Last data update: Jan 27, 2025. (Total: 48650 publications since 2009)
Records 1-13 (of 13 Records) |
Query Trace: Lin CC[original query] |
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New mechanisms in diisocyanate-mediated allergy/toxicity: are microRNAs in play?
Lin CC , Law BF , Hettick JM . Curr Opin Allergy Clin Immunol 2024 ![]() PURPOSE OF REVIEW: To describe recent findings of diisocyanate-mediated mechanisms in allergy and toxicology by addressing the role of microRNA (miR) in immune responses that may contribute to the development of occupational asthma (OA). RECENT FINDINGS: Studies of diisocyanate asthma have traditionally focused on the immune and inflammatory patterns associated with diisocyanate exposures; however, recognized knowledge gaps exist regarding the detailed molecular mechanism(s) of pathogenesis. Recent studies demonstrate the critical role endogenous microRNAs play as gene regulators in maintaining homeostasis of the human body, and in the pathophysiology of many diseases including asthma. Given that diisocyanate-OA shares many pathophysiological characteristics with asthma, it is likely that miR-mediated mechanisms are involved in the pathophysiology of diisocyanate-OA. Recent reports have shown that changes in expression of endogenous miRs are associated with exposure to the occupationally relevant diisocyanates, toluene diisocyanate (TDI) and methylene diphenyl diisocyanate (MDI). Continued mechanistic study of these relevant miRs may lead to the development of novel biomarkers of occupational exposure and/or provide efficacious targets for therapeutic strategies in diisocyanate asthma. SUMMARY: The molecular mechanisms underlying diisocyanate-OA pathophysiology are heterogeneous and complicated. In this review, we highlight recent research into the roles and potential regulation of miRs in diisocyanate-OA. |
Circular RNA hsa_circ_0008726 targets the hsa-miR-206-3p/KLF4 axis to modulate 4,4'-methylene diphenyl diisocyanate-glutathione conjugate-induced chemokine transcription in macrophages
Lin CC , Law BF , Hettick JM . Cells 2025 13 (20) 1725 Exposure to 4,4'-methylene diphenyl diisocyanate (MDI) in the workplace may lead to the development of occupational asthma (OA). However, the specific mechanism(s) by which MDI induces OA are poorly understood. Previous reports have demonstrated that MDI and MDI-glutathione (GSH) conjugate exposure downregulates endogenous human/murine (hsa/mmu)-microRNA(miR)-206-3p, resulting in the activation of mmu/hsa-miR-206-3p-regulated signaling pathways in macrophages. Circular RNAs (circRNAs) regulate many important biological processes by targeting endogenous miRs; however, whether MDI/MDI-GSH exposure may influence circRNA expressions is unknown. Several circRNAs have been identified that regulate hsa-miR-206-3p. We hypothesize that MDI-GSH conjugate exposure induces endogenous circRNA(s) to regulate hsa-miR-206-3p in macrophages. The expression of candidate hsa-miR-206-3p-binding circRNAs was determined from MDI-GSH conjugate-treated differentiated THP-1 macrophages using RT-qPCR. MDI-GSH exposures induced hsa_circ_0008726 and its host gene transcript DNAJB6, whereas other circRNA(s) examined were either not detected or unchanged. RNA-induced silencing complex-immunoprecipitation (RISC-IP) experiments confirm that hsa-miR-206-3p can bind to hsa_circ_0008726. The expressions of endogenous hsa-miR-206-3p, hsa-miR-206-3p-regulated KLF4, and KLF4-activated M2 macrophage-associated markers and chemokines were up-/down-regulated by transfection of hsa_circ_0008726 siRNAs or hsa_circ_0008726 overexpression plasmid in macrophages, respectively. These results suggest MDI-GSH exposure downregulates hsa-miR-206-3p via induction of endogenous hsa_circ_0008726/DNAJB6, resulting in the upregulation of hsa-miR-206-3p-mediated regulations in macrophages. |
Human keratinocyte response to 4,4'-methylene diphenyl diisocyanate-glutathione conjugate exposure
Law BF , Lin CC , Hettick JM . Xenobiotica 2024 1-16 ![]() Workplace exposure to diisocyanates like 4,4'-methylene diphenyl diisocyanate can cause occupational asthma (MDI-OA), and the underlying biological pathways are still being researched.Although uncertainty remains, evidence supports the hypothesis that dermal exposure to MDI plays an important role in the development of MDI-OA.Gene expression, proteomics, and informatics tools were utilized to characterize changes in expression of RNA and protein in cultured human HEKa keratinocyte cells following exposure to conjugates of MDI with glutathione (MDI-GSH).RT-qPCR analysis using a panel of 39 candidate primers demonstrated 9 candidate genes upregulated and 30 unchanged.HPLC-MS/MS analysis of HEKa cell lysate identified 18,540 proteins across all samples Sixty proteins demonstrate statistically significant differential expression in exposed cells, some of which suggest activation of immune and inflammatory pathways.The results support the hypothesis that dermal exposures have the potential to play an important role in the development of MDI-OA. Furthermore, proteomic and gene expression data suggest multiple immune (adaptive and innate) and inflammatory pathways may be involved in the development of MDI-OA. |
Microrna-mediated Krüppel-Like Factor 4 upregulation induces alternatively activated macrophage-associated marker and chemokine transcription in 4,4'-methylene diphenyl diisocyanate exposed macrophages
Lin CC , Law BF , Hettick JM . Xenobiotica 2024 1-22 Occupational exposure to 4,4'-methylene diphenyl diisocyanate (MDI) is associated with occupational asthma (OA) development. Alveolar macrophage-induced recruitment of immune cells to the lung microenvironment plays an important role during asthma pathogenesis. Previous studies identified that MDI/MDI-glutathione (GSH)-exposure downregulates endogenous hsa-miR-206-3p/hsa-miR-381-3p. Our prior report shows that alternatively activated (M2) macrophage-associated markers/chemokines are induced by MDI/MDI-GSH-mediated Krüppel-Like Factor 4 (KLF4) upregulation in macrophages and stimulates immune cell chemotaxis. However, the underlying molecular mechanism(s) by which MDI/MDI-GSH upregulates KLF4 remain unclear.Following MDI-GSH exposure, microRNA(miR)-inhibitors/mimics or plasmid transfection, endogenous hsa-miR-206-3p/hsa-miR-381-3p, KLF4, or M2 macrophage-associated markers (CD206, TGM2), and chemokines (CCL17, CCL22, CCL24) were measured by either RT-qPCR, western blot, or luciferase assay.MDI-GSH exposure downregulates hsa-miR-206-3p/hsa-miR-381-3p by 1.46- to 9.75-fold whereas upregulates KLF4 by 1.68- to 1.99-fold, respectively. In silico analysis predicts binding between hsa-miR-206-3p/hsa-miR-381-3p and KLF4. Gain- and loss-of-function, luciferase reporter assays and RNA-induced silencing complex-immunoprecipitation (RISC-IP) studies confirm the posttranscriptional regulatory roles of hsa-miR-206-3p/hsa-miR-381-3p and KLF4 in macrophages. Furthermore, hsa-miR-206-3p/hsa-miR-381-3p regulate the expression of M2 macrophage-associated markers and chemokines via KLF4.In conclusion, hsa-miR-206-3p/hsa-miR-381-3p play a major role in regulation of MDI/MDI-GSH-induced M2 macrophage-associated markers and chemokines by targeting the KLF4 transcript, and KLF4-mediated regulation in macrophages. |
4,4'-Methylene diphenyl diisocyanate exposure induces expression of alternatively activated macrophage-associated markers and chemokines partially through Krüppel-like factor 4 mediated signaling in macrophages
Lin CC , Law BF , Hettick JM . Xenobiotica 2023 53 (12) 1-17 Occupational exposure to the most widely used monomeric diisocyanate (dNCO), 4,4'-methylene diphenyl diisocyanate (MDI), may lead to the development of occupational asthma (OA). Alveolar macrophages with alternatively activated (M2) phenotype have been implicated in allergic airway responses and the pathogenesis of asthma. Recent in vivo studies demonstrate that M2 macrophage-associated markers and chemokines are induced by MDI-exposure, however, the underlying molecular mechanism(s) by which this proceeds is unclear.Following MDI exposure (in vivo and in vitro) M2 macrophage-associated transcription factors (TFs), markers, and chemokines were determined by RT-qPCR, western blots, and ELISA.Expression of M2 macrophage-associated TFs and markers including Klf4/KLF4, Cd206/CD206, Tgm2/TGM2, Ccl17/CCL17, Ccl22/CCL22, and CCL24 were induced by MDI/MDI-GSH exposure in bronchoalveolar lavage cells (BALCs)/THP-1 macrophages. The expression of CD206, TGM2, CCL17, CCL22, and CCL24 are upregulated by 3.83-, 7.69-, 6.22-, 6.08-, and 1.90-fold in KLF4-overexpressed macrophages, respectively. Endogenous CD206 and TGM2 were downregulated by 1.65-5.17-fold, and 1.15-1.78-fold, whereas CCL17, CCL22, and CCL24 remain unchanged in KLF4-knockdown macrophages. Finally, MDI-glutathione (GSH) conjugate-treated macrophages show increased chemotactic ability to T-cells and eosinophils, which may be attenuated by KLF4 knockdown.Our data suggest that MDI exposure may induce M2 macrophage-associated markers partially through induction of KLF4. |
MicroRNA-Mediated Calcineurin Signaling Activation Induces CCL2, CCL3, CCL5, IL8 and Chemotactic Activities in 4,4'-Methylene Diphenyl Diisocyanate Exposed Macrophages
Lin CC , Law BF , Hettick JM . Xenobiotica 2021 51 (12) 1-20 Occupational exposure to 4,4'-methylene diphenyl diisocyanate (MDI), the most widely used monomeric diisocyanate, is one of the leading causes of occupational asthma (OA). Previously, we identified microRNA (miR)-206-3p/miR-381-3p-mediated PPP3CA/calcineurin signaling regulated iNOS transcription in macrophages and bronchoalveolar lavage cells (BALCs) after acute MDI exposure; however, whether PPP3CA/calcineurin signaling participates in regulation of other asthma-associated mediators secreted by macrophages/BALCs after MDI exposure is unknown.Several asthma-associated, macrophage-secreted mediator mRNAs from MDI exposed murine BALCs and MDI-glutathione (GSH) conjugate treated differentiated THP-1 macrophages were analyzed using RT-qPCR.Endogenous IL1B, TNF, CCL2, CCL3, CCL5, and TGFB1 were upregulated in MDI or MDI-GSH conjugate exposed BALCs and macrophages, respectively. Calcineurin inhibitor tacrolimus (FK506) attenuated the MDI-GSH conjugate-mediated induction of CCL2, CCL3, CCL5, and CXCL8/IL8 but not others. Transfection of either miR-inhibitor-206-3p or miR-inhibitor-381-3p in macrophages induced chemokine CCL2, CCL3, CCL5, and CXCL8 transcription, whereas FK506 attenuated the miR-inhibitor-206-3p or miR-inhibitor-381-3p-mediated effects. Finally, MDI-GSH conjugate treated macrophages showed increased chemotactic ability to various immune cells, which may be attenuated by FK506.In conclusion, these results indicate that MDI exposure to macrophages/BALCs may recruit immune cells into the airway via induction of chemokines by miR-206-3p and miR-381-3p-mediated calcineurin signaling activation. |
Rural-urban differences in delivery hospitalization costs by severe maternal morbidity status
Lin CC , Hirai AH , Li R , Kuklina EV , Fisher SK . Ann Intern Med 2020 173 S59-s62 Background: Severe maternal morbidity (SMM) during hospitalizations for deliveries affects more than 50 000 U.S. women annually, with risks for long-term morbidity and immediate health care costs more than double that of unaffected deliveries (1, 2). Women in rural areas face greater barriers to preventive and specialty health care services, including limited provider availability, longer distances to care, and financial constraints (3), which may contribute to adverse obstetric outcomes (4) and higher costs during delivery hospitalizations than their urban counterparts. A previous study found that rural hospitals incurred significantly higher average costs for low-risk deliveries, by nearly $500, compared with urban hospitals (5). It is unclear whether this finding reflects patient residence versus facility location only and whether it applies to the broader population of deliveries, including those affected by SMM. To address this literature gap, this study compares delivery costs between rural and urban residents with and without SMM, with adjustment for other sociodemographic and facility characteristics. |
Acute 4,4'-methylene diphenyl diisocyanate exposure-mediated downregulation of miR-206-3p and miR-381-3p activates inducible nitric oxide synthase transcription by targeting calcineurin/NFAT signaling in macrophages
Lin CC , Law BF , Hettick JM . Toxicol Sci 2019 173 (1) 100-113 Exposure to 4,4'-methylene diphenyl diisocyanate (MDI) in the occupational setting may lead to development of occupational asthma (OA), and the underlying molecular mechanisms of MDI-induced disease pathogenesis remain an active area of research. Using a nose-only mouse inhalation model, we find that circulating microRNA (miR)-206-3p and miR-381-3p are downregulated after MDI exposure; however, cellular miR-206-3p and miR-381-3p responses after MDI aerosol exposure and their pathophysiological roles in MDI-OA are unknown. We hypothesize that miR-206-3p and miR-381-3p-regulated mechanisms cause increased expression of the inducible nitric oxide synthase (iNOS) after MDI aerosol exposure. We examined cellular miR-206-3p and miR-381-3p, calcineurins, nuclear factors of activated T-cells (NFATs) and iNOS levels from both nose-only exposed murine bronchoalveolar lavage cells (BALCs) and differentiated THP-1 macrophages treated with MDI-glutathione (GSH) conjugates. Both in vivo murine MDI aerosol exposure and in vitro MDI-GSH exposures in THP-1 macrophages results in downregulation of endogenous miR-206-3p and miR-381-3p and upregulation of PPP3CA and iNOS expression. Transfection of THP-1 macrophages with miR-inhibitor-206-3p and miR-inhibitor-381-3p resulted in the upregulation of PPP3CA and iNOS. Using RNA-induced silencing complex immunoprecipitation (RISC-IP) and translational reporter assays, we verified that PPP3CA, but not iNOS, is directly targeted by both miR-206-3p and miR-381-3p. Downregulation of miR-206-3p and miR-381-3p following by MDI exposure induces Calcineurin/NFAT signaling-mediated iNOS transcription in macrophages and BALCs. |
NS2B/NS3 mutations enhance the infectivity of genotype I Japanese encephalitis virus in amplifying hosts.
Fan YC , Liang JJ , Chen JM , Lin JW , Chen YY , Su KH , Lin CC , Tu WC , Chiou MT , Ou SC , Chang GJ , Lin YL , Chiou SS . PLoS Pathog 2019 15 (8) e1007992 ![]() Genotype I (GI) virus has replaced genotype III (GIII) virus as the dominant Japanese encephalitis virus (JEV) in the epidemic area of Asia. The mechanism underlying the genotype replacement remains unclear. Therefore, we focused our current study on investigating the roles of mosquito vector and amplifying host(s) in JEV genotype replacement by comparing the replication ability of GI and GIII viruses. GI and GIII viruses had similar infection rates and replicated to similar viral titers after blood meal feedings in Culex tritaeniorhynchus. However, GI virus yielded a higher viral titer in amplifying host-derived cells, especially at an elevated temperature, and produced an earlier and higher viremia in experimentally inoculated pigs, ducklings, and young chickens. Subsequently we identified the amplification advantage of viral genetic determinants from GI viruses by utilizing chimeric and recombinant JEVs (rJEVs). Compared to the recombinant GIII virus (rGIII virus), we observed that both the recombinant GI virus and the chimeric rJEVs encoding GI virus-derived NS1-3 genes supported higher replication ability in amplifying hosts. The replication advantage of the chimeric rJEVs was lost after introduction of a single substitution from a GIII viral mutation (NS2B-L99V, NS3-S78A, or NS3-D177E). In addition, the gain-of-function assay further elucidated that rGIII virus encoding GI virus NS2B-V99L/NS3-A78S/E177E substitutions re-gained the enhanced replication ability. Thus, we conclude that the replication advantage of GI virus in pigs and poultry is the result of three critical NS2B/NS3 substitutions. This may lead to more efficient transmission of GI virus than GIII virus in the amplifying host-mosquito cycle. |
Role of cancer history and gender in major health insurance transitions: A longitudinal nationally representative study
Virgo KS , Lin CC , Davidoff A , Guy GP Jr , de Moor JS , Ekwueme DU , Kent EE , Chawla N , Yabroff KR . Res Sociol Health Care 2018 36 59-84 Purpose -: To examine associations by gender between cancer history and major health insurance transitions (gains and losses), and relationships between insurance transitions and access to care. Methodology -: Longitudinal 2008-2013 Medical Expenditure Panel Survey data pooled yielding 2,223 cancer survivors and 50,692 individuals with no cancer history ages 18-63 years upon survey entry, with gender-specific sub-analyses. Access-to-care implications of insurance loss or gain were compared by cancer history and gender. Findings -: Initially uninsured cancer survivors were significantly more likely to gain insurance coverage than individuals with no cancer history (RR: 1.25; 95% CI: 1.08-1.44). Females in particular were significantly more likely to gain insurance (unmarried RR: 1.16; 95% CI: 1.06-1.28; married RR: 1.09; 95% CI: 1.02-1.16). Significantly higher rates of difficulty accessing needed medical care and prescription medications were reported by those remaining uninsured, those who lost insurance, and women in general. Remaining uninsured, losing insurance, and male gender were associated with lack of a usual source of care. Research implications -: Additional outreach to disadvantaged populations is needed to improve access to affordable insurance and medical care. Future longitudinal studies should assess whether major Affordable Care Act (ACA) provisions enacted after the 2008-2013 study period (or those of ACA's replacement) are addressing these important issues. Originality -: Loss of health insurance coverage can reduce health care access resulting in poor health outcomes. Cancer survivors may be particularly at risk of insurance coverage gaps due to the long-term chronic disease trajectory. This study is novel in exploring associations between cancer history by gender and health insurance transitions, both gains and losses, in a national non-elderly adult sample. |
Circulating miRs-183-5p, -206-3p and -381-3p may serve as novel biomarkers for 4,4'-methylene diphenyl diisocyanate exposure
Lin CC , Law BF , Siegel PD , Hettick JM . Biomarkers 2018 24 (1) 1-45 BACKGROUND: Occupational exposure to the most widely used diisocyanate, 4,4'-methylene diphenyl diisocyanate (MDI), is a cause of occupational asthma (OA). Early recognition of MDI exposure and sensitization is essential for the prevention of MDI-OA. OBJECTIVE: Identify circulating microRNAs (miRs) as novel biomarkers for early detection of MDI exposure and prevention of MDI-OA. MATERIALS AND METHODS: Female BALB/c mice were exposed to one of three exposure regimens: dermal exposure to 1% MDI in acetone; nose-only exposure to 4580 +/- 1497 mug/m(3) MDI-aerosol for 60 minutes; or MDI dermal exposure/sensitization followed by MDI-aerosol inhalation challenge. Blood was collected and miRCURY miRs qPCR Pro fi ling Service was used to profile circulating miRs from dermally exposed mice. Candidate miRs were identified and verified from mice exposed to three MDI-exposure regimens by TaqMan(R) miR assays. RESULTS: Up/down-regulation patterns of circulating mmu-miRs-183-5p, -206-3p and -381-3p were identified and verified. Circulating mmu-miR-183-5p was upregulated whereas mmu-miRs-206-3p and -381-3p were downregulated in mice exposed via all three MDI exposure regimens. DISCUSSION AND CONCLUSION: Upregulation of circulating miR-183-5p along with downregulation of circulating miRs-206-3p and -381-3p may serve as putative biomarkers of MDI exposure and may be considered as potential candidates for validation in exposed human worker populations. |
Mass spectrometry-based analysis of murine bronchoalveolar lavage fluid following respiratory exposure to 4,4'-methylene diphenyl diisocyanate aerosol
Hettick JM , Law BF , Lin CC , Wisnewski AV , Siegel PD . Xenobiotica 2017 48 (6) 1-32 Diisocyanates are highly reactive electrophiles utilized in the manufacture of a wide range of polyurethane products, and have been identified as causative agents of occupational allergic respiratory disease. However, in spite of the significant occupational health burden associated with diisocyanate-induced asthma, the mechanism of disease pathogenesis remains largely unknown. To better understand the fate of inhaled diisocyanates, a nose-only aerosol exposure system was constructed and utilized to expose a BALB/c mouse model to aerosol generated from 4,4'-methylene diphenyl diisocyanate (MDI). Tissue and bronchoalveolar lavage samples were evaluated 4 hours and 24 hours post-exposure for evidence of diisocyanate-protein haptenation, and a label-free quantitative proteomics strategy was employed to evaluate relative changes to protein content of the cellular fraction of the lavage fluid. Following MDI aerosol exposure, expression of a number of proteins with immunological or xenobiotic metabolism relevance is increased, including endoplasmin, cytochrome P450 and argininosuccinate synthase. Western blot analysis indicated MDI-conjugated protein in the lavage fluid, which was identified as serum albumin. Tandem mass spectrometry analysis of MDI-albumin revealed MDI conjugation occurs at a dilysine motif at Lys525, as well as at a glutamine-lysine motif at Lys414, in good agreement with previously published in vitro data on diisocyanate-conjugated serum albumin. |
Association between serious psychological distress and health care use and expenditures by cancer history
Han X , Lin CC , Li C , de Moor JS , Rodriguez JL , Kent EE , Forsythe LP . Cancer 2015 121 (4) 614-22 BACKGROUND: Serious psychological distress (SPD) is associated with adverse health outcomes such as poor quality of life and shorter survival in cancer survivors, but to the authors' knowledge, the relationship between SPD and health care use and medical expenditures is not clear. METHODS: A total of 4326 cancer survivors and 57,109 noncancer participants were identified from the 2008 through 2010 Medical Expenditure Panel Survey, a nationwide population-based survey, and their psychological distress was assessed with the 6-item Kessler Psychological Distress Scale (SPD defined by a score ≥13). The association between SPD and use and medical expenditures of various types of health care (office-based, outpatient, hospital inpatient, emergency department, dental, and prescriptions) was examined using a 2-part modeling approach that adjusted for demographic, personal, and comorbidity factors. The marginal effects of SPD on health care use and expenditures were calculated for cancer survivors and were compared with those of noncancer participants. RESULTS: The weighted prevalence of SPD in cancer survivors was 8.2% compared with 4.8% in the noncancer participants. SPD was significantly associated with higher use of all care types except dental care in cancer survivors. Cancer survivors with SPD spent $4431 (95% confidence interval, $3419-$5443) more than survivors without SPD on medical services each year, whereas this extra expenditure associated with SPD for participants without cancer was $2685 (95% confidence interval, $2099-$3271). CONCLUSIONS: In a national representative sample of cancer survivors, SPD was found to be associated with higher health care use and medical expenditures. Distress screening and psychosocial care in cancer survivors may help reduce the economic burden of cancer in the United States. |
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