Etelcalcetide ameliorates bone loss in chronic kidney disease-mineral and bone disorder by activation of IRF7 and necroptosis pathways.

Chronic kidney disease-mineral and bone disorder (CKD-MBD) is a multifaceted clinical syndrome characterized by mineral imbalances, abnormalities in bone metabolism, chronic inflammation and vascular calcification. Etelcalcetide, a second-generation intravenous calcimimetic agent, has been approved for treating high-turnover renal osteodystrophy, effectively targeting the pathophysiological mechanisms underlying this condition. We investigate the impacts of etelcalcetide on osteoclast (OC) differentiation and functionality in CKD-MBD via three critical mechanisms: inflammation initiated by interferon regulatory factor 7 (IRF7), receptor-interacting protein (RIP)-mediated necroptosis and apoptosis-induced cell death. The low-dose (CKD + L) or high-dose (CKD + H) of etelcalcetide groups significantly improved biochemical markers compared to the CKD control mice. Additionally, etelcalcetide-treated CKD mice significantly improved cortical and trabecular bone parameters. In an in vitro study, etelcalcetide was observed to bolster the IRF7-mediated IFNß response in OC differentiation. Furthermore, it stimulated RIP-mediated necroptosis via RIP and MLKL activation, inhibiting bone resorption. Moreover, the drug increased levels of caspases 3 and 9, inducing cell death in OCs. These findings suggest that etelcalcetide regulates bone metabolism and reduces skeletal issues in CKD-MBD. Etelcalcetide likely enhances bone parameters in CKD-MBD mice by regulating IRF7 pathways and inhibiting OC differentiation. It also improves bone health and promotes RIP-mediated necroptosis and apoptosis pathways within OCs.

Metal-support spin orders: Crucial effect on electrocatalytic oxygen reduction.

Magnetic property (e.g. spin order) of support is of great importance in the rational design of heterogeneous catalysts. Herein, we have taken the Ni-supported ferromagnetic (FM) CrBr3 support (Nix/CrBr3) to thoroughly investigate the effect of spin-order on electrocatalytic oxygen reduction reaction (ORR) via spin-polarized density functional theory calculations. Specifically, Ni loading induces anti-FM coupling in Ni-Cr, leading to a transition from FM-to-ferrimagnetic (FIM) properties, while Ni-Ni metallic bonds create a robust FM direct exchange, benefiting the improvement of the phase transition temperature. Interestingly, with the increase in Ni loading, the easy magnetic axis changes from out-of-plane (2D-Heisenberg) to in-plane (2D-XY). The adsorption properties of Nix/CrBr3, involving O2 adsorption energy and configuration, are not governed by the d-band center but strongly correlate with magnetic anisotropy. It is noteworthy that the applied potential and electrolyte acidity triggers spin-order transition phenomena during the ORR and induces the catalytic pathway change from 4e- ORR to 2e- ORR with the excellent onset potential of 0.93 V/reversible hydrogen electrode, comparable to the existing most excellent noble-metal catalysts. Generally, these findings offer new avenues to understand and design heterogeneous catalysts with magnetic support.

Magnetic Order Transition of a Two-Dimensional Square-Lattice Electrocatalyst Assembled by Fe-N4 Units: Crucial Role on Oxygen Reduction.

Herein, we theoretically investigate the effect of magnetic orders on electrocatalytic oxygen reduction reaction (ORR) properties on the Fe-N4 site-embedded two-dimensional (2D) covalent organic framework (Fe-N4@COF-C3N2) under realistic environments. The Fe-N4@COF-C3N2 shows a 2D square-lattice (sql) topology with three magnetic order states: one ferromagnetic state (FM) and two antiferromagnetic states (AFM1 and AFM2). Specially, the electrocatalyst in the AFM2 state shows a remarkable onset potential of 0.80 V/reversible hydrogen electrode (RHE) at pH 1, superior to the existing most excellent noble-metal catalysts. Thermodynamically, the onset potential for the 4e- ORR is 0.64 V/RHE at pH 1, with a magnetic state transition process of FM → AFM1 → FM → FM → FM, while at pH 13, the onset potential for the 4e- ORR is 0.54 V/RHE, with the magnetic transition process of FM → FM → AFM1 → FM → FM. Generally, this finding will provide new avenues to rationally design the Fe-N4 electrocatalyst.

Nomogram Based on US and Clinicopathologic Characteristics: Axillary Nodal Evaluation Following Neoadjuvant Chemotherapy in Patients With Node-Positive Breast Cancer.

BACKGROUND: To develop a convenient modality to predict axillary response to neoadjuvant chemotherapy (NAC) in breast cancer patients. MATERIALS AND METHODS: In this multi-center study, a total of 1019 breast cancer patients with biopsy-proven positive lymph node (LN) receiving NAC were randomly assigned to the training and validation groups at a ratio of 7:3. Clinicopathologic and ultrasound (US) characteristics of both primary tumors and LNs were used to develop corresponding prediction models, and a nomogram integrating clinicopathologic and US predictors was generated to predict the axillary response to NAC. RESULTS: Axillary pathological complete response (pCR) was achieved in 47.79% of the patients. The expression of estrogen receptor, human epidermal growth factor receptor -2, Ki-67 score, and clinical nodal stage were independent predictors for nodal response to NAC. Location and radiological response of primary tumors, cortical thickness and shape of LNs on US were also significantly associated with nodal pCR. In the validation cohort, the discrimination of US model (area under the curve [AUC], 0.76) was superior to clinicopathologic model (AUC, 0.68); the combined model (AUC, 0.85) demonstrates strong discriminatory power in predicting nodal pCR. Calibration curves of the nomogram based on the combined model demonstrated that substantial agreement can be observed between the predictions and observations. This nomogram showed a false-negative rates of 16.67% in all patients and 10.53% in patients with triple negative breast cancer. CONCLUSION: Nomogram incorporating routine clinicopathologic and US characteristics can predict nodal pCR and represents a tool to aid in treatment decisions for the axilla after NAC in breast cancer patients.

Phosphocholine-induced energy source shift alleviates mitochondrial dysfunction in lung cells caused by geospecific PM2.5 components.

Fine particulate matter (PM2.5) is globally recognized for its adverse implications on human health. Yet, remain limited the individual contribution of particular PM2.5 components to its toxicity, especially considering regional disparities. Moreover, prevention solutions for PM2.5-associated health effects are scarce. In the present study, we comprehensively characterized and compared the primary PM2.5 constituents and their altered metabolites from two locations: Taiyuan and Guangzhou. Analysis of year-long PM2.5 samples revealed 84 major components, encompassing organic carbon, elemental carbon, ions, metals, and organic chemicals. PM2.5 from Taiyuan exhibited higher contamination, associated health risks, dithiothreitol activity, and cytotoxicities than Guangzhou's counterpart. Applying metabolomics, BEAS-2B lung cells exposed to PM2.5 from both cities were screened for significant alterations. A correlation analysis revealed the metabolites altered by PM2.5 and the critical toxic PM2.5 components in both regions. Among the PM2.5-down-regulated metabolites, phosphocholine emerged as a promising intervention for PM2.5 cytotoxicities. Its supplementation effectively attenuated PM2.5-induced energy metabolism disorder and cell death via activating fatty acid oxidation and inhibiting Phospho1 expression. The highlighted toxic chemicals displayed combined toxicities, potentially counteracted by phosphocholine. Our study offered a promising functional metabolite to alleviate PM2.5-induced cellular disorder and provided insights into the geo-based variability in toxic PM2.5 components.

Effect of early dexamethasone on outcomes of COVID-19: A quasi-experimental study using propensity score matching.

BACKGROUND: The RECOVERY trial demonstrated that the use of dexamethasone is associated with a 36% lower 28-day mortality in hospitalized patients with COVID-19 on invasive mechanical ventilation. Nevertheless, the optimal timing to start dexamethasone remains uncertain. METHODS: We conducted a quasi-experimental study at National Taiwan University Hospital (Taipei, Taiwan) using propensity score matching to simulate a randomized controlled trial to receive or not to receive early dexamethasone (6 mg/day) during the first 7 days following the onset of symptoms. Treatment was standard protocol-based, except for the timing to start dexamethasone, which was left to physicians' decision. The primary outcome is 28-day mortality. Secondary outcomes include secondary infection within 60 days and fulfilling the criteria of de-isolation within 20 days. RESULTS: A total of 377 patients with COVID-19 were enrolled. Early dexamethasone did not decrease 28-day mortality in all patients (adjusted odds ratio [aOR], 1.03; 95% confidence interval [CI], 0.97-1.10) or in patients who required O2 for severe/critical disease at admission (aOR, 1.05; 95%CI, 0.94-1.18); but is associated with a 24% increase in superinfection in all patients (aOR, 1.24; 95% CI, 1.12-1.37) and a 23% increase in superinfection in patients of O2 for several/critical disease at admission (aOR, 1.23; 95% CI, 1.02-1.47). Moreover, early dexamethasone is associated with a 42% increase in likelihood of delayed clearance of SARS-CoV-2 virus (adjusted hazard ratio, 1.42; 95% CI, 1.01-1.98). CONCLUSION: An early start of dexamethasone (within 7 days after the onset of symptoms) could be harmful to hospitalized patients with COVID-19.

Drug repurposing screens to identify potential drugs for chronic kidney disease by targeting prostaglandin E2 receptor.

Renal inflammation and fibrosis are significantly correlated with the deterioration of kidney function and result in chronic kidney disease (CKD). However, current therapies only delay disease progression and have limited treatment effects. Hence, the development of innovative therapeutic approaches to mitigate the progression of CKD has become an attractive issue. To date, the incidence of CKD is still increasing, and the biomarkers of the pathophysiologic processes of CKD are not clear. Therefore, the identification of novel therapeutic targets associated with the progression of CKD is an attractive issue. It is a critical necessity to discover new therapeutics as nephroprotective strategies to stop CKD progression. In this research, we focus on targeting a prostaglandin E2 receptor (EP2) as a nephroprotective strategy for the development of additional anti-inflammatory or antifibrotic strategies for CKD. The in silico study identified that ritodrine, dofetilide, dobutamine, and citalopram are highly related to EP2 from the results of chemical database virtual screening. Furthermore, we found that the above four candidate drugs increased the activation of autophagy in human kidney cells, which also reduced the expression level of fibrosis and NLRP3 inflammasome activation. It is hoped that these findings of the four candidates with anti-NLRP3 inflammasome activation and antifibrotic effects will lead to the development of novel therapies for patients with CKD in the future.

Evolution of neutralizing antibodies and cross-activity against different variants of SARS-CoV-2 in patients recovering from COVID-19.

BACKGROUND: Patients recovering from COVID-19 may need vaccination against SARS-CoV-2 because acquired immunity from primary infection may wane, given the emergence of new SARS-CoV-2 variants. Understanding the trends of anti-spike IgG and neutralizing antibody titers in patients recovering from COVID-19 may inform the decision made on the appropriate interval between recovery and vaccination. METHODS: Participants aged 20 years or older and diagnosed with COVID-19 between January and December, 2020 were enrolled. Serum specimens were collected every three months from 10 days to 12 months after the onset of symptom for determinations of anti-spike IgG and neutralizing antibody titers against SARS-CoV-2 Wuhan strain with D614G mutation, alpha, gamma and delta variants. RESULTS: Of 19 participants, we found a decreasing trend of geometric mean titers of anti-spike IgG from 560.9 to 217 and 92 BAU/mL after a 4-month and a 7-month follow-up, respectively. The anti-spike IgG titers declined more quickly in the ten participants with severe or critical disease than the nine participants with only mild to moderate disease between one month and seven months after SARS-CoV-2 infection (-8.49 vs - 2.34-fold, p < 0.001). The neutralizing activity of the convalescent serum specimens collected from participants recovering from wild-type SARS-CoV-2 infection against different variants was lower, especially against the delta variants (p < 0.01 for each variant with Wuhan strain as reference). CONCLUSION: Acquired immunity from primary infection with SARS-CoV-2 waned within 4-7 months in COVID-19 patients, and neutralizing cross-activities against different SARS-CoV-2 variants were lower compared with those against wild-type strain.

Matrix metalloproteinase-7 promotes chronic kidney disease progression via the induction of inflammasomes and the suppression of autophagy.

Deposition of extracellular matrix (ECM), epithelial-mesenchymal transition (EMT) and inflammation are crucial processes in chronic kidney disease (CKD) progression. The matrix metalloproteinases (MMPs) belong to a major enzyme group of proteinases that are involved in ECM degradation. MMP controls multiple biological processes, such as cell proliferation, EMT and apoptosis. The present study identified the roles of MMP7 in CKD progression. We demonstrated the transcriptional profiles of MMPs in kidney tissues of CKD patients in the Gene Expression Omnibus (GEO) data repository. MMP7 mRNA level was markedly upregulated in kidney tissues of CKD patients. MMP7 overexpression activated the NLRP3 and NLRP6 inflammasomes and increased fibrosis-related proteins in kidney cells. MMP7 inhibited oxidative stress-induced apoptosis and rapamycin-induced autophagy. We found that MMP7 expression in the kidney was increased in various CKD animal models. Knockdown of MMP7 affected renal function and renal fibrosis in a folic acid-induced CKD model. The inhibition of MMP7 decreased fibrosis and NLRP3 and NLRP6 inflammasomes and induced autophagy in kidney tissues. Taken together, these results provide insight into targeting MMP7 as a therapeutic strategy for CKD.

Efficacy of IOTA simple rules, O-RADS, and CA125 to distinguish benign and malignant adnexal masses.

OBJECTIVE: Ovarian cancer is the most deadly deadliest gynecological tumor in the female reproductive system. Therefore, the present study sought to determine the diagnostic performance of International Ovarian Tumor Analysis Simple Rules (IOTA SR), the Ovarian-Adnexal Reporting and Data System (O-RADS), and Cancer Antigen 125 (CA125) in discriminating benign and malignant ovarian tumors. The study also assessed whether a combination of the two ultrasound categories systems and CA125 can improve the diagnostic performance. METHODS: A total of 453 patients diagnosed with ovarian tumors were retrospectively enrolled from Fujian Cancer Hospital between January 2017 and September 2020. The data collected from patients included age, maximum lesion diameter, location, histopathology, levels of CA125, and detailed ultrasound reports. Additionally, all ultrasound images were independently assessed by two ultrasound physicians with more than 5 years of experience in the field, according to the IOTA simple rules and O-RADS guidelines. Furthermore, the area under the curve (AUC), sensitivity, and specificity of the above mentioned predictors were calculated using the receiver operating characteristic curve. RESULTS: Out of the 453 patients, 184 had benign lesions, while 269 had malignant ovarian tumors. In addition, the AUCs of IOTA SR, O-RADS, and CA125 in the overall population were 0.831, 0.804, and 0.812, respectively, and the sensitivities of IOTA SR, O-RADS, and CA125 were 94.42, 94.42, and 80.30%, respectively. On the other hand, the AUCs of IOTA SR combined with CA125, O-RADS combined with CA125, and IOTA SR plus O-RADS combined with CA125 were 0.900, 0.891, and 0.909, respectively. The findings also showed that the AUCs of a combination of the three approaches were significantly higher than those of individual strategies (p<0.05) but not significantly higher than the AUC of a combination of two methods (p>0.05). CONCLUSION: The findings showed that a combination of IOTA SR or O-RADS in combination with CA125 may improve the ability to distinguish benign from malignant ovarian tumors.

Distribution and risk assessment of hexachlorobutadiene, pentachloroanisole, and chlorobenzenes in sediment and wild fish from a region affected by industrial and agricultural activities in South China.

Hexachlorobutadiene, pentachloroanisole, and chlorobenzenes are regulated to control their release into the environment. There is little information regarding the distribution and risks of these pollutants in Chinese rivers. Therefore, we selected a prosperous agricultural and industrial region in South China as our study area and investigated the contamination profiles and risks of these pollutants in sediment and fish tissue samples. The results showed that, when compared with their levels in sediment, these lipophilic pollutants tended to accumulate in fish tissues in the following order: liver > brain > muscle. Some trichlorobenzene was found to be the result of reductive dechlorination of higher chlorinated benzenes. Hexachlorobutadiene and hexachlorobenzene could pose medium risks at certain sampling sites, but in general, almost no risk was found to the ecosystem. When the estimated daily human intakes of analytes through fish consumption were calculated for different age groups, the results suggested the analytes were unlikely to be a serious health concern for human. Our results could be used to update the existing data on the occurrence of these pollutants in the aquatic environment and to provide information for further pollution control by the local government.

Discovery of emerging sulfur-containing PAHs in PM2.5: Contamination profiles and potential health risks.

We reported the discovery and identification of emerging sulfur-containing polycyclic aromatic hydrocarbons, namely polycyclic aromatic sulfur heterocycles (PASHs), in PM2.5 collected from two typical regions of China, Taiyuan and Guangzhou. Until now, there is no research on contamination status, sources and potential health risks of this unexpected group of organic contaminants in PM2.5. High atmospheric concentrations (ngm-3) and significant time-dependent variations were determined in PM2.5 of Taiyuan from 2017 to 2018. Coal combustion/secondary formation and traffic emission/secondary formation were apportioned as possible pollution sources for the PM2.5-bound PASHs in Taiyuan and Guangzhou, respectively. Dithiothreitol and cell viability assays were applied for evaluations of PASH-induced reactive oxygen species (ROS) production and cell toxicity based on the determined real exposure levels for adults. The results illustrated that PASHs in PM2.5 possibly caused oxidative stress and inhibition of human bronchial epithelial cells in seriously polluted regions such as Taiyuan, suggesting that the pollutant-induced health concerns may need more investigations. This study provides new insights into PM2.5 pollution, and is beneficial for the development of effective contamination control strategies and reduction of risks on public health.

Therapeutic Effect of Endothelin-Converting Enzyme Inhibitor on Chronic Kidney Disease through the Inhibition of Endoplasmic Reticulum Stress and the NLRP3 Inflammasome.

Chronic inflammation and oxidative stress significantly contribute to the development and progression of chronic kidney disease (CKD). The NOD-like receptor family pyrin containing domain-3 (NLRP3) inflammasome plays a key role in the inflammatory response. The renal endothelin (ET) system is activated in all cases of CKD. Furthermore, ET-1 promotes renal cellular injury, inflammation, fibrosis and proteinuria. Endothelin-converting enzymes (ECEs) facilitate the final processing step of ET synthesis. However, the roles of ECEs in CKD are not clear. In this study, we investigated the effects of ETs and ECEs on kidney cells. We found that ET-1 and ET-2 expression was significantly upregulated in the renal tissues of CKD patients. ET-1 and ET-2 showed no cytotoxicity on human kidney tubular epithelial cells. However, ET-1 and ET-2 caused endoplasmic reticulum (ER) stress and NLRP3 inflammasome activation in tubular epithelial cells. The ECE inhibitor phosphoramidon induced autophagy. Furthermore, phosphoramidon inhibited ER stress and the NLRP3 inflammasome in tubular epithelial cells. In an adenine diet-induced CKD mouse model, phosphoramidon attenuated the progression of CKD by regulating autophagy, the NLRP3 inflammasome and ER stress. In summary, these findings showed a new strategy to delay CKD progression by inhibiting ECEs through autophagy activation and restraining ER stress and the NLRP3 inflammasome.

Transcriptional identification of differentially expressed genes associated with division of labor in Apis cerana cerana.

Workers of Apis cerana cerana undergo an in-hive nursing to outdoor foraging transition, but the genes underlying this age-related transition remain largely unknown. Here, we sequenced the head transcriptomes of its 7-day-old normal nurses, 18- and 22-day-old normal foragers, 7-day-old precocious foragers and 22-day-old over-aged nurses to unravel the genes associated with this transition. Mapping of the sequence reads to Apis mellifera genome showed that the three types of foragers had a greater percentage of reads from annotated exons and intergenic regions, whereas the two types of nurses had a greater percentage of reads from introns. Pair- and group-wise comparisons of the five transcriptomes revealed 59 uniquely expressed genes (18 in nurses and 41 in foragers) and 14 nurse- and 15 forager-upregulated genes. The uniquely expressed genes are usually low-abundance long noncoding RNAs, transcription factors, transcription coactivators, RNA-binding proteins, kinases or phosphatases that are involved in signaling and/or regulation, whereas the nurse- or forager-upregulated genes are often high-abundance downstream genes that directly perform the tasks of nurses or foragers. Taken together, these results suggest that the nurse-forager transition is coordinated by a social signal-triggered epigenetic shift from introns to exons/intergenic regions and the resulting transcriptional shift between the nurse- and forager-associated genes.

Lactoferrin Contributes a Renoprotective Effect in Acute Kidney Injury and Early Renal Fibrosis.

Patients with acute kidney injury (AKI) who survive the acute stage are at notable risk for chronic kidney disease (CKD) progression. There is no single therapy that can effectively prevent the AKI to CKD transition. Autophagy is a cytoplasmic component degradation pathway and has complex functions in several diseases, such as renal fibrosis. Previous research has shown that lactoferrin has important functions in antioxidant defense and other defense systems, protecting kidneys against various injuries. The present study investigated the effect of lactoferrin in protecting against the AKI to CKD transition. We identified 62 consensus genes with two-fold changes in clinical kidney tissues from AKI and CKD patients. Among the 62 overlay genes, the mRNA levels of LTF were significantly upregulated in the kidney tissues of AKI and CKD patients. Lactoferrin induced autophagy via the activation of the AMPK and inhibition of Akt/mTOR pathway in human kidney proximal tubular cells. Lactoferrin suppressed oxidative stress-induced cell death and apoptosis by augmenting autophagy. Lactoferrin has an antifibrotic role in human kidney tubular cells. In a mouse model of folic acid-induced AKI to CKD transition, treatment with lactoferrin recovered renal function and further suppressed renal fibrosis through the inhibition of apoptosis and the induction of autophagy. These findings identify lactoferrin as a potential therapeutic target for the prevention of the AKI to CKD transition.

GC-MS/MS analysis for source identification of emerging POPs in PM2.5.

Emerging POPs have received increasing attention due to their potential persistence and toxicity, but thus far the report regarding the occurrence and distribution of these POPs in PM2.5 is limited. In this study, an extremely sensitive and reliable method, using ultrasonic solvent extraction and silica gel purification followed by gas chromatography coupled with electron ionization triple quadrupole mass spectrometry, was developed and used for the trace analysis of hexachlorobutadiene (HCBD), pentachloroanisole (PCA) and its analogs chlorobenzenes (CBs) in PM2.5 from Taiyuan within a whole year. The limits of detection and limits of quantitation of analytes were 1.14 × 10-4‒2.74 × 10-4 pg m-3 and 3.80 × 10-4‒9.14 × 10-4 pg m-3. HCBD and PCA were detected at the mean concentrations of 3.69 and 1.84 pg m-3 in PM2.5, which is reported for the first time. Based on the results of statistical analysis, HCBD may come from the unintentional emission of manufacture or incineration of chlorinate-contained products but not coal combustion, while O3-induced photoreaction was the potential source of PCA in PM2.5. The temporal distributions of CBs in PM2.5 were closely related to coal-driven or agricultural activities. Accordingly, our study reveals the contamination profiles of emerging POPs in PM2.5 from Taiyuan.

Contamination profiles and potential health risks of organophosphate flame retardants in PM2.5 from Guangzhou and Taiyuan, China.

Organophosphate flame retardants (OPFRs) are emerging contaminants in recent years. They can be present in the atmospheric fine particle (PM2.5), leading to potential adverse effects on humans. In this study, the concentrations and in vitro toxicities of OPFRs in PM2.5 samples were investigated for one year at Guangzhou and Taiyuan in China. Eleven OPFRs, including chloro-, aryl-, and alkyl-substituted OPFRs, were detected at total concentrations ranging from 3.10 to 544 ng m-3. Chloro-substituted OPFRs were the dominant contaminants. Based on the statistical analysis, the same contamination sources of all OPFRs were found except for tris(butoxyethyl) phosphate (TBOEP) and triethyl phosphate (TEP), which may come from traffic emission. The results of cell viability and dithiothreitol assays indicated that OPFRs and PM2.5 could induce the death of normal lung epithelial cells and the production of reactive oxygen species (ROS), respectively. According to the redundancy analysis, the distribution of OPFRs was significantly related to the PM2.5 concentrations and indirectly associated with ROS production induced by PM2.5 from Taiyuan. Exposure to PM2.5-bound OPFRs in Guangzhou and Taiyuan only posed minimum health risks to both toddlers and adults. These findings could provide important evidence to better clarify the contamination profiles and human health risks of OPFRs in atmospheric fine particles.

Traffic-related particulate matter exposure induces nephrotoxicity in vitro and in vivo.

Traffic emission is responsible for most small-sized particulate matter (PM) air pollution in urban areas. Several recent studies have indicated that traffic-related PM may aggravate kidney disease. Furthermore, exposure to particulate air pollution may be related to the risk of chronic kidney disease (CKD). However, the underlying molecular mechanisms have not been adequately addressed. In the present study, we studied the mechanisms of renal damage that might be associated with exposure to PM. In a real world of whole-body exposure to traffic-related PM model for 3-6 months, PM in urban ambient air can affect kidney function and induce autophagy, endoplasmic reticulum (ER) stress and apoptosis in kidney tissues. Exposure to traffic-related diesel particulate matter (DPM) led to a reduction in cell viability in human kidney tubular epithelial cells HK-2. DPM increased mitochondrial reactive oxygen species (ROS) and decreased the mitochondrial membrane potential. Furthermore, DPM induced ER stress and activated the unfolded protein response (UPR) pathway. Eventually, DPM exposure induced caspase pathways and triggered apoptosis. In addition, DPM induced autophagy through the inhibition of the Akt/mTOR pathway. Autophagy inhibition resulted in significantly increased cytotoxicity and apoptosis. These findings suggest that air pollution in urban areas may cause nephrotoxicity and autophagy as a protective role in PM-induced cytotoxicity.

Determination of HFRs and OPFRs in PM2.5 by ultrasonic-assisted extraction combined with multi-segment column purification and GC-MS/MS.

Toxic chemicals such as flame retardants are associated with atmospheric fine particles (PM2.5), which are an important pollutant in the world. In this study, a sensitive method using gas chromatography-tandem triple quadrupole mass spectrometry combined with ultrasonic-assisted extraction and multi-phase column purification was developed for simultaneously determination of 29 flame retardants including halogenated flame retardants (HFRs) and organophosphate flame retardants (OPFRs) in PM2.5 samples. Extraction time, as well as the type and volume of elution solvent were optimized. The recoveries of all target flame retardants from PM2.5 samples were in the range of 70%‒130%, with good repeatability and reproducibility (0.39%‒17.4%). The instrumental detection limits (IDLs) and method quantitation limits (MQLs) of HFRs were in the range of 0.004‒5.44 pg and 0.002‒2.52 pg m-3, while those of OPFRs were 0.003‒0.23 pg and 0.07‒5.41 pg m-3, respectively. The developed method has been successfully applied for analysis of target flame retardants in atmospheric PM2.5 collected from the cities of Guangzhou and Taiyuan, China. HFRs were found at concentrations of 45.7‒1230 pg m-3 and 51.2‒82.3 pg m-3 in Guangzhou and Taiyuan. The concentrations of HFRs were lower than those of OPFRs, which were detected at concentrations of 6004‒49,800 pg m-3 and 16,741‒34,346 pg m-3 in Guangzhou and Taiyuan. Accordingly, the analytical method is robust and useful for further elucidating the contamination profiles of flame retardants in PM2.5.

Analysis of microbial sequences in plasma cell-free DNA for early-onset breast cancer patients and healthy females.

BACKGROUND: Cell-free circulating DNA (cfDNA) is becoming a useful biopsy for noninvasive diagnosis of diseases. Microbial sequences in plasma cfDNA may provide important information to improve prognosis and treatment. We have developed a stringent method to identify microbial species via microbial cfDNA in the blood plasma of early-onset breast cancer (EOBC) patients and healthy females. Empirically, microbe-originated sequence reads were identified by mapping non-human PE reads in cfDNA libraries to microbial databases. Those mapped concordantly to unique microbial species were assembled into contigs, which were subsequently aligned to the same databases. Microbial species uniquely aligned were identified and compared across all individuals on MCRPM (Microbial CfDNA Reads Per Million quality PE reads) basis. RESULTS: The predominant microbial cfDNAs in all plasma samples examined are originated from bacteria and these bacteria were limited to only a few genera. Among those, Acinetobacter johnsonii XBB1 and low levels of Mycobacterium spp. were commonly found in all healthy females, but also present in an EOBC patient. Compared to those in healthy counterparts, bacterial species in EOBC patients are more diverse and more likely to present at high levels. Among these three EOBC patients tested, a patient who has record high titer (2,724 MCRPM) of Pseudomonas mendocina together with 8.82 MCRPM of Pannonibacter phragmitetus has passed away; another patient infected by multiple Sphingomonas species remains alive; while the third patient who has similar microbial species (Acinetobacter johnsonii XBB1) commonly seen in normal controls is having a normal life. CONCLUSIONS: Our preliminary data on the profiles of microbial cfDNA sequences suggested that it may have some prognostic value in cancer patients. Validation in larger number of patients is warranted.