Reactive aldehyde chemistry explains the missing source of hydroxyl radicals.

Hydroxyl radicals (OH) determine the tropospheric self-cleansing capacity, thus regulating air quality and climate. However, the state-of-the-art mechanisms still underestimate OH at low nitrogen oxide and high volatile organic compound regimes even considering the latest isoprene chemistry. Here we propose that the reactive aldehyde chemistry, especially the autoxidation of carbonyl organic peroxy radicals (R(CO)O2) derived from higher aldehydes, is a noteworthy OH regeneration mechanism that overwhelms the contribution of the isoprene autoxidation, the latter has been proved to largely contribute to the missing OH source under high isoprene condition. As diagnosed by the quantum chemical calculations, the R(CO)O2 radicals undergo fast H-migration to produce unsaturated hydroperoxyl-carbonyls that generate OH through rapid photolysis. This chemistry could explain almost all unknown OH sources in areas rich in both natural and anthropogenic emissions in the warm seasons, and may increasingly impact the global self-cleansing capacity in a future low nitrogen oxide society under carbon neutrality scenarios.

How autophagy, a potential therapeutic target, regulates intestinal inflammation.

Inflammatory bowel disease (IBD) is a group of disorders that cause chronic inflammation in the intestines, with the primary types including ulcerative colitis and Crohn's disease. The link between autophagy, a catabolic mechanism in which cells clear protein aggregates and damaged organelles, and intestinal health has been widely studied. Experimental animal studies and human clinical studies have revealed that autophagy is pivotal for intestinal homeostasis maintenance, gut ecology regulation and other aspects. However, few articles have summarized and discussed the pathways by which autophagy improves or exacerbates IBD. Here, we review how autophagy alleviates IBD through the specific genes (e.g., ATG16L1, IRGM, NOD2 and LRRK2), crosstalk of multiple phenotypes with autophagy (e.g., Interaction of autophagy with endoplasmic reticulum stress, intestinal antimicrobial defense and apoptosis) and autophagy-associated signaling pathways. Moreover, we briefly discuss the role of autophagy in colorectal cancer and current status of autophagy-based drug research for IBD. It should be emphasized that autophagy has cell-specific and environment-specific effects on the gut. One of the problems of IBD research is to understand how autophagy plays a role in intestinal tract under specific environmental factors. A better understanding of the mechanism of autophagy in the occurrence and progression of IBD will provide references for the development of therapeutic drugs and disease management for IBD in the future.

Cellular and Humoral Responses to Recombinant and Inactivated SARS-CoV-2 Vaccines in CKD Patients: An Observational Study.

BACKGROUND: It remains unclear what B cell and humoral responses are mounted by chronic kidney disease (CKD) patients in response to recombinant and inactivated SARS-CoV-2 vaccines. In this study, we aimed to explore the cellular and humoral responses, and the safety of recombinant and inactivated SARS-CoV-2 vaccines in CKD patients. METHODS: 79 CKD and 420 non-CKD individuals, who completed a full course of vaccination, were enrolled in the study. Adverse events (AEs) were collected via a questionnaire. Cellular and humoral responses were detected at 1, 3, and 6 months, including IgG antibody against the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein (anti-RBD-IgG), neutralizing antibodies (NAbs), the positive rate of NAbs and anti-RBD-IgG, RBD-atypical memory B cells (MBCs) (CD3 - CD19 + RBD + CD21 - CD27-), RBD-activated MBCs (CD3 - CD19 + RBD + CD21 - CD27+), RBD-resting MBCs (CD3 - CD19 + RBD + CD21 + CD27+), and RBD-intermediate MBCs (CD3 - CD19 + RBD + CD21 + CD27-). RESULTS: We found no differences in the positivity rates of NAbs (70.89% vs. 79.49%, p = 0.212) and anti-RBD IgG (72.15% vs. 83.33%, p = 0.092) between the CKD and control groups. A total of 22 CKD individuals completed the full follow-up (1, 3, and 6 months). Significant and sustained declines were found at 3 months in anti-RBD IgG (26.64 BAU/mL vs. 9.08 BAU/mL, p < 0.001) and NAbs (161.60 IU/mL vs. 68.45 IU/mL p < 0.001), and at 6 months in anti-RBD IgG (9.08 BAU/mL vs. 5.40 BAU/mL, p = 0.064) and NAbs (68.45 IU/mL vs. 51.03 IU/mL, p = 0.001). Significant differences were identified in MBC subgroups between CKD patients and healthy controls, including RBD-specific atypical MBCs (60.5% vs. 17.9%, p < 0.001), RBD-specific activated MBCs (36.3% vs. 14.8%, p < 0.001), RBD-specific intermediate MBCs (1.24% vs. 42.6%, p < 0.001), and resting MBCs (1.34% vs. 22.4%, p < 0.001). Most AEs in CKD patients were mild (grade 1 and 2) and self-limiting. One patient with CKD presented with a recurrence of nephrotic syndrome after vaccination. CONCLUSIONS: The recombinant and inactivated SARS-CoV-2 vaccine was well-tolerated and showed a good response in the CKD cohort. Our study also revealed differences in MBC subtypes after SARS-CoV-2 vaccination between CKD patients and healthy controls.

Observation and modeling of organic nitrates on a suburban site in southwest China.

Here we report the measurements of two types of organic nitrates (ONs), peroxy nitrates (PNs) and alkyl nitrates (ANs), in Chengdu, China, during summer 2019. The average concentrations of PNs and ANs were 1.3 ± 1.1 ppbv and 0.5 ± 0.3 ppbv during the day, with peaks of 7.7 ppbv and 1.9 ppbv, respectively, which were in the middle and upper end of the reported levels in China. Much higher PNs and ANs concentrations were found during the photochemical pollution period than during the clean period. Box model simulation was capable of reproducing PNs during photochemical pollution episodes but showed overestimation in other periods, which was likely caused by the simplification of PNs sinks. The OH oxidation of aldehydes and ketones was the most important source of the PNs precursors, PAs (peroxyacyl radicals), except for the thermal decomposition of PNs, which was further confirmed by the relative incremental reactivity (RIR) analysis. The model basically reproduced the observed ANs by the refinement of related mechanisms, with isoprene contributing to its formation by 29.2 %. The observed PNs and total oxidants (Ox = NO2 + O3) showed a good positive correlation, with a ratio of PNs to Ox of 0.079, indicating a strong suppression of PNs chemistry to ozone formation. The model quantified the suppression of PNs chemistry on the peak ozone production rate by 21.3 % on average and inhibited ozone formation up to 20 ppbv in total. The RIR analysis suggests that the production of both O3 and ANs was in the VOC-limited regime and highlights the importance of VOC control (especially aromatics) to mitigate photochemical pollution in Chengdu. The study deepens the understanding of photochemical pollution in urban areas of western China and further emphasizes the impacts of ONs chemistry on ozone pollution.

Pectolinarigenin Suppresses LPS-Induced Inflammatory Response in Macrophages and Attenuates DSS-Induced Colitis by Modulating the NF-κB/Nrf2 Signaling Pathway.

Pectolinarigenin (PEC), a natural flavonoid present in cirsium chanroenicum and citrus fruits, has possess the distinct pharmacological activities. However, its molecular mechanisms and pharmacological effects on intestinal illness have not been elucidated. In the present study, we investigated the potential beneficial effects of pectolinarigenin (PEC) on lipopolysaccharide (LPS)-induced macrophage cells and the dextran sulfate sodium (DSS)-induced colitis model. Our findings showed that PEC pretreatment inhibits the LPS-induced nuclear factor-kappa B (NF-κB) activation by interfering with the degradation of IκB-α. Further, increased Nrf2 protein expression was reported on PEC treated RAW 264.7 and THP1 cell lines. In addition, we revealed that PEC mediated the NF-κB/Nrf2 pathway regulation, which in turn inhibits the synthesis of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), interleukin-1beta (IL-1ß), and tumor necrosis factor-alpha (TNF-α) on RAW 264.7 and THP1 cells. Furthermore, PEC dose-dependently reduced the DSS-induced inflammation in the colon by regulating NF-κB/Nrf2 signaling pathway and enhancing the myeloperoxidase (MPO) activity and redox regulators such as superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), and lipid peroxidation byproduct malondialdehyde (MDA) in DSS-induced inflamed colon. Similarly, we reported the minimal pathological damages in the PEC-treated mice colon, as well as increase goblet cell population and mucin-2 production. In conclusion, our findings demonstrate that PEC reduces the DSS-induced colitis in mice by regulating the NF-κB/Nrf2 pathway. Thus, PEC might be a promising therapeutic agent for the treatment of inflammatory bowel disease.

TEPP-46-Based AIE Fluorescent Probe for Detection and Bioimaging of PKM2 in Living Cells.

Pyruvate kinase (PK) M2 (PKM2), a glycolytic enzyme, is a hallmark of different types of tumors and plays a significant role in the Warburg effect. However, there is no fluorescent probe for PKM2 that has been reported yet. In this study, TEPC466, a novel TEPP-46-based aggregation-induced emission (AIE) probe for the detection of PKM2, was designed, synthesized, and fully characterized by 1H NMR, 13C NMR, and high-resolution mass spectrometry. When the fluorescent agent, coumarine, was conjugated to TEPP-46, the bioprobe TEPC466 showed a high degree of selectivity and sensitivity for the detection of PKM2 protein via the AIE effect. TEPC466 was then successfully applied in imaging the PKM2 protein in colorectal cancer cells with low toxicity. Moreover, structure-based modeling and the PK activity assay confirmed that TEPC466 has a better binding with PKM2 than TEPP-46, which suggests that TEPC466 could also be a good agonist of PKM2. Taken together, the bioprobe shows potential in selective detection of PKM2 and provides a useful tool for cancer diagnosis and therapy.

Field Determination of Nitrate Formation Pathway in Winter Beijing.

Particulate nitrate (pNO3-) has often been found to be the major component of fine particles in urban air-sheds in China, the United States, and Europe during winter haze episodes in recent years. However, there is a lack of knowledge regarding the experimentally determined contribution of different chemical pathways to the formation of pNO3-. Here, for the first time, we combine ground and tall-tower observations to quantify the chemical formation of pNO3- using observationally constrained model approach based on direct observations of OH and N2O5 for the urban air-shed. We find that the gas-phase oxidation pathway (OH+NO2) during the daytime is the dominant channel over the nocturnal uptake of N2O5 during pollution episodes, with percentages of 74% in urban areas and 76% in suburban areas. This is quite different from previous studies in some regions of the US, in which the uptake of N2O5 was concluded to account for a larger contribution in winter. These results indicate that the driving factor of nitrate pollution in Beijing and different regions of the US is different, as are the mitigation strategies for particulate nitrate.

Orientin suppresses oxidized low-density lipoproteins induced inflammation and oxidative stress of macrophages in atherosclerosis.

Atherosclerosis is a main reason for peripheral vascular disease. The present study aims to investigate the effects of macrophage foam cells which is an initial part in atherosclerosis. RAW 264.7 were treated with 80 µg/mL oxidized low-density lipoproteins (ox-LDL) to mimic atherosclerosis in vitro. Orientin, a flavonoid from plants, inhibited ox-LDL induced TNFα, IL-6, IL-1ß expression increase. In addition, Orientin also can inhibit the emergence of ox-LDL-induced lipid droplets. The scavenger receptor CD 36 of ox-LDL was significantly downregulated after the treatment of orientin. Inhibition of ROS generation and increasing of eNOS expression by Orientin treatment was used to show the alteration of oxidative stress. Moreover, the expression levels of Angiopoietin-like 2 (angptl2) and NF-κB were significantly upregulated after cells induced by ox-LDL, whereas orientin significantly reversed the effects of ox-LDL. Orientin inhibited ox-LDL-induced inflammation and oxidative stress, and CD36 may be the key regulator during Orientin action.

Use of Interferon-γ release assay for the diagnosis of female genital tuberculosis in Northwest China.

BACKGROUND: Female genital tuberculosis (FGTB) is one of the major causes of infertility. However, nonspecific manifestations and the lack of easy access to gold-standard diagnostic test render a diagnostic difficult for FGTB. The objective of this study was to determine T-SPOT.TB (an interferon-γ release assay, IGRA) performance in patients with FGTB. METHODS: A total of 213 female patients with validated T-SPOT.TB results were recruited in this retrospective study. Among which, 103 were confirmed FGTB, and 110 were excluded from tuberculosis (control). Of the confirmed FGTB patients, 52 were confirmed by microbiologically/histopathologically examination, while the remaining 51 were clinically confirmed (successfully responsive to anti-tuberculosis treatment). T-SPOT.TB test was performed in both FGTB and control group during the diagnostic procedure. RESULTS: The overall sensitivity and specificity of T-SPOT.TB were 86.41% and 75.45% respectively. Sensitivity of T-SPOT.TB was significantly higher when compared with conventional tuberculosis diagnostic tests. Moreover, T-SPOT.TB test using pelvic effusion (PE) showed higher sensitivity than using corresponding peripheral blood (PB) (94.44% vs 72.22%, P < 0.001). Mean value of spot forming cells (SFCs) of T-SPOT.TB using PE was significantly higher than that of PB in FGTB group (193 (IQR 105-280) SFCs/2.5 × 105 PEMCs vs 71 (IQR 36-107) SFCs/2.5 × 105 PBMCs, P = 0.01), while this was not detected in control group (11 (IQR 0-22) SFCs/2.5 × 105 PEMCs vs 9 (IQR 0-18) SFCs/2.5 × 105 PBMCs, P = 0.77). CONCLUSION: These results demonstrated that T-SPOT.TB, especially PE T-SPOT.TB, is an useful adjunct in FGTB diagnosis.

Short-Term Outcomes Using a Drug-Coated Balloon for Transplant Renal Artery Stenosis.

BACKGROUND This study aimed to evaluate the early and mid-term outcomes of drug-coated balloon (DCB) use in patients who underwent intervention for transplant renal artery stenosis (TRAS). MATERIAL AND METHODS We retrospectively reviewed the records of TRAS patients who received endovascular therapy with DCB in our institution from March 2016 to January 2017. Statistical analysis of pre-/postoperative levels of serum creatinine (Scr), systolic blood pressure (SBP), and renal artery peak systolic velocities (PSV) were performed. RESULTS Fourteen patients presenting with TRAS, which were mostly located at the anastomosis (n=9) and transplanted artery proximal portion (n=2), were treated with DCB. Three TRAS patients with in-stent restenosis (ISR) were also included in the series. The procedure technique success rate was 100%. The mean follow-up time was 8.6 months. The Scr level decreased from 481.8 µmol/L (208.5-746.2µmol/L) pre-operation to 154µmol/L (89.1-301.2 µmol/L, p<0.01) at 1 month post-intervention. The SBP varied from 161.4 mmHg (152-173 mmHg) to 144.8 mmHg (136-154 mmHg, p<0.01). Renal artery PSV decreased from 364.1 cm/s (217.6-511.9 cm/s) to 134.9 cm/s (79.8-184.2 cm/s, p<0.01). Eleven patients finished mid-term (>6 months) follow-up. The statistical results were not significant compared to those at 1 month, although they all slightly decreased. No re-intervention was performed. CONCLUSIONS The endovascular approach to TRAS with DCB was a safe and effective treatment for restore and maintain the artery flow and renal function in short-term follow-up.

[Effects of alcohol on benign prostate hyperplasia induced by testosterone propionate in mice].

OBJECTIVE: To study the effects of alcohol administration on benign prostate hyperplasia(BPH) and the reproductive toxicity during development of benign prostate hyperplasia. METHODS: Seventy adult male Kunming mice were randomly divided into seven groups:control (group CON), negative control (group NC, injected subcutaneously with soybean oil, 25 mg/(kg·d), intragastric administration of distilled water, 7.5 ml/(kg·d)), alcohol for 7 and 21 days (group AL7 and AL21, intragastric administration with wine of 50% alcohol, 7.5 ml/(kg·d)), testosterone propionate for 7 and 21 days (group TP7 and TP21, injected subcutaneously with testosterone propionate, 25 mg/(kg·d)), testosterone propionate+alcohol for 7 days (group TP+AL7, injected subcutaneously with testosterone propionate, 25 mg/(kg·d), and intragastric administration with wine of 50% alcohol, 7.5 ml/(kg·d)),10 mice in each groups. Twenty-four hours after the last administration, mice were sacrificed. The indexes of prostate and testis and the parameters of sperm were determined in mice. The levels of free radicals, antioxidation and histopathological changes in testis and prostate were determined. RESULTS: Compared with the control, TP7d group, AL7 and AL21d groups, the prostate coefficient of TP + AL7d group was increased significantly and the quantity and quality of sperm were decreased significantly (P<0.05), the content of MDA in prostate and testis was increased significantly, meanwhile the activities of SOD and GPx were decreased significantly (P< 0.05). Compared with TP21d group, the prostate coefficient of TP + AL7d group had no significant difference (P>0.05). CONCLUSIONS: The typical BPH state could be induced after 7-day treatment of testosterone propionate and alcohol. The testicular and sperm were damaged which enhanced the oxidative stress in reproductive system. The results indicated that alcohol could significantly promote the prostate hyperplasia induced by testosterone propionate in mice.

Heat-Labile Enterotoxin-Induced PERK-CHOP Pathway Activation Causes Intestinal Epithelial Cell Apoptosis.

Enterotoxigenic Escherichia coli (ETEC) is a leading cause of diarrhea among children and travelers in developing countries, and heat-labile enterotoxin (LT) is one of the most important virulence factors. The pathogenesis of and virulence factors associated with ETEC have been well-characterized; however, the extent to which ETEC damages host cells remains unclear. In this study, we found that LT could induce decreases in intestinal epithelial cell viability and induce apoptosis in a dose- and time- dependent manner in both HCT-8 and Caco-2 cells. We analyzed the expression profiles of apoptosis-related proteins via protein array technology and found that Bax, p-p53(S46), cleaved caspase-3, and TNFRI/TNFRSF1A expression levels were significantly up-regulated in wild-type ETEC- but not in ΔLT ETEC-infected HCT-8 cells. Bax is essential for endoplasmic reticulum (ER) stress-triggered apoptosis, and our RNAi experiments showed that the PERK-eIF2-CHOP pathway and reactive oxygen species (ROS) are also main participants in this process. LT-induced ROS generation was decreased in CHOP-knockdown HCT-8 cells compared to that in control cells. Moreover, pretreatment with the ROS inhibitor NAC down-regulated GRP78, CHOP, Bim, and cleaved caspase-3 expression, resulting in a reduction in the apoptosis rate from 36.2 to 20.3% in LT-treated HCT-8 cells. Furthermore, ROS inhibition also attenuated LT-induced apoptosis in the small intestinal mucosa in the ETEC-inoculation mouse model.