Joint association of weight-adjusted-waist index and physical activity with insulin resistance in adolescents: a cross-sectional study.

BACKGROUND: The weight-adjusted waist index (WWI) is a recently developed obesity metric, and the aim of this study was to investigate the relationship between physical activity (PA) and WWI and the homeostasis model assessment of insulin resistance (HOMA-IR) in adolescents, as well as the joint association of HOMA-IR. METHODS: This study was based on the National Health and Nutrition Survey conducted between 2013 and 2016 and included 1024 adolescents whose median age was 15.4. Multivariate linear regression was used to examine the associations between HOMA-IR and PA and WWI. Using generalized additive models, a potential nonlinear link between WWI and HOMA-IR was evaluated. Subgroup analysis was also carried out. RESULTS: The fully adjusted model revealed a positive association (ß: 0.48, 95% CI: 0.43, 0.53) between the WWI and HOMA-IR. The HOMA-IR was lower in physically active (ß: -0.16, 95% CI: -0.26, -0.05) participants versus inactive participants. Participants who had higher WWI and were not physically active (ß: 0.69; 95% CI: 0.56, 0.82) had the highest levels of HOMA-IR compared to participants who had lower WWI and were physically active. Subgroup analysis revealed that these correlations were similar in males and females. CONCLUSION: Our results demonstrated that higher WWI and PA were associated with a lower HOMA-IR and that WWI and PA had a combined association with HOMA-IR. The findings of this study are informative for the preventing insulin resistance in adolescents.

Relationship of urinary glyphosate concentrations with glycosylated hemoglobin and diabetes in US adults: a cross-sectional study.

BACKGROUND: Glyphosate is a commonly used herbicide worldwide and is purportedly associated with multiple health effects. Research assessing the association of glyphosate concentrations with glycosylated hemoglobin (HbA1c) levels and the prevalence of diabetes is scarce. We sought to evaluate the association between urinary glyphosate levels and HbA1c levels and the prevalence of diabetes. METHODS: A total of 2,745 adults in the National Health and Nutrition Examination Survey from 2013 to 2016 were included in this study. Generalized linear models (GLM) were applied to evaluate the associations of glyphosate concentrations with HbA1c levels and the prevalence of diabetes. The dose-response relationship was examined using restricted cubic splines (RCS). RESULTS: Significantly positive correlations of urinary glyphosate concentrations with HbA1c levels (percentage change: 1.45; 95% CI: 0.95, 1.96; P < 0.001) and the prevalence of diabetes (OR: 1.45; 95% CI: 1.24, 1.68; P < 0.001) were found after adjustment. Compared with the lowest quartile of glyphosate levels, the highest quartile was positively associated with HbA1c levels (percentage change: 4.19; 95% CI: 2.54, 5.85; P < 0.001) and the prevalence of diabetes (OR: 1.89; 95% CI: 1.37, 2.63; P < 0.001). The RCS curves demonstrated a monotonically increasing dose-response relationship between urinary glyphosate levels and the prevalence of diabetes and HbA1c levels. CONCLUSIONS: Urinary glyphosate concentrations are positively associated with HBA1c levels and the prevalence of diabetes. To verify our findings, additional large-scale prospective investigations are required.

Granulysin-mediated reduction of PDZRN3 induces Cx43 gap junctions activity exacerbating skin damage in trichloroethylene hypersensitivity syndrome.

Trichloroethylene (TCE)-induced hypersensitivity syndrome (THS) has been a concern for many researchers in the field of environmental and occupational health. Currently, there is no specific treatment for THS, leaving patients to contend with severe infections arising from extensive skin lesions, consequently leading to serious adverse effects. However, the pathogenesis of severe skin damage in THS remains unclear. This study aims to investigate the specific danger signals and mechanisms underlying skin damage in THS through in vivo and in vitro experiments. We identified that cell supernatant containing 15 kDa granulysin (GNLY), released from activated CD3-CD56+NK cells or CD3+CD56+NKT cells in PBMC induced by TCE or its metabolite, promoted apoptosis in HaCaT cells. The apoptosis level decreased upon neutralization of GNLY in the supernatant by a GNLY-neutralizing antibody in HaCaT cells. Subcutaneous injection of recombinant 15 kDa GNLY exacerbated skin damage in the THS mouse model and better mimicked patients' disease states. Recombinant 15 kDa GNLY could directly induce cellular communication disorders, inflammation, and apoptosis in HaCaT cells. In addition to its cytotoxic effects, GNLY released from TCE-activated NK cells and NKT cells or synthesized GNLY alone could induce aberrant expression of the E3 ubiquitin ligase PDZRN3, causing dysregulation of the ubiquitination of the cell itself. Consequently, this resulted in the persistent opening of gap junctions composed of connexin43, thereby intensifying cellular inflammation and apoptosis through the "bystander effect". This study provides experimental evidence elucidating the mechanisms of THS skin damage and offers a novel theoretical foundation for the development of effective therapies targeting severe dermatitis induced by chemicals or drugs.

Association between blood metals mixture and chronic kidney disease in adults: NHANES 2013-2016.

BACKGROUND: The association between single metal exposure and chronic kidney disease (CKD) has been established. However, there is limited research on the effects of multi-metal mixtures and their potential age-specific associations with kidney injury. This study aimed to examine the relationship between metal mixtures and kidney function in adults, while also exploring the modifying effects of age. METHODS: We included a subset (n = 4250) of a nationally representative adult population in the National Health and Nutrition Examination Survey (NHANES) 2013-2016. Kidney function was assessed using the glomerular filtration rate (eGFR) and creatinine albumin ratio (ACR). The individual and combined effects of lead (Pb), cadmium (Cd), mercury, and manganese on kidney injury and the risk of CKD were evaluated. RESULTS: Pb and Cd were found to be positively associated with decreased kidney function. For a one Ln-unit increase in lead and cadmium, the adjusted ORs of CKD were 1.60 (95% CI: 1.35, 1.90) and 1.41 (95% CI:1.12, 1.77), respectively. We also observed an interaction between lead and cadmium for ACR. We also observed the joint effect between Pb and Cd on eGFR, ACR and CKD. Stratified analysis found a higher risk of decreased kidney function among older individuals. The quantile-g calculation model further showed that metal mixture was associated with decreased kidney function and the risk of CKD (OR = 1.53, 95% CI: 1.22, 1.90). And lead and cadmium were the main contributors. And Pb and Cd were the major components that increased the risk of CKD. CONCLUSION: Co-exposure to metal mixture were associated with reduced kidney function in adults, especially in older. Our findings support co-exposure to lead and cadmium as risk factors of CKD in adults.

Herpesvirus activated NF-κB-mediated antigen processing and presentation to aggravate trichloroethylene-induced hypersensitivity dermatitis.

Trichloroethylene-induced hypersensitivity dermatitis (TIHD) is a delayed hypersensitivity response that is affected by genetic and environmental factors. Occupational exposure to trichloroethylene (TCE) enhances antigen presentation, leading to hypersensitivity in workers with the HLA-B* 13:01 allele. Several studies have observed the activation of herpesviruses, such as EpsteinBarr virus (EBV), in TIHD patients. However, the underlying mechanisms remain unclear. Toll-like receptors (TLRs) play a pivotal role in the pathogenesis of herpesvirus infection. This study aimed to explore whether TLRs serve as a shared mechanism for both herpesvirus and allergenic chemicals. In this study, HLA-B* 13:01-transfected Hmy2. A C1R cell model was constructed, and cells were treated with TCOH and EBV to explore the possible mechanisms. We established a mouse model of dermatitis and used a TLR4 agonist to verify the effect of herpesvirus on TIHD. The results showed that EBV and TCOH synergistically enhance antigen processing and presentation via the TLR2/NF-κB axis. Furthermore, TLR4 agonist further aggravated skin lesions and liver damage in TCE-sensitized mice through TLR4/NF-κB axis-mediated antigen processing and presentation. Together, this study indicates that viral infection further aggravates the inflammatory response in TIHD based on environment-gene interactions.

Unveiling the mechanisms of trichloroethylene hypersensitivity syndrome: Exploring the role of connexin 43 gap junctions in severe skin damage.

Trichloroethylene (TCE), extensively used as an organic solvent in various industrial applications, has been identified as a causative factor in inducing hypersensitivity syndrome (THS). Currently, there is no specific treatment for THS, and most patients experience serious adverse outcomes due to extensive skin damage leading to severe infection. However, the pathogenesis of THS-associated skin damage remains unclear. This study aims to elucidate the mechanism underlying skin damage from the perspective of intercellular communication and gap junctions in THS. Our results verified that hyperactivation of connexin43 gap junctions, caused by the aberrantly elevated expression of connexin43, triggers a bystander effect that promotes apoptosis and inflammation in THS via the TNF-TNFRSF1B and mitochondria-associated pathways. Additionally, we identified the gap junction inhibitor Carbenoxolone disodium (CBX) as a promising agent for the treatment of skin damage in THS. CBX protects against inflammatory cell infiltration in the skin and decreases immune cell imbalance in the peripheral blood of THS mice. Furthermore, CBX reduces connexin43 expression, apoptosis and inflammation in THS mice. The study reveals new insights into the mechanisms underlying TCE-induced skin damage, offering a potential treatment strategy for the development of effective therapies targeting severe dermatitis induced by chemical exposure.

Membrane Attack Complex C5b-9 Promotes Renal Tubular Epithelial Cell Pyroptosis in Trichloroethylene-Sensitized Mice.

Trichloroethylene (TCE), a commonly used organic solvent, is known to cause trichloroethylene hypersensitivity syndrome (THS), also called occupational medicamentosa-like dermatitis due to TCE (OMDT) in China. OMDT patients presented with severe inflammatory kidney damage, and we have previously shown that the renal damage is related to the terminal complement complex C5b-9. Here, we sought to determine whether C5b-9 participated in TCE-induced immune kidney injury by promoting pyroptosis, a new form of programed cell death linked to inflammatory response, with underlying molecular mechanisms involving the NLRP3 inflammasome. A BALB/c mouse-based model of OMDT was established by dermal TCE sensitization in the presence or absence of C5b-9 inhibitor (sCD59-Cys, 25µg/mouse) and NLRP3 antagonist (MCC950, 10 mg/kg). Kidney histopathology, renal function, expression of inflammatory mediators and the pyroptosis executive protein gasdermin D (GSDMD), and the activation of pyroptosis canonical NLRP3/caspase-1 pathway were examined in the mouse model. Renal tubular damage was observed in TCE-sensitized mice. GSDMD was mainly expressed on renal tubular epithelial cells (RTECs). The caspase-1-dependent canonical pathway of pyroptosis was activated in TCE-induced renal damage. Pharmacological inhibition of C5b-9 could restrain the caspase-1-dependent canonical pathway and rescued the renal tubular damage. Taken together, our results demonstrated that complement C5b-9 plays a central role in TCE-induced immune kidney damage, and the underlying mechanisms involve NLRP3-mediated pyroptosis.

ROS-mediated inflammatory response in liver damage via regulating the Nrf2/HO-1/NLRP3 pathway in mice with trichloroethylene hypersensitivity syndrome.

Trichloroethylene hypersensitivity syndrome (THS), mainly caused by occupational exposure to trichloroethylene (TCE), can give rise to serious and fatal hepatic damage. To date, the precise mechanisms of hepatic damage in THS remain unclear. Recent studies showed that reactive oxygen species (ROS) play a core role in cell death and inflammatory response. Therefore, the present study sought to explore whether ROS-mediated inflammatory responses contribute to the hepatic damage in TCE sensitization. To this end, a mouse model of TCE sensitization was established; in some cases, hosts were pretreated with tempol, an ROS scavenger. The results showed that TCE sensitization caused hepatic pathological/functional changes, ROS generation, and oxidative stress, alterations of the anti-oxidant defense Nrf2/HO-1/NLRP3 pathway, and pro-inflammatory cytokine formation in the liver. ROS scavenging via pretreatment with tempol was found not only to inhibit the hepatic oxidative stress, but also to regulate Nrf2/HO-1/NLRP3 pathway activity. In all cases, tempol was able to mitigate the pathologic changes induced by TCE sensitization. In summary, the results here demonstrated a novel molecular mechanism wherein ROS-mediated inflammatory responses play a central role in TCE-induced liver damage. Therapies targeting ROS scavenging could help to protect against hepatic damage by regulating Nrf2/HO-1/NLRP3 pathway activities in TCE-sensitized hosts.

Renal tubular cell necroptosis: A novel mechanism of kidney damage in trichloroethylene hypersensitivity syndrome mice.

Trichloroethylene (TCE) hypersensitivity syndrome (THS), called occupational medicamentosa-like dermatitis due to TCE (OMDT) in China, is a fatal occupational disorder caused by TCE exposure. Visceral damage, including kidney injury, is one of the major complications. Necroptosis is a regulated cell death form linked to local inflammatory response. This study aimed to investigate whether renal cell necroptosis was involved in TCE-induced kidney injury. A Balb/c mouse model of TCE sensitization was utilized to study mechanisms of modulation of TCE-induced renal necroptosis. Renal histology (using light and transmission electron microscopy) and renal tubular impairment indexes, including α1-microglobulin (α1-MG), and ß2-microglobulin (ß2-MG), were evaluated. In addition, tissue expression of necroptosis-related proteins, including tumor necrosis factor (TNF)-α, TNF receptor 1 (TNFR1), receptor-interacting protein kinase 3 (RIPK3), p-RIK3, mixed lineage kinase domain-like protein (MLKL), and p-MLKL, were also evaluated. The study here confirmed TCE sensitization caused damage to renal tubules and renal tubular epithelial cell (RTEC) necroptosis. In mice treated with R7050 (a specific TNFα antagonist), it was also seen that inhibition of TNFα expression could effectively inhibit RTEC necroptosis and improve renal function in the TCE-sensitized mice. Taken together, these results help to define a novel mechanism by which RTEC necroptosis plays a key role in TCE-induced kidney damage.

Endothelin-1/Endothelin Receptor Type A-Angiopoietins/Tie-2 Pathway in Regulating the Cross Talk Between Glomerular Endothelial Cells and Podocytes in Trichloroethylene-Induced Renal Immune Injury.

INTRODUCTION: This study aimed to investigate the mechanism in regulating the cross talk between glomerular endothelial cells and podocytes in "occupational medicamentosa-like dermatitis induced by trichloroethylene (OMLDT)" patients. METHODS: Totally 6 OMLDT patients, 18 controls, and 102 BALB/c female mice were involved in this study. Patient's serum endothelin-1 (ET-1), angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2), blood urea nitrogen (BUN), and podocalyxin (PCX) were detected. All the mice were used to establish the trichloroethylene (TCE) sensitized mouse model. Transmission electron microscope results were used to reflect renal glomerulus injury. Protein levels were detected by Western blot. Ang-1/Ang-2 gene level was reflected by RT-PCR. Cell apoptosis level was detected by using TUNEL assay kit. RESULTS: We found that in OMLDT patients, ET-1, Ang-2, BUN, and PCX were highly expressed but Ang-1 was inhibited. In TCE sensitized positive mouse, the downregulation of Ang-1, pTie-2 and the upregulation of Ang-2 were mediated by ET-1/ETAR but not ET-1/ETBR. The promotor of apoptosis proteins was downregulated and the inhibitor of apoptosis proteins was upregulated by treating with BQ123. DISCUSSION: ET-1/ETAR-Angs/Tie-2 pathway mediated the cross talk between glomerular endothelial cells and podocytes. BQ123 can alleviate glomerulus immune injury.

A novel taxane, difluorovinyl-ortataxel, effectively overcomes paclitaxel-resistance in breast cancer cells.

Paclitaxel (PTX) is widely used to treat breast and ovarian cancers, but innate and acquired resistance often compromises its applications. The objective of this study was to screen new-generation taxanes for their efficiency against both PTX-sensitive and PTX-resistant breast cancer cells. From twelve compounds, difluorovinyl-ortataxel (DFV-OTX) displayed potent cytotoxic activities against both PTX-sensitive and PTX-resistant breast cancer cells. Moreover, DFV-OTX effectively induced tubulin/microtubule polymerization and G2/M phase arrest, leading to apoptosis in both PTX-sensitive and PTX-resistant cancer cells. Molecular docking analysis showed that DFV-OTX possesses unique hydrogen-bonding and van der Waals interactions with ß-tubulin. LC-MS/MS analysis also demonstrated that the intracellular drug amount of DFV-OTX was lower than that of PTX, which would be critical to overcome PTX-resistance. Furthermore, DFV-OTX exhibited clear efficacy in the MCF-7R and MDA-MB-231R tumor xenografts in mouse models. Taken together, our results demonstrate that the novel taxane, DFV-OTX, can effectively overcome PTX-resistance in MDA-MB-231R cells, wherein the drug resistance was attributed to ABCB1/ABCG2 upregulation and a distinct mode of action in MCF-7R cells. Our results strongly indicate that DFV-OTX is a promising chemotherapeutic agent for the treatment of PTX-resistant cancers.

Experimental study of destruction of acetone in exhaust gas using microwave-induced metal discharge.

Volatile organic compounds (VOCs) are air pollutants that pose a major concern, and novel treatment technologies must be continuously explored and developed. In this study, microwave-induced metal discharge was applied to investigate the destruction of acetone as a representative model VOC compound. Results revealed that metal discharge intensity largely depended on microwave output power and the number of metal strips. Microwave metal discharge exerted the distinct combined effects of intense heat, strong light, and plasma. In the case of MW without metal discharge, the decrease in acetone at 200 ppm was remarkably limited (approximately 5.5% (mol/mol)). By contrast, in the case of microwave-induced metal discharge, a considerably high destruction efficiency of up to 65% (mol/mol) was obtained at low concentrations. This finding highlights the potential of microwave-induced discharge for VOC removal. Initial assessment indicated that energy consumption can be acceptable.

Pentafluorosulfanyl-Substituted Benzopyran Analogues As New Cyclooxygenase-2 Inhibitors with Excellent Pharmacokinetics and Efficacy in Blocking Inflammation.

In this report, we disclose the design and synthesis of a series of pentafluorosulfanyl (SF5) benzopyran derivatives as novel COX-2 inhibitors with improved pharmacokinetic and pharmacodynamic properties. The pentafluorosulfanyl compounds showed both potency and selectivity for COX-2 and demonstrated efficacy in several murine models of inflammation and pain. More interestingly, one of the compounds, R,S-3a, revealed exceptional efficacy in the adjuvant induced arthritis (AIA) model, achieving an ED50 as low as 0.094 mg/kg. In addition, the pharmacokinetics of compound R,S-3a in rat revealed a half-life in excess of 12 h and plasma drug concentrations well above its IC90 for up to 40 h. When R,S-3a was dosed just two times a week in the AIA model, efficacy was still maintained. Overall, drug R,S-3a and other analogues are suitable candidates that merit further investigation for the treatment of inflammation and pain as well as other diseases where COX-2 and PGE2 play a role in their etiology.

Synthesis of Deuterated Benzopyran Derivatives as Selective COX-2 Inhibitors with Improved Pharmacokinetic Properties.

We designed a series of specifically deuterated benzopyran analogues as new COX-2 inhibitors with the aim of improving their pharmacokinetic properties. As expected, the deuterated compounds retained potency and selectivity for COX-2. The new molecules possess improved pharmacokinetic profiles in rats compared to their nondeuterated congeners. Most importantly, the new compounds showed pharmacodynamic efficacy in several murine models of inflammation and pain. The benzopyran derivatives were separated into their enantiomers, and the activity was found to reside with the S-isomers. To streamline the synthesis of the desired S-isomers, an organocatalytic asymmetric domino oxa-Michael/aldol condensation reaction was developed for their preparation.