on child-bearing women, a follow-up study was performed on a 39-year-old survivor 16 years after a (60)Co radiation accident. The woman, Fang, was 19 weeks pregnant at the time of exposure. Physical examinations, a full range of clinical laboratory and imaging tests, as well as cytogenetic analyses were conducted to evaluate Fang's current health conditions. Fang shows the appearance of premature ageing and has a decreased menstrual period. Laboratory studies and imaging tests suggest nodular goitre disease and osteoporosis. Otherwise, no apparent abnormalities were found in the major organs. No malignant tumours were detected by either tumour markers or imaging tests. However, the existence of chromosome aberrations warrants long-term follow-up for tumour incidence in the future. Fang became pregnant 8 years after the accident, but suffered a miscarriage due to the death of the foetus at 6 months into the pregnancy. In conclusion, our findings suggest that the intrauterine death of the foetus might be associated with the previous exposure. There is no evidence of malignant tumours as of the date of the follow-up study. Non-cancerous diseases, i.e. thyroid disease and osteoporosis, which may be related to radiation exposure, are the major manifestations of the long-term effects of the accident.

Clinical observation of a 16-year-old female exposed to radiation in utero: follow-up after the Shanxi Xinzhou radiation accident.

A follow-up study of the late effects of intrauterine exposure to irradiation has been made on a 16-year-old girl whose mother was exposed to external (60)Co irradiation during the Xinzhou radiation accident 16 years previously. The outcomes of the general medical examinations, conventional chromosome aberration analyses and fluorescence in situ hybridisation (FISH) are presented and the China-revised Wechsler Intelligence Scale for Children (C_WISC) was used to identify her IQ level, which was well below normal for her age. The biological dose of the radiation to which she was exposed when she was in her mother's uterus was inferred to be 1.85 Gy. Although there is no evidence of any other developmental changes or tumour induction at this stage in her life, the child's total intelligence level does appear to have been affected.

Cigarette smoking and cancer risk: modeling total exposure and intensity.

A recent analysis showed that the excess odds ratio (EOR) for lung cancer due to smoking can be modeled by a function which is linear in total pack-years and exponential in the logarithm of smoking intensity and its square. Below 15-20 cigarettes per day, the EOR/pack-year increased with intensity (direct exposure rate or enhanced potency effect), suggesting greater risk for a total exposure delivered at higher intensity (for a shorter duration) than for an equivalent exposure delivered at lower intensity. Above 20 cigarettes per day, the EOR/pack-year decreased with increasing intensity (inverse exposure rate or reduced potency effect), suggesting greater risk for a total exposure delivered at lower intensity (for a longer duration) than for an equivalent exposure delivered at higher intensity. The authors applied this model to data from 10 case-control studies of cancer, including cancers of the lung, bladder, oral cavity, pancreas, and esophagus. At lower intensities, there was enhanced potency for several cancer sites, but narrow ranges for pack-years increased uncertainty, precluding definitive conclusions. At higher intensities, there was a consistent reduced potency effect across studies. The intensity effects were statistically homogeneous, indicating that after accounting for risk from total pack-years, intensity patterns were comparable across the diverse cancer sites.

Spectroscopic studies on the interaction between human hemoglobin and CdS quantum dots.

The interaction between human adult hemoglobin (Hb) and bare CdS quantum dots (QDs) was investigated by fluorescence, synchronous fluorescence, circular dichroism (CD), and Raman spectroscopic techniques under physiological pH 7.43. The intrinsic fluorescence of Hb is statically quenched by CdS QDs. The quenching obeys the Stern-Volmer equation, with an order of magnitude of binding constant (K) of 10(7). The electrostatic adsorption of Hb on the cationic CdS QDs surface is energetically favorable (DeltaS(0)=70.22 Jmol(-1)K(-1), DeltaH(0)=-23.11 kJmol(-1)). The red shift of synchronous fluorescence spectra revealed that the microenvironments of tryptophan and tyrosine residues at the alpha(1)beta(2) interface of Hb are disturbed by CdS QDs, which are induced from hydrophobic cavities to a more exposed or hydrophilic surrounding. The secondary structure of the adsorbed Hb has a loose or extended conformation for which the content of alpha-helix has decreased from 72.5 to 60.8%. Moreover, Raman spectra results indicated that the sulfur atoms of the cysteine residues form direct chemical bonds on the surface of the CdS QDs. The binding does not significantly affect the spin state of the heme iron, and deoxidation is not expected to take place on the coated oxyhemoglobin. The change of orientation of heme vinyl groups was also detected.

[Influence of menstrual and reproductive factors on the risk of lung cancer].

OBJECTIVE: Hypothesis showed that women have higher risks of lung cancer than men when given similar levels of tobacco exposure, implying that sex-related hormones might have a role to play. The study is to identify the influence of female hormones on risk of lung cancer. METHODS: We evaluated the association between lung cancer risk and menstrual/reproductive factors on a subset of self-responding females in a population based case-control study in Eastern Gansu, 1994 - 1998. The analysis included 109 lung cancer cases and 435 controls selected from the census list and matched to cases on age and prefecture. RESULTS: Odds ratios were lower for later ages at menarche (trend, P = 0.015) and later ages at menopause (trend, P = 0.074). CONCLUSION: Despite limitations, these findings suggested a possible role related to hormones in the etiology of lung cancer in females.

Menstrual and reproductive factors and risk of lung cancer among Chinese women, Eastern Gansu Province, 1994-1998.

There are suggestions that women have higher relative risks of lung cancer than men given similar levels of tobacco exposure, implying that sex-related hormones may influence lung cancer risk. We evaluated the association between lung cancer risk and menstrual and reproductive factors on a subset of self-responding females in a population based case-control study in Eastern Gansu Province, China, 1994-1998. The analysis included 109 incident lung cancer cases and 435 controls selected from the census list and frequency matched to cases on age and prefecture. Odds ratios were lower for later ages at menarche (trend, P = 0.015) and later ages at menopause (trend, P = 0.074). Despite limitations, these findings suggest a possible role of hormones in the etiology of lung cancer in females.

Lung cancer and indoor exposure to coal and biomass in rural China.

Incomplete combustion of coal in homes has been linked with lung cancer in China. We report on a lung cancer case-control study in a rural area of China, where many residents live in underground dwellings and burn coal and unprocessed biomass (crop residues, wood, sticks, and twigs) for heating and cooking. We interviewed 846 patients with lung cancer (626 men, 220 women; aged 30 to 75 years) diagnosed between 1994 and 1998, and 1740 population-based controls. The odds ratio for lung cancer associated with coal use compared with that for biomass in the house of longest residence was 1.29 (95% confidence interval, 1.03 to 1.61), adjusted for smoking and socioeconomic status. The risk for lung cancer increased relative to the percentage of time that coal was used over the past 30 years (P = 0.02). Our findings suggest that coal may contribute to the risk of lung cancer in this rural area of China.

Residential radon and lung cancer risk in a high-exposure area of Gansu Province, China.

In the general population, evaluation of lung cancer risk from radon in houses is hampered by low levels of exposure and by dosimetric uncertainties due to residential mobility. To address these limitations, the authors conducted a case-control study in a predominantly rural area of China with low mobility and high radon levels. Included were all lung cancer cases diagnosed between January 1994 and April 1998, aged 30-75 years, and residing in two prefectures. Randomly selected, population-based controls were matched on age, sex, and prefecture. Radon detectors were placed in all houses occupied for 2 or more years during the 5-30 years prior to enrollment. Measurements covered 77% of the possible exposure time. Mean radon concentrations were 230.4 Bq/m(3) for cases (n = 768) and 222.2 Bq/m(3) for controls (n = 1,659). Lung cancer risk increased with increasing radon level (p < 0.001). When a linear model was used, the excess odds ratios at 100 Bq/m(3) were 0.19 (95% confidence interval: 0.05, 0.47) for all subjects and 0.31 (95% confidence interval: 0.10, 0.81) for subjects for whom coverage of the exposure interval was 100%. Adjusting for exposure uncertainties increased estimates by 50%. Results support increased lung cancer risks with indoor radon exposures that may equal or exceed extrapolations based on miner data.

Cooking oil fumes and risk of lung cancer in women in rural Gansu, China.

Cooking oil fumes have been suggested to increase the risk of lung cancer in Chinese women by exposing them to mutagenic substances. We investigated the association between lung cancer and locally made rapeseed and linseed oils in a population-based case-control study in Gansu Province, China. Two hundred and thirty-three incident, female lung cancer cases diagnosed from 1994-98 were identified. A control group of 459 women was selected from census lists and were frequency matched on age and prefecture. Interviewers obtained information on cooking practices and cooking oil use. The odds ratio (OR) for lung cancer associated with ever-use of rapeseed oil, alone or in combination with linseed oil, was 1.67 (95% CI 1.0-2.5), compared to use of linseed oil alone. ORs for stir-frying with either linseed or rapeseed oil 15-29, 30 and > or =31 times per month were 1.96,1.73, and 2.24, respectively (trend, P=0.03), relative to a lower frequency of stir-frying. Lung cancer risks also increased with total number of years cooking (trend, P<0.09). Women exposed to cooking fumes from rapeseed oil appeared to be at increased risk of lung cancer, and there was some evidence that fumes from linseed oil may have also contributed to the risk.